COVID-19

Initiatief: FMS / SWAB Aantal modules: 72

Ivermectine

Uitgangsvraag

Wat is de plaats van ivermectine bij de behandeling van COVID-19 patiënten?

Aanbeveling

Ivermectine wordt niet aanbevolen als behandeling van patiënten met COVID-19

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Er is literatuuronderzoek verricht naar de verschillen in klinische uitkomsten tussen behandeling met en zonder ivermectine bij patiënten opgenomen in het ziekenhuis met COVID-19 en patiënten niet opgenomen in het ziekenhuis. Tot 7 april 2022 werden er 17 gerandomiseerde gecontroleerde studies (RCT’s) gevonden. Tien studies onderzochten het effect van behandeling met ivermectine in patiënten met COVID-19 die waren opgenomen in het ziekenhuis en zeven studies werden uitgevoerd in patiënten die niet waren opgenomen in het ziekenhuis.

 

Er werden alleen RCT’s geïncludeerd in de analyse, waardoor de kwaliteit van bewijs initieel hoog was. De geïncludeerde studies hadden in wisselende mate methodologische beperkingen (risk of bias). Er was in sommige studies een risico op bias door onder andere ontoereikende documentatie, lost of follow-up en missende data, of de gebruikte statistische analyse (risk of bias). Daarnaast waren de studiebevindingen onderling inconsistent (inconsistency) en waren er meerdere studies met een relatief kleine populatie en mede hierdoor een grote spreiding van de puntschatter van de uitkomstmaat (imprecision). Hierdoor werd de kwaliteit van dit bewijs naar beneden werd bijgesteld. Ook werden er veel verschillende doseringen ivermectine gebruikt en verschilde de duur van de behandeling.

De bewijskracht van de literatuur bij patiënten die waren opgenomen in het ziekenhuis en ambulante patiënten werd voor zowel de cruciale als belangrijke uitkomstmaten, door bovenstaande bevindingen gegradeerd als ‘laag’ of ‘zeer laag’.

 

Ivermectine bij patiënten opgenomen in het ziekenhuis

Er werden 10 studies geïncludeerd die ivermectine onderzochten bij patiënten die opgenomen waren in het ziekenhuis. Acht van de negen studies randomiseerden minder dan 100 patiënten naar ivermectine. Alleen de studie van Lim (2022) was groter: deze onderzocht bij 490 patiënten met minder dan 7 dagen klachten van COVID-19, een relatief hoge dosering ivermectine (400 microg/kg gedurende 5 dagen). De gerandomiseerde open-label trial was daarnaast van relatief goede kwaliteit. Er werd geen statistisch significant verschil gezien in de kans op progressie naar ernstige ziekte en ook een numeriek voordeel van ivermectine op deze uitkomst maat werd niet gezien (21,6% progressie naar ernstige ziekte in de ivermectine groep versus 17,3% in de controle groep). Voor de uitkomstmaat mortaliteit werd ook geen significant verschil gevonden, al was er hier wel een numeriek voordeel van ivermectine (1,2% mortaliteit binnen 28 dagen in de ivermectine groep versus 4,0% in de controlegroep).  

Ook de andere RCT’s die in deze richtlijn werden geïncludeerd lieten geen overtuigend bewijs zien in het voordeel van ivermectine bij opgenomen patiënten. Ook als de data gepoold weergegeven werden (zoals gedaan bij de mortaliteit binnen 28 dagen en bij start van uitgebreide respiratoire ondersteuning), werd er geen overtuigend bewijs gezien in het voordeel van ivermectine.

 

Ivermectine bij ambulante patiënten

Ook bij ambulante patiënten waren er een aantal kleine studies die minder dan 100 patiënten randomiseerden naar ivermectine. Twee grotere studies die het gebruik van ivermectine onderzochten in de ambulante setting, zijn de studie van López-Medina (2021) en Vallejos (2021). Verreweg het meeste bewijs naar ivermectine bij ambulante patiënten wordt verkregen uit de studie van Reis (2022) die 1358 patiënten includeerde.

 

López-Medina (2021) verrichtte een dubbelblinde, 1:1 gerandomiseerde, placebo-gecontroleerde, prospectieve studie bij 400 patiënten met milde ziekte in een vroege fase (minder dan 7 dagen klachten). De kwaliteit van deze studie is hoog met betrekking tot de opzet, uitvoering (inclusief blindering), analyse en documentatie. Ook de beperkingen zijn transparant benoemd. De gebruikte dosering en het doseringsschema van ivermectine is duidelijk hoger (300 microgram/kg gedurende 5 aaneengesloten dagen) dan de geregistreerde standaard dosis (200 microgram/kg eenmalig eventueel met een herhaling 1 week later). De mediane tijd tot verdwijnen van symptomen was 10 dagen (IQR 9 –13 d) met ivermectine versus 12 dagen (IQR 9 –13 d) met placebo, maar niet statistisch significant verschillend (HR: 1,07 [95% CI: 0,87 –1,32]; P = 0,53 met log-rank test). Op dag 21 waren 82% van de patiënten met ivermectine versus 79% met placebo symptoomvrij. Deze studie was niet gepowered om een effect op mortaliteit in de studiepopulatie aan te tonen, die bij patiënten in deze leeftijdsgroep (mediaan 37 jaar) met milde COVID-19 hoe dan ook zeer laag is. Ook is er geen data over (het beloop) van viral load en bereikte ivermectine spiegels. In de ivermectine-groep werden niet meer bijwerkingen gerapporteerd dan in de placebogroep.

 

De studie van Vallejos (2021) onderzocht ivermectine bij ruim 500 patiënten met COVID-19. Net zoals de voorgaande studie, was ook deze studie van relatief goede kwaliteit en was de gebruikte dosering van ivermectine hoger dan de geregistreerde standaarddosis. Wel was de studie ‘underpowered’ omdat deze relatief klein was voor de gekozen uitkomstmaat (opname in het ziekenhuis). Patiënten waren relatief jong (42 jaar) en zij hadden nog maar kort klachten (gemiddeld 4 dagen bij randomisatie). Opname in het ziekenhuis was minder vaak nodig bij patiënten die ivermectine gebruikte (5,6% versus 8,4%), echter, dit verschil was niet statistisch significant. Ook werden er geen statistisch significante verschillen gevonden in de virale klaring, de kans op mechanische ventilatie of mortaliteit.

 

Een grote Braziliaanse, placebogecontroleerde RCT onderzocht ivermectine bij 1358 ambulante patiënten met COVID-19 (Reis, 2022). Deze zeer grote, kwalitatief goede studie includeerde patiënten met COVID-19 als ze maximaal 7 dagen klachten hadden van COVID-19 en minimaal 1 risicofactor voor progressie van ziekte. De mediane leeftijd van de gerandomiseerde patiënten was 49 jaar. Randomisatie bestond uit 400 microgram/kg ivermectine gedurende 3 dagen of placebo (gedurende 1, 3, 10 of 14 dagen). Er werd geen verschil gezien in de kans op opname in het ziekenhuis of bezoek aan de spoedeisende hulp vanwege COVID-19, in de groep met ivermectine versus placebo (14,7% in de ivermectine groep versus 16,3% in de placebo groep; relatief risico 0,90; 95% Bayesian CI 0,70-1,16). Ook werd er geen verschil gezien in mortaliteit of virale klaring.  

Concluderend zijn er nu een drietal relatief grote en kwalitatief (redelijk) goede studies beschikbaar die het effect van ivermectine bij ambulante patiënten onderzochten. Geen van deze studies laat aanwijzingen zien voor een positief effect van ivermectine op de kans op opname in het ziekenhuis of mortaliteit.

 

Overige overwegingen

Studies bij zowel opgenomen als ambulante patiënten laten geen overtuigend positief effect zien van ivermectine op belangrijke klinische eindpunten. Dit betreft de mortaliteit, voorkomen van (ernstige) ziekte, voorkomen van opname op de intensive care, duur van ziekenhuisopname, en behoefte aan respiratoire ondersteuning.

Meerdere studies laten wel een verschil zien in de resolutie van symptomen in de groep die behandeld werd met ivermectine (bij opgenomen patiënten: Ahmed, 2020; Lim, 2020; Mohan, 2021; Okumuş 2021; Ravikirti, 2021; Shahbaznejad, 2021; bij ambulante patiënten: Buonfrate, 2022; Chachar, 2020; López-Medina, 2021; Podder, 2020). Echter, deze klachten werden vaak alleen gedocumenteerd door middel van self reporting, hetgeen kans geeft op bias bij een niet geblindeerd studieontwerp. De relatief grote en kwalitatief betere studies van Lim (2022) en López-Medina (2021) lieten geen evident verschil zien in de resolutie van klachten.

Ook onderzochten meerdere studies het effect van ivermectine op de viral load, met een wisselend resultaat. De studie van Ahmed (2021) toonde een significante reductie in de viral load na 3 dagen bij patiënten die met ivermectine behandeld werden, terwijl de studie van Chaccour (2021) en Vallejos (2021) dit niet bevestigen.

Naast de bovengenoemde gepubliceerde artikelen zijn er diverse andere studies verschenen die niet gepeer-reviewed werden, of alleen verschenen in bronnen of tijdschriften die niet in de gebruikelijke online medische bibliografieën (bijvoorbeeld MEDLINE/Pubmed) zijn geïndexeerd. De richtlijncommissie heeft samen met het kennisinstituut van de FMS tevens een extra literatuuronderzoek gedaan naar de laatstgenoemde groep studies. Vele daarvan includeerden slechts kleine aantallen patiënten, lieten grote onduidelijkheid en/of gebreken zien wat betreft de gevolgde methodologie, of rapporteerden het resultaat op onduidelijke wijze.

 

Er zijn inmiddels wel- en niet gepeer-reviewde meta-analyses en reviews te vinden waarin onder andere de bovengenoemde studies ook werden opgenomen, en die dan op een positief advies uitkomen. De bron van deze meta-analyses is vaak onduidelijk, en deze meta-analyses bevatten aanzienlijke methodologische gebreken. Bijvoorbeeld: Bij het nalopen van deze meta-analyses bleek dat de waardering van het bewijsniveau van de afzonderlijke studies (volgens de GRADE-methodologie) niet goed was uitgevoerd, en dat ook studies en eindpunten werden meegenomen die (om diverse redenen) niet gepooled zouden mogen worden met de resultaten van andere studies (Hill, 2022) (heterogeniciteit).

Bijwerkingen

Behandeling met ivermectine lijkt relatief veilig, al worden centraal zenuwstelsel bijwerkingen, zoals hoofdpijn en duizeligheid, maar ook encephalopathie, beschreven (Guzzo, 2002). ‘Adverse events’ tijdens behandeling van COVID-19 werden onder andere bekeken in de studie van Lim (2022) en López-Medina (2021). Bij Lim (2022) werden ‘adverse events’ gezien bij 13,7% van de patiënten die met ivermectine behandeld werden versus 4,4% van de patiënten in de controle groep. Dit verschil werd met name bepaald door het optreden van diarree. In de studie van López-Medina (2021) werden ‘adverse events’ niet vaker gezien in de ivermectine groep vergeleken met de placebo groep, wel stopte iets meer mensen in de ivermectine groep met hun behandeling vanwege klachten (7,5% versus 2,5%).

 

Dosering

In de beschreven studies worden veel verschillende doseringen van ivermectine gebruikt, daarnaast is de frequentie van toediening erg wisselend. Op basis van de huidige literatuur is behandeling met ivermectine niet geadviseerd. Ook zal er dus geen advies over een dosering plaatsvinden.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Op grond van de bekende onderzoeksgegevens wordt ivermectine niet aanbevolen in de behandeling van patiënten met COVID-19. Behandeling met ivermectine is relatief veilig, alhoewel er wel (ernstige) bijwerkingen zijn beschreven. Ondanks dit advies om ivermectine niet te gebruiken in de behandeling van COVID-19, verwachten wij dat patiënten bij hun waardering van ivermectine ook hun persoonlijke voorkeur en maatschappelijke beeldvorming zullen laten meewegen.

 

Kosten (middelenbeslag)

Ivermectine wordt niet aanbevolen bij de behandeling van COVID-19, de kosten zullen hier daarom niet beschreven worden.

 

Aanvaardbaarheid, haalbaarheid en implementatie

Ivermectine wordt niet aanbevolen bij de behandeling van COVID-19, dus implementatie is niet van toepassing.

 

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

De huidige literatuur bevat inmiddels zowel in de ambulante setting als bij opgenomen patiënten enkele relatief grote en kwalitatief (redelijk) goede studies die het effect van ivermectine bij COVID-19 onderzochten. Op basis van deze literatuur wordt er geen voordeel verwacht van ivermectine bij de behandeling van COVID-19. Op basis van de beschikbare in vitro en in vivo data is het ook twijfelachtig of van ivermectine een (relevant) antiviraal effect bij patiënten te verwachten is. Het (off label) gebruik van ivermectine in de behandeling van COVID-19 wordt dan ook niet aanbevolen.

 

Ook de richtlijnen van de WHO, de Infectious Diseases Society of America (IDSA) en de National Institute of Health (NIH) hebben ivermectine niet opgenomen als standaardbehandeling. De fabrikant Merck heeft op 4-2-2021 bevestigd dat ivermectine als niet geschikt wordt beschouwd voor de behandeling van COVID-19 (zie: www.merck.com/news/merck-statement-on-ivermectin-use-during-the-covid-19-pandemic)

Onderbouwing

Ivermectine is een semisynthetisch derivaat van avermectine en wordt gebruikt voor de behandeling van parasitaire infestaties of infecties met mijten of nematoden bij dieren en mensen. Over ivermectine werd in vitro activiteit tegen SARS-CoV-2 bij een derivaat van Vero cellen (niercellen afkomstig van groene meerapen) gerapporteerd (Caly, 2020). Het mechanisme voor de anti-parasitaire werking is gebaseerd op verslapping van gladde spiercellen door remming van Cl- channels, warentegen het mechanisme voor anti-virale werking zou kunnen berusten op de remming van nuclear import (Jans, 2020). Een latere studie met humane primaire bronchiaalepitheel cellen als model, dat beter overeenkomt met de situatie bij mensen, toonde echter geen remming van de virusreplicatie in vitro (Dinesh Kumar, 2021). Dit maakt de extrapolatie naar klinische effecten niet eenvoudiger.

Klinische behandeling van COVID-19 met ivermectine werd in het begin van de pandemie ontraden omdat met een 10 keer hogere dan de geregistreerde dosis de in vitro EC50 (die ook niet klinisch gevalideerd is), in de long niet bereikt zou kunnen worden. Alleen met een vele malen (>35-100x) hogere dosis dan de standaarddosis zouden theoretisch pas de benodigde concentraties ook in vivo bereikt kunnen worden (Schmith, 2020). Klinische dose-finding studies ontbreken.

Inmiddels hebben diverse gerandomiseerde gecontroleerde studies (RCT’s) de effectiviteit van ivermectine onderzocht om de plaats van dit middel bij de behandeling van COVID-19 patiënten te bepalen.

PICO 1: Hospitalized patients

 

Mortality (crucial)

Very low GRADE

The evidence is very uncertain about the effect of treatment with ivermectin on mortality when compared with treatment without ivermectin in hospitalized patients with COVID-19.

 

Source: Abd-Elsalam, 2021; Gonzalez, 2022; Krolewiecki, 2020; Lim, 2022; Mohan, 2021; Okumuş 2021; Ravikirti, 2021

 

Extensive respiratory support (crucial)

Very low GRADE

The evidence is very uncertain about the effect of treatment with ivermectin on extensive respiratory support when compared with treatment without ivermectin in hospitalized patients with COVID-19.

 

Source: Abd-Elsalam, 2021; Lim, 2022; Mohan, 2021; Ravikirti, 2021; Shahbaznejad, 2020

 

Duration of hospitalization (important)

 

Very low GRADE

The evidence is very uncertain about the effect of treatment with ivermectin on the length of stay when compared with treatment without ivermectin in hospitalized patients with COVID-19.

 

Source: Abd-Elsalam, 2021; Ahmed, 2020; Gonzalez, 2022; Kishoria, 2020; Li, 2022; Mohan, 2021; Rivikirti, 2021; and Shahbaznejad, 2021

 

Time to clinical improvement (important)

 

Very low GRADE

The evidence is very uncertain about the effect of treatment with ivermectin on time to clinical improvement when compared with treatment without ivermectin in hospitalized patients with COVID-19.

 

Source: Ahmed, 2020; Lim, 2020; Mohan, 2021; Okumuş 2021; Ravikirti, 2021; Shahbaznejad, 2021

 

 

 

PICO 2: Non-hospitalized patients

 

Mortality (crucial)

Low GRADE

Treatment with ivermectin may result in little to no difference in mortality when compared with treatment without ivermectin in non-hospitalized patients with COVID-19.

 

Source: Chaccour, 2021; López-Medina, 2021; Reis, 2022; Vallejos, 2021

 

Respiratory support (crucial)

Very low GRADE

The evidence is very uncertain about the effect of treatment with ivermectin on extensive respiratory support when compared with treatment without ivermectin in non-hospitalized patients with COVID-19.

 

Source: López-Medina, 2021; Reis, 2022; Vallejos, 2021

 

Hospitalization (important)

 

Low GRADE

Treatment with ivermectin may result in little to no difference in hospitalization when compared with treatment without ivermectin in non-hospitalized patients with COVID-19.

 

Source: Buonfrate, 2022; Reis, 2022; Vallejos, 2021

 

Time to clinical improvement (important)

 

Low GRADE

Treatment with ivermectin may result in little to no difference in time to clinical improvement when compared with treatment without ivermectin in non-hospitalized patients with COVID-19.

Source: Buonfrate, 2022; Chaccour, 2021; Chachar, 2020; López-Medina, 2021; Podder, 2020; Reis, 2022

Hospitalized patients

 

Abd-Elsalam (2021) described an open-label randomized controlled trial, which was conducted in 2 university hospitals in Egypt. They evaluated the efficacy and safety of ivermectin in patients hospitalized with mild to moderate COVID-19. Of 172 patients, 164 patients were included as they met the inclusion criteria and were willing to participate. These patients were randomized to receive ivermectin and standard care (n=82) or standard care alone (n=82). The mean (SD) age was 42.38 (16.02) years in the intervention group, compared with 39.38 (16.92) years in the control group. In the intervention group 37/82 (45.1%) were males, compared with 45/82 (54.9%) in the control group. Patients in the intervention group received a single dose of oral ivermectin tablets (12 mg) every day for 3 days. In addition, all patients continued to receive standard of care for 14 days, which included paracetamol, oxygen, fluids (according to the condition of the patient), empiric antibiotic, oseltamivir if needed (75 mg/12 h for 5 days), and invasive mechanical ventilation with hydrocortisone for severe cases. The length of the follow-up was 1 month. The following relevant outcome measures were included: mortality, duration of hospitalization and extensive respiratory support. The primary outcome was all-cause mortality within 1 month. This occurred in 3/82 (3.7%) patients in the intervention group, compared with 4/82 (4.9%) patients in the control group. This resulted in a rate difference of -0.01 (95% CI -0.07 to 0.05).

 

Ahmed (2020) described a randomized, double-blind, placebo-controlled trial, which was conducted in 1 hospital in Bangladesh. They evaluated the efficacy and safety of ivermectin in patients hospitalized with mild COVID-19. Patients were randomized to receive ivermectin alone (N=24), ivermectin and doxycycline (N=24) or placebo (N=24). For the current literature summary, the group receiving ivermectin alone was included as the intervention group. The standard care was not described. The mean age and sex were only reported for the three groups combined. Patients had a mean age of 42 years and 54% was female. Patients in the intervention groups received oral ivermectin alone (12 mg once daily, for 5 days). The control group received a placebo, which was not further specified. The length of the follow-up was 2 weeks. The following relevant outcome measures were included: non-invasive respiratory support, duration of hospitalization, time to clinical improvement, time to viral clearance. The primary outcomes were time to viral clearance and time to clinical improvement (remission of fever and cough). At day 14, viral clearance occurred in 17/22 (77.3%) patients in the intervention group and 9/23 (39.1%) patients in the control group. This resulted in a rate difference of -0.38 (95% CI 0.12 to 0.65). Remission of fever (≥37.5°C) within 7 days occurred in 17/17 (100%) patients in the intervention group and 16/19 (84.2%) patients in the control group (RD 0.16 (95% CI -0.03 to 0.34). Remission of cough within 7 days occurred in 7/18 (38.9%) patients in the intervention group and 9/15 (60%) patients in the control group (RD -0.21, 95% CI -0.55 to 0.12).

 

Gonzalez (2022) described a double-blind, placebo-controlled, randomized clinical trial, which was conducted in Mexico. They evaluated the efficacy and safety of ivermectin in hospitalized COVID-19 patients that did not have severe respiratory failure. Patients were randomized to receiving ivermectin and standard of care or a placebo and standard of care. Another study arm was included, in which patients received hydroxychloroquine. This information is not included in the current summary. The mean age of patients was 56 (SD 16.5) years in the intervention group and 53.8 (SD 16.9) years in the control group. Patients in the intervention and control group were 58.3% and 62.1% male, respectively. The intervention group received a single dose of 12 mg (weight < 80kg) or 18 mg (weight ≥ 80kg) of ivermectin. The control group received calcium citrate as a placebo, which was administered as 2 tablets every 12 h on the first day, followed by one tablet every 12 h for the following 4 days. As standard of care, all patients received pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin according to local and international guidelines. The length of the follow-up was 28 days. The following relevant outcome measures were included: mortality and duration of hospitalization. The primary outcomes were length of hospital stay (median, days) and the rate of respiratory deterioration or dead. The median length of stay was 6 (IQR 4-11) days in the intervention group and 5 (IQR 4-7) days in the control group. The rate of respiratory deterioration or death was 8/36 (22.2%) in the intervention group, compared with 9/37 (24.3%) in the control group (RD -0.02; 95% CI -0.21 to 0.17).

 

 

Kishoria (2020) described an open-label randomized controlled trial, which was conducted in one hospital in India. They evaluated the efficacy and safety of ivermectin in hospitalized patients. Patients were randomized to receiving ivermectin and standard of care or standard of care alone. The mean age of all patients was 38 years (SD not reported) and 23/32 (72%) patients were male. The intervention group received a single dose of 12 mg of ivermectin. Standard of care provided to both groups and included hydroxychloroquine, vitamin C, and paracetamol. The length of the follow-up was 6 days. The following relevant outcome measure was included: duration of hospitalization. The primary outcome was negative RT-PCR throat swab for SARS-CoV-2 after 48 hours. In the intervention group, 8/19 (42.2%) patients had a negative swab, compared to 6/13 (46%) patients in the control group (RD -0.04, 95% CI -0.39 to 0.31).

 

Krolewiecki (2020) described a proof-of-concept, pilot, multicenter, open-label, randomized, controlled trial, which was conducted in four hospitals in Argentina. They evaluated the efficacy and safety of ivermectin in hospitalized patients with COVID-19 not requiring intensive care. Patients were randomized to receiving ivermectin and standard of care or standard of care alone. The mean (±SD) age in the intervention group was 42.3 years (±12.8) and 38.1 years (±11.7) in the control group. In the intervention group, 15/30 (50%) of the patients were male, compared with 10/15 (67%) of the patients in the control group. The intervention group received oral treatment with ivermectin at a single dose of 600 μg/kg for 5 consecutive days. Standard of care was provided to both groups and included hospitalization, but was not further specified. The length of the follow-up was 30 days. The following relevant outcome measure was included: mortality. The primary outcome was the difference in SARS-CoV-2 viral load between baseline and day 5. At day 5, 6/20 (30%) patients in the intervention group and 1/12 (8.3%) patients in the control group had a viral load value below the limit of quantification of 10 copies/reaction (RD 0.22, 95% CI -0.04 to 0.47).

 

Lim (2022) described a multicenter, open-label randomized controlled trial, which was conducted at 20 public hospitals and a COVID-19 quarantine center in Malaysia. They evaluated the efficacy of ivermectin in preventing progression to severe disease among high-risk patients with COVID-19. Patients were randomized to receiving ivermectin and standard of care or standard of care alone. The mean (±SD) age in the intervention group was 63.0 years (±8.9) and 62.0 years (±8.4) in the control group. In the intervention group, 111/241 (46.1%) of the patients were male, compared with 112/249 (45.0%) of the patients in the control group. The intervention group received oral ivermectin 400 μg/kg body weight daily for 5 days. Standard of care was provided to both groups and consisted of symptomatic therapy and monitoring for signs of early deterioration based on clinical findings, laboratory test results, and chest imaging, but was not further specified. The length of the follow-up was 28 days. The following relevant outcome measures were included: mortality, duration of hospitalization, time to clinical improvement and extensive respiratory support. The primary outcome was proportion of patients who progressed to severe COVID-19. Of the intervention group, 52/ 241 patients (21.6%) progressed to severe COVID-19, compared to 43/249 (17.3%) patients in the control group (RD 0.04, 95% CI -0.03 to 0.11).

 

Mohan (2021) described a single-center, pilot, double-blind, randomized, placebo-controlled trial, which was conducted at a cancer institute in India. They evaluated the efficacy and safety of ivermectin in adult patients with non-severe COVID-19. Patients were randomized to receiving ivermectin 12 mg, ivermectin 24 mg or placebo. The mean (±SD) age in the ivermectin 12 mg group was 36.3 years (±10.54), 34.3 years (±10.45) in the ivermectin 24 mg group and 35.3 years (±10.52) in the control group. In the ivermectin 12 mg group, 35/40 (57.5%) of the patients were male, compared with 37/40 (92.5%) of the patients in the ivermectin 24 mg group and 39/52 (86.7%) of the patients in the control group. The intervention groups received oral treatment with ivermectin at a single dose of 12 mg (200 μg/kg) or 24 mg (400 μg/kg). The length of the follow-up was 28 days. The following relevant outcome measures were included: mortality, duration of hospitalization, time to clinical improvement and extensive respiratory support. The co-primary outcomes were the reduction of viral load (estimated from CT value) and conversion to negativity of nasopharyngeal/oropharyngeal RT-PCR on day 5 after the intervention. The decrease in viral load (mean log10 viral copies/mL; ±SD) from baseline up to day 5 was 3.05 (±2.29) in the first intervention group (ivermectin 24mg), 3.04 (±2.05) in the second intervention group (ivermectin 12mg) and 3.08 (±1.98) in the control group. At day 5, the RT-PCR was negative for 33/80 (41.3%) patients in the intervention group and 14/45 (31.1%) patients in the control group (RD 0.10, 95% CI -0.07 to 0.27).

 

Okumuş (2021) described a multicenter, single-blind, quasi-randomized, controlled phase 3 trial, which was conducted at 4 tertiary referral hospitals in Turkey. They evaluated the efficacy and safety of ivermectin in adult severely ill COVID-19 patients with pneumonia. Patients were randomized to receiving ivermectin and standard of care or standard care alone. The intervention group received treatment with ivermectin at a dose of 200 μg/kg for 5 days. Six patients (16.7%) in the intervention group were excluded after randomisation because a SNP mutation in MDR-1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene were detected (mutations involved in ivermectin metabolism). The mean (±SD) age in the intervention group was 58.17 years (±11.52) and 66.23 years (±13.31) in the control group. In the intervention group, 21/30 (70.0%) of the patients were male, compared with 19/30 (63.3%) of the patients in the control group. The length of the follow-up was 10 days. The following relevant outcome measures were included: mortality and time to clinical improvement. The primary outcomes were the clinical responses and drug side effects obtained in patients on the 5th day. At the end of the five-day treatment period, the rate of clinical improvement was 46.7% (14/30) in the intervention group, compared with 36.7% (11/30) in the control group.

 

(Ravi)kirti (2021) described a single-center, pilot, double-blind, randomized, placebo-controlled trial, which was conducted at the All India Institute of Medical Sciences, which served as a COVID-19 dedicated tertiary healthcare facility. They evaluated the efficacy and safety of ivermectin in adult patients with mild to moderate COVID-19. Patients were randomized to receiving ivermectin 12 mg or placebo. The mean (±SD) age in the intervention group was 50.7 years (±12.7) and 54.2 years (±16.3) in the control group. In the intervention group, 40/55 (72.7%) of the patients were male, compared with 41/57 (71.9%) of the patients in the control group. The intervention group received oral treatment with ivermectin at a single dose of 12 mg for two consecutive days. The length of the follow-up was 10 days. The following relevant outcome measures were included: mortality, duration of hospitalization, time to clinical improvement and extensive respiratory support. The primary outcome was the was a negative RT PCR report on day 6. Negative RT-PCR was reported for 13/55 (24%) patients in the intervention group and 18/57 (32%) patients in the control group (RD -0.08, 95% CI -0.24 to 0.09).

 

Shahbasznejad (2021) described a double-blind, placebo-controlled randomized controlled trial, which was conducted in two referral tertiary hospitals in Mazandaran, Iran. They evaluated the efficacy and safety of ivermectin in patients with COVID-19. Patients were randomized to receive ivermectin or a placebo in addition to standard care. The study included both children and adults (inclusion criterium: age > 5 years). The mean (±SD) age was 47.63 (22.20) years in the intervention group and 45.18 (23.11) years in the control group. In the intervention group, 18/35 (51.4%) of the patients were male, compared with 18/34 (52.9%) of the patients in the control group. The intervention group received a single weight-based dose of oral dose of 200 μg/kg. The length of follow-up was 7 days. The following relevant outcome measures were included: mortality, duration of hospitalization, time to clinical improvement and extensive respiratory support. The primary outcome was mean time (±SD) to clinical improvement, which was on average 4.2 (±0.3) days in the intervention group and 5.2 (±0.3) days in the control group (MD -1.00, 95% CI -1.14 to -0.86).

 

Non-hospitalized patients

Buonfrate (2022) described a phase 2, dose-finding, randomized, double-blind, placebo-controlled trial, which was conducted in 4 centres (not hospitals) in the United States. They evaluated the efficacy and safety of 2 dosages of ivermectin in outpatients. Patients were randomized to receive ivermectin (two dosages; N=29, N=32) or placebo (control group; N=32). The median (range) age was 47.0 (31.0-62.0) and 44.5 (31.0-55.5) years in the intervention groups and 50.0 (26.0-57.0) years in the control group. An imbalance in the sex ratio was observed; 14/29 (48.3%) and 8/32 (25.0%) of the patients in the intervention groups were female, compared with 17/32 (53.1%) of the patients in the control group. The intervention groups received either ivermectin 600 μg/kg plus placebo for 5 days or ivermectin 1200 μg/kg for 5 days. The control group received a placebo which was identical in number, appearance and taste to the ivermectin tablets. The length of follow-up was 30 days. The following relevant outcome measure was included: time to clinical improvement.

The primary outcomes were number of serious adverse drug reactions and change in viral load from baseline to day 7. In both groups, no serious adverse drug reactions occurred. The mean (±SD) change in viral load was 2.5 log10 (±2.2) in the first intervention group (ivermectin 600 μg/kg), 2.0 log10 (±2.1) in the second intervention group (1200 μg/kg) and 2.9 log10 (±1.6) in the control group.

 

Chaccour (2021) described a pilot, double-blind, placebo-controlled randomized controlled trial, which was conducted in a university hospital in Spain. They evaluated the efficacy and safety of ivermectin in outpatients. Patients were randomized to receive ivermectin or placebo. The median (IQR) age was 26 (19-36) years in the intervention group and 26 (21-44) years in the control group. In the intervention group, 7/12 (58%) of the patients were male, compared with 5/12 (43%) of the patients in the control group. The intervention group received a single oral, tailored dosage of ivermectin. According to their weight and using tablets of 3 mg, the individual dose ranged from 400 μg/kg to a maximum of 457 μg/kg. The control group received a placebo. No details were provided about the standard of care.

The length of the follow-up was 28 days. The following relevant outcome measure was included: mortality. The primary outcome was the proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swabs at day 7. At day 7 post treatment, 12/12 (100%) patients had a positive PCR for gene N in both groups. For gene E, 11/12 (91%) in the ivermectin and 12/12 (100%) in the placebo group had a positive PCR.

 

Chachar (2020) described an open-label randomized controlled trial, which was conducted in one hospital in Pakistan. They evaluated the efficacy and safety of ivermectin in outpatients. Patients were randomized to receiving ivermectin or not receiving ivermectin. The mean (±SD) age was 40.60 (±17) years in the intervention group and 43.08 (±14.8) years in the control group. In the intervention group, 7/25 (68%) of the patients were male, compared with 14/25 (56%) of the patients in the control group. The intervention group received 3 doses of 12 mg of ivermectin in the first 24 hours. The control group received symptomatic treatment only, which was not further specified. The length of the follow-up was 7 days. The following relevant outcome measure was included: time to clinical improvement. The primary outcome was not specified and the other outcomes of interest for the current summary were not described in the study.

 

López-Medina (2021) described a double-blind, randomized, placebo-controlled trial, which was conducted at a single site in Colombia. They evaluated the efficacy and safety of ivermectin in adult patients with mild COVID-19 and symptoms for 7 days or fewer (at home or hospitalized). The majority (99%) of patients was not hospitalized at recruitment. Therefore, this study is included in the analysis of non-hospitalized COVID-19 patients (PICO 2). Patients were randomized to receiving ivermectin or placebo. The median (IQR) age in the intervention group was 37 years (29-47.7) and 37 years (28.7-49.2) in the control group. In the intervention group, 78/200 (39%) of the patients were male, compared with 89/198 (45%) of the patients in the control group. The intervention group received oral treatment with ivermectin at a single dose of 300 μg/kg for 5 days. The length of the follow-up was 21 days. The following relevant outcome measures were included: mortality and time to clinical improvement. The primary outcome was the time from randomization to complete resolution of symptoms within the 21-day follow-up period. In intervention group, the time to complete resolution symptom was median (IQR) 10 days (9-13), compared with 12 days (9-13) in the control group (absolute difference -2, 95% CI -4 to 2; HR 1.07, 95% CI 0.87 to 1.32).

 

Podder (2020) described a single-center, open-label, quasi-randomized, controlled trial, which was conducted at health complex in Bangladesh. They evaluated the efficacy and safety of ivermectin in adult outpatients with COVID-19. Patients were recruited from the outpatient clinic and randomized to receiving ivermectin and standard of care or standard care alone. The mean (±SD) age in the intervention group was 38.41 years (±11.02) and 39.97 years (±13.24) in the control group. In the intervention group, 23/32 (71.9%) of the patients were male, compared with 21/30 (70.0%) of the patients in the control group. The intervention group received treatment with ivermectin at a single dose of 200 μg/kg. The length of follow-up was 10 days. The following relevant outcome measure was included: time to clinical improvement. The primary outcome was not defined.

 

Reis (2022) described a double-blind, randomized, placebo-controlled, adaptive platform trial (TOGETHER), which was conducted in 12 public health clinics in Brazil. They evaluated the efficacy and safety of ivermectin in non-hospitalized patients with COVID-19. Patients were randomized to receiving ivermectin and standard of care or a placebo and standard of care. The median age of patients was 49 (IQR 39-57) years in the intervention group and 49 (IQR 37-56) years in the control group. Patients in the intervention and control group were 43.6% and 39.9% male, respectively. The intervention group received ivermectin at a dose of 400 µg per kilogram of body weight for 3 days. The control group received a placebo for 1, 3, 10, or 14 days, comparable to the active-treatment groups in the trial. Standard of care was the care provided by health care professionals in Brazil at the time of the trial. The length of the follow-up was 28 days. The following relevant outcome measures were included: mortality, duration of hospitalization and time to symptom resolution.

 

The primary outcomes was a composite outcome, combining hospitalization due to COVID-19 or an emergency department visit due to clinical worsening of COVID-19 (defined as the participant remaining under observation for > 6 hours), both within 28 days after randomization. This outcome occurred in 100/679 (14.7%) of the patients in the intervention group and in 111/679 (16.3%) patients in the control group (reported RR 0.90, 95% CI 0.70 to 1.16; calculated RD -0.02, 95% CI -0.05 to 0.02).

 

Vallejos (2021) described a double-blind, placebo-controlled randomized controlled trial, which was conducted in the community in the province of Corrientes, Argentina. They evaluated the efficacy and safety of ivermectin in preventing hospitalizations in patients with COVID-19. Patients were randomized to receive ivermectin or a placebo in addition to standard of care. The mean (±SD) age was 42.58 (±15.29) years in the intervention group and 42.40 (±15.75) years in the control group. In the intervention group, 139/250 (55.6%) of the patients were male, compared with 125/251 (49.8%) of the patients in the control group. The intervention group received a weight-based dose of oral ivermectin for two consecutive days.

The length of the follow-up was 30 days. The following relevant outcome measures were included: mortality, extensive respiratory support and duration of hospitalization. The primary outcome was hospitalization, which was required for 14/250 (5.6%) patients in the intervention group and for 21/251 (8.4%) patients in the control group (RR 0.67, 95% CI 0.35 to 1.29; RD -0.03, 95% CI -0.07 to 0.02).

 

Table 1. Overview of RCTs comparing IL-1 inhibitors with standard care (or placebo) in hospitalized COVID-19 patients.

Author

 

Registration nr.

Disease severity, based on need for respiratory support*

Sample size

Dosage

Hospitalized patients

Abd-Elsalam 2021

NCT04403555

Unclear;

included in mixed patient group as the authors described mild and moderate disease

I: N=82

C: N=82

Total: 164

Single dose of oral ivermectin tablets (12 mg) every day for 3 days

Ahmed 2020

Not registered

Mild;

disease severity was not specified but the results indicate that none of the patients required oxygen.

I: N=23

II: N=23

C: N=23

Total:

N=72

I: oral ivermectin alone (12 mg daily, for 5 days)

II: oral ivermectin in combination with doxycycline (12 mg ivermectin single dose and 200 mg stat doxycycline day-1 followed by 100 mg 12 hourly for next 4 days)

Gonzalez (2022)

 

Moderate;

Patients were excluded if they required high oxygen volumes (face mask > 10 L/ min), if they had predictors of a poor response to high-flow oxygen nasal prong therapy, or if

they required mechanical ventilation [9]. In the absence of these exclusion criteria, patients were included regardless of other risk factors for poor prognosis.

I: N= 36

C: N=37

Total:

N= 73

ivermectin, 12 mg or 18 mg, according to patient weight

( 12 mg in patients <80 kg, 18 mg ≥ 80 kg)

 

Kishoria 2020

Not registered

Mild; described as mild/asymptomatic; hospitalized without oxygen supplementation

I: N=19

C: N=16

Total:

N=35

ivermectin 12 mg, single dose

Krolewiecki 2020

NCT04381884

Mild; Only 1 patient (intervention group) had oxygen saturation < 94 % at baseline; none of the patients required intensive care

I: N=30

C: N=15

Total:

N=45

single oral dose of ivermectin 600 μg/kg for 5 consecutive days

Lim 2022

NCT04920942

Mild; Patients that required oxygen were excluded

I: 241

C: 249

Total:
N=490

oral ivermectin,

400 μg/kg body weight daily for 5 consecutive days

Mohan 2021

CTRI/2020/06/026001

Mild; inclusion criteria ‘nonsevere COVID-19, i.e., room air saturation (SpO2) >90%, and with no hypotension or requirement of mechanical ventilation’. Authors report that the baseline clinical severity by WHO ordinal scale was 3 (i.e., hospitalized, not requiring supplemental oxygen) in the majority (92%) of patients, and was 4 (i.e., hospitalized, requiring supplemental oxygen) in the remaining patients.

I1: N=49

I2: N=51

C: N=52

Total:

N=152

single oral dose of ivermectin 12 mg (200 μg/kg) or 24 mg (400 μg/kg)

Okumuş 2021

NCT04646109

Severe; inclusion criteria: presence of tachypnea ≥ 30/min, peripheral capillary oxygen saturation (SpO2) level < 90% in room air, Partial pressure of oxygen (PaO2)/FiO2 < 300 in oxygen receiving patient b. Presence of specific radiological finding for COVID-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities) c. Mechanical ventilation requirement d. Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score > 2

I: N=36 (N=30 included in final analysis due to exclusion of patients with genetic mutations)

C: N=30

Total:

N=66

ivermectin 200 μg/kg for 5 days (36-50 kg: 9 mg; 51-65 kg: 12 mg; 66-79 kg: 15 mg; > 80 kg: 200 μg/kg)

(Ravi)kirti 2021

 

CTRI/2020/08/027225)

Mixed: mild (76.4%) and moderate (23.6%) disease; the majority of the patients was classified as ‘mild’ according since there was no evidence of breathlessness or hypoxia (normal saturation).

 

Moderate (23.6%) was classified as breathlessness and/or hypoxia (saturation 90-94% on room air), respiratory rate of 24 or more and no features of severe disease.

I: N=55

C: N=57

Total:

N=115

Single oral dose of ivermectin 12 mg for 2 consecutive days

 

 

Shahbasznejad 2021

IRCT20111224008507N3

Mixed: mild to severe; 13 patients (37.1%) in the intervention group and 18 patients (52.9%) in the control group presented with severe disease (tachypnea (respiratory rate of ≥24 breaths/min), need for mechanical ventilation, need for supplemental oxygen, and oxygen saturation of <94% in the ambient air)

I: N=35

C: N=34

Total:

N=69

Single oral dose of ivermectin 200 μg/kg

Non-hospitalized patients

Buonfrate 2022

NCT04438850

Mild; outpatient setting, participants not required oxygen supplementation (COVID severity score <3 )

I: N=32

II: N=29

C: N=32

Total:

N=93

I: single dose ivermectin 600 μg/kg plus placebo for 5 days

II: single dose ivermectin

1200 μg/kg for 5 days

Chaccour 2021

NCT04390022

Mild; outpatient setting

 

I: N=12

C: N=12

Total:

N=24

400 mcg/kg single oral dose or placebo; individual dose ranged from 400 μg/kg to a maximum of 457 μg/kg.

Chachar 2020

NCT04739410

Mild; outpatient setting

I: N=25

C: N=25

Total:

N=50

ivermectin 12 mg, 3 doses within the first 24 hours

López-Medina 2021

NCT04405843

Mild; patients were at home or hospitalized but not receiving high-flow nasal oxygen or mechanical ventilation

I: N=200

C: N=198

Total:

N=398

single oral dose of ivermectin 300 μg/kg for 5 days

Podder 2020

Not registered

 

Mild; outpatient setting, no report of supplemental oxygen

I: N=32

C: N=30

Total:

N=62

single oral dose of ivermectin 200 μg/kg

Reis (2022)

 

 

Mild; outpatient setting, no report of supplemental oxygen

I: N=679

C: N=679

Total:

N= 1358

(total study including other arms N=2157)

 

Ivermectin at a dose of 400 µg per kilogram of body weight for 3 days

 

Vallejos 2021

NCT04529525.

Mild; outpatient setting; participants were excluded if they were they required home oxygen or required hospitalization

I: N=250

C: N=251

Total: N=501

2 oral doses of 6mg for body weight at inclusion and after 24 h for body weight of <80 kg (total 24 mg), 3 tablets of 6 mg for 80-110 kg (total 36 mg), 4 tablets >110 kg (total 48 mg)

 

*Disease severity categories:

  • mild disease (no supplemental oxygen);
  • moderate disease (supplemental oxygen: low flow oxygen, non-rebreathing mask);
  • severe disease (supplemental oxygen: high flow oxygen [high flow nasal cannula (HFNC)/Optiflow], continuous positive airway pressure [CPAP], non-invasive ventilation [NIV], mechanical ventilation, extracorporeal membrane oxygenation [ECMO or ECLS]).

N: Total sample size; I: Intervention; C: Control

 

Results

Ten studies included patients that were admitted to the hospital and seven RCTs studied ivermectine in an outpatient setting. One study (López-Medina, 2021) included both patients that were admitted to the hospital and outpatients. As the majority of included patients (99%) were outpatients, this study was included in the literature summary for outpatients (PICO 2). Outcomes were pooled, if possible.

 

PICO 1: Hospitalized patients

 

Mortality (crucial)

Five studies (Abd-Elsalam, 2021; Gonzalez, 2022; Krolewiecki, 2020; Lim, 2022; Mohan, 2021) reported the mortality at 28 to 30 days follow-up. Two studies (Okumuş 2021; Ravikirti, 2021) reported mortality at a different follow-up and three studies (Ahmed, 2020; Kishoria, 2020; Shahbaznejad, 2020) did not report mortality rates.

 

Mortality, 28-30 days

Both Krolewiecki (2020) and Mohan (2021) reported that none of the patients in both groups died and therefore no difference was found between the intervention and control group.

 

Abd-Elsalam (2021) reported mortality for 3/82 (3.7%) patients in the intervention group and 4/82 (4.9%) patients in the control group (RR 0.75, 95% CI 0.17 to 3.25; RD -0.01, 95% CI -0.07 to 0.05). This difference is not considered clinically relevant.

Gonzalez (2022) reported mortality for 5/36 (13.8%) patients in the intervention group and

 6/37 (16.2%) patients in the control group (RR 0.86, 95% CI 0.29 to 2.56; RD -0.02, 95% CI -0.19 to 0.14). This difference is not considered clinically relevant.

Lim (2022) reported mortality for 3/241 (1.2%) patients in the intervention group and for 10/249 (4.0%) patients in the control group (RR 0.31, 95% CI 0.09 to 1.11; RD -0.03, 95% CI -0.06 to 0.00). This difference is considered clinically relevant.

 

The pooled incidence of mortality in hospitalized patients was 11/489 (2.2%) in the intervention group, compared to 20/435 (4.6%) in the control group. In two of the five studies, none of the patients died. The pooled relative risk (RR) was 0.60 (95% CI 0.29 to 1.23; Figure 1), and the risk difference (RD) was -0.01 (95%CI -0.03 to 0.00). This is not considered clinically relevant.

 

Figure 1: Mortality (28-30 days) in hospitalized patients

Z: p-value of overall effect; df: degrees of freedom; I2: statistical heterogeneity; CI: confidence interval

 

Mortality, other follow-up

Ravikirti (2021) reported the mortality at a shorter follow-up of day 10. The incidence of mortality was 0/55 (0%) in the intervention group and 4/57 (7%) in the control group. This resulted in a RR of 0.12 (95% CI 0.01 to 2.09) and a RD of -0.07 (95% CI -0.14 to 0.00). This difference is considered clinically relevant.

Okumuş (2021) reported the mortality at a longer follow-up of 3 months. The incidence of mortality was 6/30 (20%) in the intervention group and 9/30 (30%) in the control group. This resulted in a RR of 0.67 (95% CI 0.27 to 1.64) and a RD of -0.10 (95% CI -0.32 to 0.12). This difference is considered clinically relevant.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1), few events and wide CIs (imprecision, -2). Therefore, level of evidence for the outcome ‘mortality’ is considered very low.

 

Extensive respiratory support (crucial)

Initiation of extensive respiratory support in hospitalized patients with COVID-19 was reported in five studies (Abd-Elsalam, 2021; Lim, 2022; Mohan, 2021; Ravikirti, 2021; Shahbaznejad, 2020). All five studies described the need or initiation of mechanical ventilation and did not further specify the ventilation method. Five studies did not report extensive respiratory support (Ahmed, 2020; Gonzalez, 2022; Kishoria, 2020; Krolewiecki, 2020; Okumuş, 2021).

 

Figure 2: Extensive respiratory support in hospitalized patients

Z: p-value of overall effect; df: degrees of freedom; I2: statistical heterogeneity; CI: confidence interval

 

The pooled incidence of extensive respiratory support in hospitalized was 10/513 (1.9%) in the intervention group, compared to 19/474 (4.0%) in the control group. In one study (Mohan, 2021) none of the patients needed extensive respiratory support. The pooled RR was 0.56 (95% CI 0.25 to 1.25; Figure 1), and the RD was -0.01 (95% CI -0.03 to 0.01). This is not considered clinically relevant.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1), inconsistent findings (inconsistency, -1), few events, and wide CIs (imprecision, -1). Therefore, the level of evidence for the outcome ‘extensive respiratory support’ is considered very low.

 

Duration of hospitalization (important)

Eight studies (Abd-Elsalam, 2021; Ahmed, 2020; Gonzalez, 2022; Kishoria, 2020; Li, 2022; Mohan, 2021; Rivikirti, 2021; and Shahbaznejad, 2021) reported the duration of hospitalization or the percentage of patients that was discharged at a specific follow-up. Two studies (Krolewiecki, 2020; Okumuş, 2021) did not report the duration of hospitalization.

 

Abd-Elsalam (2021), Ahmed (2020) Gonzalez (2022) and Shahbaznejad (2021) reported the length of hospital stay, whereas Lim (2022) reported the ICU stay. Abd-Elsalam (2021) reported that the mean duration of hospitalization was 8.82 (SD 4.94) days in the intervention group and 10.97 (SD 5.28) days in the control group (MD -2.15, 95% CI -3.72 to -0.58). Ahmed (2020) reported a mean duration of hospitalization of 9.6 (SD 4.39) days in the intervention group and 9.7 (SD 3.7) in the control group (MD -0.10, 95% CI -2.45 to 2.25). Gonzalez (2022) reported that the median length of stay was 6 (IQR 4-11) days in the intervention group and 5 (IQR 4-7) days in the control group. Shahbaznejad (2021) reported that the mean duration of hospitalization was 7.1 (SD 0.5) days in the intervention group and 8.4 (SD 0.6) days in the control group (MD -1.30, 95% CI -1.56 to -1.04). These differences are not considered clinically relevant.

 

In addition, Lim (2022) reported the duration of ICU stay. Patients in the intervention group stayed at the ICU for on average 7.7 (SD 4.4) days, compared to 7.3 days (SD 4.3) days in the control group (MD 0.40; 95% CI -0.36 to 1.16). This difference is not considered clinically relevant.

 

Kishoria (2020) reported the incidence of patients being discharged from the hospital at day 6. Of the intervention group, 8/19 (42.2%) patients were discharged, compared to 6/13 (46%) patients of the control group (RR 0.91, 95% CI 0.41 to 2.01; RD -0.04, 95% CI -0.39 to 0.31). This difference is not considered clinically relevant.

Ravikirti (2021) reported the incidence of patients being discharged from the hospital at day 10. Of the intervention group, 44/55 (80%) patients were discharged, compared to 42/57 (74%) patients of the control group (RR 1.09, 95% CI 0.89 to 1.33; RD 0.06, 95% CI -0.09 to 0.22). Mohan (2021) reported the incidence of patients being discharged from the hospital at day 14. Of the intervention group, 75/80 (93.8%) patients were discharged, compared to 39/45 (86.7%) patients of the control group (RR 1.08, 95% CI 0.97 to 1.21; RD 0.07, 95% CI -0.02 to 0.16). These differences are considered clinically relevant.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1), inconsistent findings (inconsistency, -1) and low number of patients (imprecision, -1) Therefore, the level of evidence for the outcome ‘duration of hospitalization’ is considered very low.

 

Time to clinical improvement (important)

Six studies (Ahmed, 2020; Lim, 2020; Mohan, 2021; Okumuş 2021; Ravikirti, 2021; Shahbaznejad, 2021) reported the time to clinical improvement or the incidence of clinical improvement at a specific follow up. Four studies (Abd-Elsalam, 2021; Gonzalez, 2022; Kishoria, 2020; Krolewiecki, 2020) did not report time to clinical improvement.

 

Mohan (2021) reported an average time to symptom resolution of 4.42 (SD 2.8) days in the intervention group and 4.58 (SD 2.94) days in the control group (MD -0.16, 95% CI -1.21 to 0.89). This difference is not considered clinically relevant.

Shahbaznejad (2021) defined clinical improvement as resolving a patient’s baseline status on persistent and continuous cough (persistent cough for > 1 hour, or ≥3 coughing episodes in 24 hours, that interferes with activities of daily living and the ability to work) and tachypnea in addition to increasing oxygen saturation to > 94%. The mean time to clinical improvement was 4.2 (SD 0.3) days in the intervention group and 5.2 (SD 0.3) days in the control group (MD -1.00, 95% CI -1.14 to -0.86). This difference is not considered clinically relevant.

 

The other studies did not report the time to clinical improvement, but the incidence of resolution of symptoms within 5 to 7 days from the start of treatment.

Ahmed (2020) reported that remission of fever (≥37.5 °C) within 7 days occurred in 17/17 (100%) patients in the intervention group, compared to 16/19 (84.2%) patients in the control group (RD 0.16, 95% CI -0.03 to 0.34).

Lim (2022) reported that complete symptom resolution at day 5 occurred in 122/238 (51.3%) patients in the intervention group compared to 131/247 (53.0%) patients in the control group (RD -0.02, 95% CI -0.11 to 0.07).

Okumuş (2021) reported clinical improvement for clinical improvement at day 5 for 14/30 (46.7%) patients in the intervention group and 11/30 (36.7%) patients in the control group and for 22/30 (73.3%) and 16/30 (53.3%) patients at day 10 respectively (RD day 5: 0.10, 95% CI -0.15 to 0.35; RD day 10: 0.20, 95% CI -0.04 to 0.44).

Ravikirti (2021) reported that 46/55 (84%) patients in the intervention group and 51/57 (90%) patients in the control group were symptom free at day 6 (RD -0.06, 95% CI -0.18 to 0.07).

These differences are inconsistent, as they include both clinically relevant and irrelevant differences, in favour of the intervention group and control group.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1), and wide CIs (imprecision, -1) and inconsistent findings (inconsistency, -1). The level of evidence for the outcome ‘time to clinical improvement’ is considered very low.

 

PICO 2: Non-hospitalized patients

 

Mortality (crucial)

Three studies (Chaccour, 2021; Reis, 2022; Vallejos, 2021) reported the 28 to 30 days mortality, one study reported mortality at a different follow-up (López-Medina, 2021) and three studies (Buonfrate, 2022; Chachar, 2020; Podder, 2020) did not report mortality.

 

Chaccour (2021) reported that none of the patients progressed to severe disease or death during the 28-day trial (RD mortality 0.00, 95% CI -0.15 to 0.15).

Reis (2022) reported mortality for 21/679 (3.1%) patients in the intervention group and 24/679 (3.5%) patients in the control group (RR 0.88, 95% CI 0.49 to 1.55; RD -0.00, 95% CI -0.02 to 0.01).

Vallejos (2021) reported all-cause mortality for 4/250 (1.6%) patients in the intervention group and 3/251 (1.2%) patients in the control group (RR 1.34, 95% CI 0.30 to 5.92; RD 0.00, 95% CI -0.02 to 0.02). Taken together, these studies reported mortality for 25/941 (2.7%) patients in the intervention group and 27/942 (2.9%) patients in the control group (RR 0.92, 95% CI 0.54 to 1.58; RD -0.00, 95% CI -0.01, 0.01). This is not considered a clinically relevant difference.

 

López-Medina (2021) reported mortality on day 21. The incidence of mortality was 0/200 (0%) in the intervention group and 1/198 (0.5%) in the control group. This resulted in a RR of 0.33 (95% CI 0.01 to 8.05) and a RD of 0.01 (95%CI -0.02 to 0.01). This is not considered a clinically relevant difference.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 2 levels, because of study limitations (risk of bias, -1), few events and wide CIs (imprecision, -2). Therefore, level of evidence for the outcome ‘mortality’ is low.

 

Respiratory support (crucial)

Three studies (López-Medina, 2021; Reis, 2022; Vallejos, 2021) reported the need for respiratory support in non-hospitalized patients. The other four studies (Buonfrate 2022; Chaccour, 2021; Chachar 2020; Podder, 2020) did not reported the need for respiratory support in non-hospitalized patients.

 

López-Medina (2021) reported that 1 of the 200 (0.5%) patients in the intervention group needed respiratory support, compared to 1 of the 199 (0.5%) in the control group (RR 1.00; 95% CI 0.06 to 15.79). This is not considered a clinically relevant difference.

 

Reis (2022) reported that 19 of the 679 (2.8%) patients in the intervention group needed respiratory support, compared to 25 of the 679 (3.7%) patients in the control group (RR 0.77; 95% CI 0.43-1.36). This is not considered a clinically relevant difference.

 

Vallejos (2021) reported that 4 of the 250 (1.6%) patients in the intervention group needed respiratory support, compared to 3 of the 251 (1.2%) patients in the control group (OR 1.34; 95% CI 0.30 to 6.07). This is not considered a clinically relevant difference.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1), few events and wide CIs (imprecision, -2). Therefore, level of evidence for the outcome ‘respiratory support’ is very low.

 

Hospitalization (important)

Three studies (Buonfrate 2022; Reis, 2022; Vallejos, 2021) reported the incidence of hospitalization. The other four studies (Chaccour, 2021; Chachar 2020; López-Medina, 2021; Podder, 2020) did not report the incidence of hospitalization.

 

Buonfrate (2022) reported that hospitalization was required for 4/59 (6.8%) patients in the combined intervention group and for 0/32 (0%) patients in the control group (RR 4.95, 95% CI 0.27 to 89.13; RD 0.07, 95% CI -0.01 to 0.15). This difference is considered clinically relevant.

 

Reis (2022) reported that hospitalization was required for 21/679 (3.1%) patients in the intervention group and for 24/679 (3.5%) patients in the control group (RR 0.83, 95% CI 0.63 to 1.10; RD -0.02, 95% CI -0.06 to 0.01). This difference is not considered clinically relevant.

 

Vallejos (2021) reported that hospitalization was required for 14/250 (5.6%) patients in the intervention group and for 21/251 (8.4%) patients in the control group (RR 0.67, 95% CI 0.35 to 1.29; RD -0.03, 95% CI -0.07 to 0.02). This difference is not considered clinically relevant.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 2 levels, because of study limitations (risk of bias, -1), low number of events (imprecision, -1). The level of evidence for the outcome ‘hospitalization’ is considered low.

 

Time to clinical improvement (important)

Six studies (Buonfrate, 2022; Chaccour 2021; Chachar, 2020; López-Medina, 2021; Podder, 2020; Reis, 2022) reported the time to clinical improvement or the incidence of clinical improvement at a specific follow up. One study (Vallejos 2021) did not report time to clinical improvement.

 

Buonfrate (2022) reported the time to clinical improvement as the time from randomisation to clinical resolution, in which clinical resolution was not further specified. The median time to clinical resolution was 29 (IQR 13.5–32.0) days in the first intervention group (single dose ivermectin 600 μg/kg plus placebo for 5 days) and 14 (IQR 7–37) days in the second intervention group (single dose ivermectin 1200 μg/kg for 5 days) compared to 14 (IQR 13–30) days in the control group. The difference between the first intervention group receiving the low dose ivermectin and the control group is considered clinically relevant.

 

López-Medina (2021) reported that the median (IQR) time to resolution of symptoms was 10 (IQR 9-13) days for the intervention group and 12 (IQR 9-13) days for the control group. The reported absolute difference was -2 (95% CI -4 to 2) with an HR of 1.07 (95% CI 0.87 to 1.32). This difference is not considered clinically relevant.

 

Podder (2020) reported the time from the date of enrolment to symptom resolution. Time to symptom resolution was on average 5.31 (SD 2.48) days in the intervention group compared to 6.33 (SD 4.23) days in the control group. The MD was -1.02 (95% CI -2.76 to 0.72). This difference is not considered clinically relevant.

 

Reis (2022) reported the median (IQR) time to clinical recovery, which was assessed with the use of the World Health Organization clinical progression scale, but the threshold for ‘recovery’ was not further specified. Median recovery time was 14 (IQR 11-14) days in both the intervention and control group (HR 1.05 (0.88-1.24). This difference is not considered clinically relevant.

 

Chachar (2020) reported the incidence of patients being asymptomatic at day 7. In the intervention group, 16/25 (64%) patients were asymptomatic compared to 15/25 (60%) patients in the control group (RR 1.07, 95% CI 0.69 to 1.65; RD 0.04, 95% CI -0.23 to 0.31). This difference is not considered clinically relevant.

 

Chaccour (2021) reported the total number of patient-days that was self-reported by the treatment groups. Absolute data about the mean number of patient-days per patient, at which days these symptoms were reported or the hazard ratio were not available. Overall, the patients in the intervention group together reported fewer patient-days of any symptoms than those in the placebo group (symptoms reported for 171 vs 255 patient-days respectively). The authors report that this difference was mostly driven by the difference in anosmia/hyposmia (76 vs 158 patient-days) and cough (68 vs 97 patient-days). There were no major differences between the intervention and control group in the self-reported patient-days of fever (12 vs 12), general malaise (51 vs 61), headache (34 vs 38), or nasal congestion (91 vs 97). Only a small number of patient-days were reported for the experience of gastrointestinal symptoms (21 vs 6) and shortness of breath (3 vs 15).

 

Studies were not pooled, however, taken together the majority of studies did not find a clinically relevant difference between the intervention and control group.

 

Level of evidence of the literature

The level of evidence started as high, because the studies were RCTs. The level of evidence was downgraded by 2 levels, because of study limitations (risk of bias, -1) and wide CIs (imprecision, -1). The level of evidence for the outcome ‘time to clinical improvement’ is considered low.

A systematic review of the literature was performed to answer the following question:

What is the effectivity of treatment with ivermectin compared to treatment without ivermectin in patients with COVID-19?

 

PICO 1

P:           hospitalized with COVID-19 (subgroups mild, moderate, severe)

I:            ivermectin + standard care

C:           standard care only / placebo treatment + standard care

O:           28-30 day mortality (if not available, any other reports of mortality), extensive respiratory support, duration of hospitalization, time to clinical improvement

 

PICO 2

P:           non-hospitalized with COVID-19 (subgroups mild, moderate, severe)

I:            ivermectin + standard care

C:           standard care only / placebo treatment + standard care

O:           28-30 day mortality (if not available, other follow-up), respiratory support, hospitalization, time to clinical improvement

 

Relevant outcome measures

PICO 1: For hospitalized COVID-19 patients, mortality and need for extensive respiratory support were considered as crucial outcome measures for decision making. Duration of hospitalization and time to clinical improvement were considered as important outcome measures for decision making.

 

PICO 2: For non-hospitalized COVID-19 patients, mortality was considered as a critical outcome measure for decision making. Hospitalization, respiratory support and time to clinical improvement were considered as important outcome measures for decision making.

 

Extensive respiratory support was defined as high flow nasal cannula (HFNC)/Optiflow, continuous positive airway pressure (CPAP), non-invasive ventilation (NIV), mechanical ventilation or extracorporeal membrane oxygenation (ECMO or ECLS).

 

The working group defined 3% points absolute difference as a minimal clinically important difference for mortality (resulting in a NNT of 33), 3 days for duration of hospitalization and time to clinical improvement, 5% points absolute difference need for respiratory support and hospital admission (resulting in a NNT of 20).

 

Studies of hospitalized patients were categorized based on the respiratory support that was needed at baseline (preferably based on patient inclusion/exclusion criteria; otherwise on baseline characteristics). The following categories were used:

  • mild disease (no supplemental oxygen);
  • moderate disease (supplemental oxygen: low flow oxygen, non-rebreathing mask);
  • severe disease (supplemental oxygen: high flow oxygen [high flow nasal cannula (HFNC)/Optiflow], continuous positive airway pressure [CPAP], non-invasive ventilation [NIV], mechanical ventilation, extracorporeal membrane oxygenation [ECMO or ECLS]).

 

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until April 7th, 2022. The detailed search strategy is outlined under the tab Methods. Studies were selected based on the following criteria: randomized controlled trial, peer reviewed and published in indexed journal, comparing treatment with ivermectin and standard care to standard care alone or treatment with ivermectin and standard care to placebo and standard care in patients with COVID-19. Studies with n < 10 were excluded.

 

The systematic literature search resulted in 82133hits. Studies were selected based on the following criteria: systematic review or randomized controlled trials. Eventually, 17 randomized controlled trials were included. Study inclusion was compared to studies included in a recent systematic review (Popp, 2021). In the current summary, two of these studies (Gonzalez, 2021; (Shah)Bukhari, 2021) were excluded because they were included as a preprint and not published in the meantime, and one study (Pott-Junior, 2021) was not included because of number of patients (<10 per arm). In addition, one individual study (Samaha, 2021) was first identified but was excluded as the publication was retracted by the journal.

 

Statistical methods

Statistical analyses were conducted using Review Manager (RevMan) software 5.4. For dichotomous outcomes, Mantel Haenszel random‐effects risk ratios (RRs) and risk differences (RDs) were calculated. For continuous outcomes, a random‐effects mean difference (MD) weighted by the inverse variance was calculated. The random-effects model estimates the mean of a distribution of effects.

 

Results

In total, 17 studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

  1. Abd-Elsalam, S., Noor, R. A., Badawi, R., Khalaf, M., Esmail, E. S., Soliman, S., Abd El Ghafar, M. S., Elbahnasawy, M., Moustafa, E. F., Hassany, S. M., Medhat, M. A., Ramadan, H. K., Eldeen, M., Alboraie, M., Cordie, A., & Esmat, G. (2021). Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: A randomized controlled study. Journal of medical virology, 93(10), 5833–5838. https://doi.org/10.1002/jmv.27122
  2. Ahmed, S., Karim, M. M., Ross, A. G., Hossain, M. S., Clemens, J. D., Sumiya, M. K., Phru, C. S., Rahman, M., Zaman, K., Somani, J., Yasmin, R., Hasnat, M. A., Kabir, A., Aziz, A. B., & Khan, W. A. (2021). A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 103, 214–216. https://doi.org/10.1016/j.ijid.2020.11.191
  3. Buonfrate, D., Chesini, F., Martini, D., Roncaglioni, M. C., Ojeda Fernandez, M. L., Alvisi, M. F., de Simone, I., Rulli, E., Nobili, A., Casalini, G., Antinori, S., Gobbi, M., Campoli, C., Deiana, M., Pomari, E., Lunardi, G., Tessari, R., & Bisoffi, Z. (2021). High Dose Ivermectin for the Early Treatment of COVID-19 (COVIER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3918289
  4. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3. PMID: 32251768; PMCID: PMC7129059.
  5. Chaccour, C., Casellas, A., Blanco-Di Matteo, A., Pineda, I., Fernandez-Montero, A., Ruiz-Castillo, P., Richardson, M. A., Rodríguez-Mateos, M., Jordán-Iborra, C., Brew, J., Carmona-Torre, F., Giráldez, M., Laso, E., Gabaldón-Figueira, J. C., Dobaño, C., Moncunill, G., Yuste, J. R., Del Pozo, J. L., Rabinovich, N. R., Schöning, V., … Fernández-Alonso, M. (2021). The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine, 32, 100720. https://doi.org/10.1016/j.eclinm.2020.100720
  6. Dinesh Kumar N, Ter Ellen BM, Bouma EM, Troost B, van de Pol DPI, van der Ende-Metselaar HH, van Gosliga D, Apperloo L, Carpaij OA, van den Berge M, Nawijn MC, Stienstra Y, Rodenhuis-Zybert IA, Smit JM. Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0154321. doi: 10.1128/AAC.01543-21. Epub 2021 Oct 11. PMID: 34633839; PMCID: PMC8765325.
  7. (Zeeshan Khan) Chachar, A., Ahmad Khan, K., Asif, M., Tanveer, K., Khaqan, A., & Basri, R. (2020). Effectiveness of Ivermectin in SARS-CoV-2/COVID-19 Patients. International Journal of Sciences, 9(09), 31–35. https://doi.org/10.18483/ijsci.2378
  8. Beltran Gonzalez, J. L., González Gámez, M., Mendoza Enciso, E. A., Esparza Maldonado, R. J., Hernández Palacios, D., Dueñas Campos, S., Robles, I. O., Macías Guzmán, M. J., García Díaz, A. L., Gutiérrez Peña, C. M., Martinez Medina, L., Monroy Colin, V. A., & Arreola Guerra, J. M. (2022). Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled Trial. Infectious disease reports, 14(2), 160–168. https://doi.org/10.3390/idr14020020
  9. Gonzalez, J. L. B., González Gámez, M., Enciso, E. A. M., Maldonado, R. J. E., Hernández Palacios, D., Dueñas Campos, S., Robles, I. O., Macías Guzmán, M. J., García Díaz, A. L., Gutiérrez Peña, C. M., Medina, L. M., Colin, V. A. M., & Manuel, A. G. J. (2021). Efficacy and safety of Ivermectin and Hydroxychloroquine in patients with severe COVID-19. A randomized controlled trial. MedRxiv. https://doi.org/10.1101/2021.02.18.21252037
  10. Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002 Oct;42(10):1122-33. doi: 10.1177/009127002401382731. PMID: 12362927.
  11. Hill A, Mirchandani M, Pilkington V. Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud. Open Forum Infect Dis. 2022;9(2):ofab645. Published 2022 Jan 17. doi:10.1093/ofid/ofab645
  12. Jans DA, Wagstaff KM. Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal? Cells. 2020 Sep 15;9(9):2100. doi: 10.3390/cells9092100. PMID: 32942671; PMCID: PMC7564151.
  13. Kishoria, N., Mathur, S., Parmar, V., Kaur, R. J., Agarwal, H., Parihar, B., & Verma, S. (2020). IVERMECTIN AS ADJUVANT TO HYDROXYCHOLOROQUINE IN PATIENTS RESISTANT TO STANDARD TREATMENT FOR SARS-CoV-2: RESULTS OF AN OPEN-LABEL RANDOMIZED CLINICAL STUDY. PARIPEX INDIAN JOURNAL OF RESEARCH, 1–4. https://doi.org/10.36106/paripex/4801859
  14. Krolewiecki, A., Lifschitz, A., Moragas, M., Travacio, M., Valentini, R., Alonso, D. F., Solari, R., Tinelli, M. A., Cimino, R. O., Álvarez, L., Fleitas, P. E., Ceballos, L., Golemba, M., Fernández, F., Fernández de Oliveira, D., Astudillo, G., Baeck, I., Farina, J., Cardama, G. A., Mangano, A., … Lanusse, C. (2021). Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial. EClinicalMedicine, 37, 100959. https://doi.org/10.1016/j.eclinm.2021.100959
  15. Lim, S., Hor, C. P., Tay, K. H., Mat Jelani, A., Tan, W. H., Ker, H. B., Chow, T. S., Zaid, M., Cheah, W. K., Lim, H. H., Khalid, K. E., Cheng, J. T., Mohd Unit, H., An, N., Nasruddin, A. B., Low, L. L., Khoo, S., Loh, J. H., Zaidan, N. Z., Ab Wahab, S., … I-TECH Study Group (2022). Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial. JAMA internal medicine, 10.1001/jamainternmed.2022.0189. Advance online publication. https://doi.org/10.1001/jamainternmed.2022.0189
  16. López-Medina, E., López, P., Hurtado, I. C., Dávalos, D. M., Ramirez, O., Martínez, E., Díazgranados, J. A., Oñate, J. M., Chavarriaga, H., Herrera, S., Parra, B., Libreros, G., Jaramillo, R., Avendaño, A. C., Toro, D. F., Torres, M., Lesmes, M. C., Rios, C. A., & Caicedo, I. (2021). Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA, 325(14), 1426–1435. https://doi.org/10.1001/jama.2021.3071
  17. Mohan, A., Tiwari, P., Suri, T. M., Mittal, S., Patel, A., Jain, A., Velpandian, T., Das, U. S., Boppana, T. K., Pandey, R. M., Shelke, S. S., Singh, A. R., Bhatnagar, S., Masih, S., Mahajan, S., Dwivedi, T., Sahoo, B., Pandit, A., Bhopale, S., Vig, S., … Guleria, R. (2021). Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 27(12), 1743–1749. https://doi.org/10.1016/j.jiac.2021.08.021
  18. Okumuş, N., Demirtürk, N., Çetinkaya, R. A., Güner, R., Avcı, S. Y., Orhan, S., Konya, P., ŞAylan, B., Karalezli, A., Yamanel, L., Kayaaslan, B., Yılmaz, G., Savaşçı, M., Eser, F., & Taşkın, G. (2021). Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infectious Diseases, 21(1). https://doi.org/10.1186/s12879-021-06104-9
  19. Podder, C. S., Chowdhury, N., Sina, M. I., & Haque, W. M. M. U. (2021). Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC Journal of Medical Science, 14(2), 11–18. https://doi.org/10.3329/imcjms.v14i2.52826
  20. Popp, M., Stegemann, M., Metzendorf, M. I., Gould, S., Kranke, P., Meybohm, P., Skoetz, N., & Weibel, S. (2021). Ivermectin for preventing and treating COVID-19. The Cochrane database of systematic reviews, 7(7), CD015017. https://doi.org/10.1002/14651858.CD015017.pub2
  21. Ravikirti, Roy, R., Pattadar, C., Raj, R., Agarwal, N., Biswas, B., Manjhi, P. K., Rai, D. K., Shyama, Kumar, A., & Sarfaraz, A. (2021). Evaluation of Ivermectin as a Potential Treatment for Mild to Moderate COVID-19: A Double-Blind Randomized Placebo Controlled Trial in Eastern India. Journal of Pharmacy & Pharmaceutical Sciences, 24, 343–350. https://doi.org/10.18433/jpps32105
  22. Reis, G., Silva, E., Silva, D., Thabane, L., Milagres, A. C., Ferreira, T. S., Dos Santos, C., Campos, V., Nogueira, A., de Almeida, A., Callegari, E. D., Neto, A., Savassi, L., Simplicio, M., Ribeiro, L. B., Oliveira, R., Harari, O., Forrest, J. I., Ruton, H., Sprague, S., … TOGETHER Investigators (2022). Effect of Early Treatment with Ivermectin among Patients with Covid-19. The New England journal of medicine, 10.1056/NEJMoa2115869. Advance online publication. https://doi.org/10.1056/NEJMoa2115869
  23. (retracted publication) Samaha, A. A., Mouawia, H., Fawaz, M., Hassan, H., Salami, A., Bazzal, A. A., Saab, H. B., Al-Wakeel, M., Alsaabi, A., Chouman, M., Moussawi, M. A., Ayoub, H., Raad, A., Hajjeh, O., Eid, A. H., & Raad, H. (2021). Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon. Viruses, 13(6), 989. https://doi.org/10.3390/v13060989
  24. Schmith VD, Zhou JJ, Lohmer LRL. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19. Clin Pharmacol Ther. 2020 Oct;108(4):762-765. doi: 10.1002/cpt.1889. Epub 2020 Jun 7. PMID: 32378737; PMCID: PMC7267287.
  25. Shah Bukhari, K. H., Asghar, A., Perveen, N., Hayat, A., Mangat, S. A., Butt, K. R., Abdullah, M., Fatima, T., Mustafa, A., & Iqbal, T. (2021). Efficacy of Ivermectin in COVID-19 Patients with Mild to Moderate Disease. MedRxiv. https://doi.org/10.1101/2021.02.02.21250840
  26. Shahbaznejad, L., Davoudi, A., Eslami, G., Markowitz, J. S., Navaeifar, M. R., Hosseinzadeh, F., Movahedi, F. S., & Rezai, M. S. (2021). Effects of Ivermectin in Patients With COVID-19: A Multicenter, Double-blind, Randomized, Controlled Clinical Trial. Clinical therapeutics, 43(6), 1007–1019. https://doi.org/10.1016/j.clinthera.2021.04.007
  27. Vallejos, J., Zoni, R., Bangher, M., Villamandos, S., Bobadilla, A., Plano, F., Campias, C., Chaparro Campias, E., Medina, M. F., Achinelli, F., Guglielmone, H. A., Ojeda, J., Farizano Salazar, D., Andino, G., Kawerin, P., Dellamea, S., Aquino, A. C., Flores, V., Martemucci, C. N., . . . Aguirre, M. G. (2021). Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infectious Diseases, 21(1). https://doi.org/10.1186/s12879-021-06348-5

 

Study reference

 

(first author, publication year)

Was the allocation sequence adequately generated? a

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?b

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?c

 

Were patients blinded?

 

Were healthcare providers blinded?

 

Were data collectors blinded?

 

Were outcome assessors blinded?

 

Were data analysts blinded?

 

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?d

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?e

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?f

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measureg

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

LOW

Some concerns

HIGH

 

Abd-Elsalam,

2021

Probably yes

 

Reason: Computerized randomization; included patients were randomized using a computer random number generator to select random permuted blocks with a block size of eight and an equal allocation ratio. Three members of the study team (Soliman S, Mai Khalaf, and Eslam Saber Esmail) recruited,

enrolled, and assigned

participants to a

computer‐generated

randomization sequence, held by an

independent observer

Probably yes

 

Reason: Sequentially numbered, opaque, sealed envelopes were used to ensure concealment.

Definitely no

 

Reason: open-label study

Probably yes

 

Reason: All the patients continued the study medications to the end of the duration of treatment and follow‐up.

Probably no

 

Reason: Outcomes mentioned in the Methods section

were reported in the

Results section as well and similar to register; study registered May 2020 while study started March 2020.

Probably no

 

Reason: source of funding not reported; study registered May 2020 while study started March 2020.

LOW (mortality)

Some concerns (mechanical ventilation, duration of hospitalization)

 

Reason: open-label study

Ahmed, 2020

Probably no

 

Reason: not reported

Probably no

 

Reason: not reported

Probably yes

 

Reason: double blind RCT, but not further described

Probably yes

 

Reason: One patient

from each of the ivermectin + doxycycline and placebo groups and

two patients in the 5-day ivermectin group withdrew their consent

during the study

Definitely no

 

Reason: Not all outcome measures mentioned in the method section are reported; no study registration; analyses in sub groups reported but sub groups not specified

Probably no

 

Reason: handling of missing data was not described

HIGH

Buonfrate, 2022

Probably yes

 

Reason:

Participants were randomly assigned by a centralized computer system to one of the three arms with an allocation ratio 1:1:1.

Definitely yes

 

Reason: “The treatment ID was obtained through RED-Cap, used as a web-based clinical data management system for the study. Following randomisation, the treatment ID and the patient’s weight were communicated to the hospital pharmacist who was in charge to prepare the study treatment according to the randomisation list.”

Probably yes

 

Reason: The investigators, subjects, analysts and sponsor were blinded to the treatments received

Probably yes

 

Reason: infrequent number of patients excluded from analysis due to withdrawn consent of missing sample of viral load

Probably yes

 

Reason: All outcome measures described in the trial protocol are reported in the results

Probably no

 

Reason: recruitment was stopped due to dramatic drop in cases; high proportion of patients that did not receive treatment in intervention group due to intolerability

Some concerns

Chaccour, 2021

Definitely yes

 

Reason: “Randomized in a 1:1 ratio to ivermectin (400 mcg/kg) single oral dose or placebo. The randomization sequence

was computer-generated by the trial statistician using blocks of four.”

Definitely yes

 

Reason: “Allocation was made by the attending investigator

using opaque envelopes.”

Probably yes

 

Reason: “double blind trial”; “in order for the clinical trial team to

remain blinded, treatment was administered under direct supervision

by a non-participant nurse that picked up the opaque bottles

directly from the pharmacy and administered the content behind

closed doors. The clinical trial team had no contact with the investigational

products.”; nothing mentioned regarding analyses

Definitely yes

 

Reason: All randomized participants completed follow-up. There was good compliance with the daily online questionnaire with 282 patient-days reports (84%) and 295 patient-days reports (88%) in the ivermectin and placebo group respectively.

Probably yes

 

Reason: outcomes reported as announced

Probably yes

 

Reason: not mentioned

LOW

Chachar, 2020

Definitely yes

 

Reason: “Patients were allocated randomly to the groups by computer generated

number.”

No information

 

Reason: “Patients were allocated randomly to the groups by computer generated

number.” Concealment not described

Definitely no:

 

Reason: ”open label RCT”

Probably yes:

 

Reason: No loss to follow-up or missing data reported.

Probably no

 

Reason: Outcome of symptoms was combined to one outcome parameter (symptomatic vs a-symptomatic); study not registered; primary and secondary outcomes not predefined

Probably no

 

Reason: intention to treat analysis not mentioned; groups differed at baseline; conflicts of interest en funding not specified.

Some concerns (time to symptom resolution)

Gonzalez, 2022

No information

 

Method of randomisation not reported

No information

 

Method of randomisation and concealment not reported

Definitely yes

 

Reason: Patients and investigators remained blinded to randomization until the final analysis

No information

 

Not reported

Definitely yes

 

Reason: Outcome measures described in the method section are also reported

Definitely no

 

Reason: Patient recruitment was stopped due to the therapeutic futility of hydroxychloroquine (one of the treatment arms in this RCT)

 

 

HIGH

 

 

Kishoria, 2020

Definitely yes

 

Reason: “The randomization list was generated by a computerized system by a unit independent of the study team”

Probably yes

 

Reason: “The randomization codes was kept in sealed

sequentially numbered opaque envelopes and was not be opened until the patient shows throat swab positive test after completion of study for SARS-CoV-2 confirmed by reverse transcriptase –polymerase- chain-reaction (RT-PCR) assay”

Definitely no

 

Reason: open label study

Probably no

 

Reason: missing outcome data not further explained

Probably yes

 

Reason: outcomes mentioned in the method section are reported, but trial method is not reported previously.

Probably no

 

Reason: intention to treat analysis is not mentioned, handling missing data is unclear; no trial registration or study protocol

HIGH

Krolewiecki, 2020

Definitely yes

 

Reason: “The randomization list was developed prior to study initiation and by means of a centralized eCRF/IWRS web system (Jazz Clinical, Buenos Aires, Argentina). For reproducibility, a random seed of 1701214029 was used.”

Probably yes

 

Reason: “Once the availability of the informed consent and the verification of all eligibility criteria had been confirmed, the assignment was communicated to the investigators on the computer screen and by email.”

Definitely no

 

Reason: “The patients and center personnel were not blinded to the allocated group. The outcome assessors (personnel in charge of viral load determinations) were blinded to the allocated group upon receiving the samples labeled with the randomization number and the visit number.”

Probably yes

 

Reason: Lost to follow-up was almost equal in both groups.

Definitely no

 

Reason: Not all outcomes mentioned in the trial protocol (clinicaltrials.gov) were reported in the article.

Probably yes

 

Reason: not mentioned

Some concerns

Lim, 2022

Definitely yes

 

Reason: The

randomization (1:1) was based on an investigator-blinded randomization

list uploaded to REDCap, which allocated the patients

via a central, computer-generated randomization scheme

across all study sites during enrollment. The randomization

list was generated independently using random permuted

block sizes 2 to 6. The randomization was not stratified by site.

Probably yes

 

Reason: The

randomization was based on an investigator-blinded randomization

list uploaded to REDCap, which allocated the patients

via a central, computer-generated randomization scheme

across all study sites during enrollment

Definitely no

 

Reason:

Open label

Probably yes

 

Reason: 6 patients in the intervention arm withdrew consent

before taking a dose of ivermectin. The modified intention-to-

treat population for the primary analysis included 490 patients

(98% of those enrolled), with 241 in the intervention

group and 249 in the control group

Probably yes

 

Reason: All outcomes mentioned in the methods section were reported in the article. The trial register only mentions the co-primary outcomes, which are described in the article.

Probably no

 

Reason: trials was underpowered for all-cause mortality outcome; no other problems reported

Some concerns

 

open label design, underpowered for secondary outcome mortality

López-Medina, 2021

Definitely yes

 

Reason: “Patients were randomized in permuted blocks of 4 in a randomization sequence prepared by the unblinded pharmacist in Microsoft Excel version 19.0 who provided masked ivermectin or placebo to a field nurse for home or hospital patient visits..”

Probably yes

 

Reason: “Allocation assignment was concealed from investigators and patients.”

Probably yes

 

Reason: “The only person not blinded to the study procedures will be the pharmaceutical chemist who will randomize the study participants. […] Allocation assignment was concealed from investigatorsand patients.”

Definitely no

 

Reason: In both groups, about 16% or the patients were excluded from analyses due to a labelling error causing patients to receive the wrong treatment. Additional patients were included in the study to meet the numbers derived from the sample size calculation.

Definitely no

 

Reason: Not all outcome mentioned in the trial protocol were reported in the article.

Probably yes

 

Reason: not mentioned

Some concerns

Mohan, 2021

Definitely yes

 

Reason: Eligible patients were randomized in a 1:1:1 ratio. A variable block randomization stratified based on disease severity was done using a centralized telephone-based system.

Probably yes

 

Reason: not mentioned

Definitely yes

 

Reason: patients, investigators, caregivers, and statisticians were blinded to the allocation.

Definitely yes

 

Reason: Lost to follow-up was infrequent and similar in all three groups.

Probably yes

 

Reason: All outcome mentioned in the methods section were reported in the article. The trial register only mentions the co-primary outcomes, which are described in the article.

Probably no

 

Reason: pilot study with small study population

Some concerns

Okumuş, 2021

Definitely no

 

Reason: “The distinction between study and control groups was made by a single-blind randomized method. Starting from the first patient included in the study, patients with odd numbers were grouped as the study group, and patients with even numbers as the control group.”

Definitely no

 

Reason: “The distinction between study and control groups was made by a single-blind randomized method. Starting from the first patient included in the study, patients with odd numbers were grouped as the study group, and patients with even numbers as the control group.”

Definitely no

 

Reason: Single blind study.

Definitely no

 

Reason: “Six (16.7%) patients in the study group were excluded from the study, continuing only the reference treatment after taking the first dose of ivermectin, as a mutation was detected in genetic tests affecting ivermectin metabolism.”

Definitely yes

 

Reason: All outcome measures reported at clinicaltrials.gov were mentioned.

Probably no

 

Reason: No adherence to intention-to-treat protocol described; no report of handling missing or incomplete data.

HIGH

Podder, 2020

Definitely no

 

Reason: “Randomisation was done using an odd-even methodology applied to registration numbers, in a consecutive fashion of 1:1 ratio”

Probably no

 

Reason:

“Randomisation was done using an odd-even methodology applied to registration numbers, in a consecutive fashion of 1:1 ratio”

Definitely no

 

Reason:

Open-label study

Definitely no

 

Reason: “Twenty patients were excluded as 18 had symptoms for more than seven days at the time of enrolment and two other patients had insufficient data. “ It is unclear in which groups these patients were randomized.

Probably yes

 

Reason: All outcomes in method section reported, but no trial protocol was published.

Probably yes

 

Reason: not mentioned

HIGH

Ravikirti, 2021

Definitely yes

 

Reason: “A random allocation list of 120 patients was generated using the sealed envelope (an online block randomisation list generating software) (24) and kept with a third person (not a part of the investigation team) prior to the commencement of the trial.”

Definitely yes

 

Reason: “A random allocation list of 120 patients was generated using the sealed envelope (an online block randomisation list generating software) (24) and kept with a third person (not a part of the investigation team) prior to the commencement of the trial.”

Definitely yes

 

Reason: “Once an eligible study participant has provided consent for the trial, the investigation team doctor used to contact the concerned third person having the random allocation list over telephone to know the treatment group (A/B) for that particular patient. One of these two groups was the intervention group, and the other was the placebo group. However, up until the analysis of the data, this information was confined to the pharmacist dispensing the tablets.”

Probably no

 

Reason: 23% in the intervention group and 13% in the control group had no or inconclusive report regarding viral clearance. A relatively large difference in patients discharged before 6th day (9 versus 3) was reported

Probably yes

 

Reason: All outcomes mentioned in Methods were reported

Probably no

 

Reason: 3 randomized patients were not included in the analysis due to low to follow-up or unblinded Ivermectin administering after randomization; no sample size calculation performed.

LOW (other outcome measures)

Some concerns (viral clearance)

Reis, 2022

Definitely yes

 

Reason: An independent pharmacist conducted the randomization

at a central trial facility, from which

the trial sites requested randomization by means

of text message. Patients underwent randomization

by means of a block randomization procedure

for each participating site, with stratification

according to age (≤50 years or >50 years).

Definitely yes

 

Reason: The trial team, site staff, and patients were unaware

of the randomized assignments. Only the pharmacist who was

responsible for randomization was aware of

which letter referred to which assignment.

Definitely yes

 

Reason: The trial team, site staff, and patients were unaware

of the randomized assignments

Definitely yes

 

Reason: Reasons for missing outcome data unlikely to be related to outcome

Definitely yes

 

All outcomes reported in the study protocol were reported in the paper.

Probably yes

 

Reason: The study appears to be free of other sources of bias.

 

LOW

 

 

Shahbaznejad, 2021

Definitely yes

 

Reason: The patients were randomly divided into 2 groups (ivermectin and control) by a simple randomization

method using a table of random numbers.

Probably yes

 

Reason: Neither the participants nor the evaluators

were aware of the randomization process or group

allocation.

Probably no

 

Reason: Blinding of caregivers is unknown: “Neither the participants nor the evaluators were aware of the randomization process or group

allocation.”

Probably no

Reason: 10.5% of the control group withdrew, but 0% of the intervention group

Definitely yes

 

Reason: Description of outcome measures were not always consistent with reported outcome measures; duration of supplemental oxygen with non-invasive ventilation was not reported.

Probably no

 

Reason: possibly selection bias (high % unwilling to participate); no sample size calculation performed; some differences in patient characteristics (including disease severity) at baseline noted; reporting results is inconsistent between text and tables.

Some concerns (mortality)

HIGH (other outcome measures)

Vallejos, 2021

Definitely yes

 

Reason: “through the web-based system using randomly permuted

blocks in a 1:1 ratio”

Definitely yes

 

Reason: “The investigator who performed the randomization was

not involved in the dispensing of the medication, inclusion,

and follow-up of the patients.; Patients were consecutively assigned to the treatment kit in ascending order at inclusion.”

Definitely yes

 

Reason: “The rest of the investigators

were blinded to the treatment received, as were

the patients.”

Definitely yes

Reason: “All 501 patients completed the 30-day

follow-up after the final visit.”

Definitely yes

 

Reason: All outcomes mentioned at clinicaltrials.gov were reported.

Probably no

 

Reason: trials was underpowered for primary outcome; no other problems reported

LOW (mortality)

 

Some concerns (hospitalization, mechanical ventilation, safety)

 

 

 

  1. Randomization: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
  2. Allocation concealment: refers to the protection (blinding) of the randomization process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomization (performed at a site remote from trial location). Inadequate procedures are all procedures based on inadequate randomization procedures or open allocation schedules..
  3. Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments, but this should not affect the risk of bias judgement. Blinding of those assessing and collecting outcomes prevents that the knowledge of patient assignment influences the process of outcome assessment or data collection (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is usually not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary. Finally, data analysts should be blinded to patient assignment to prevents that knowledge of patient assignment influences data analysis.
  4. If the percentage of patients lost to follow-up or the percentage of missing outcome data is large, or differs between treatment groups, or the reasons for loss to follow-up or missing outcome data differ between treatment groups, bias is likely unless the proportion of missing outcomes compared with observed event risk is not enough to have an important impact on the intervention effect estimate or appropriate imputation methods have been used.
  5. Results of all predefined outcome measures should be reported; if the protocol is available (in publication or trial registry), then outcomes in the protocol and published report can be compared; if not, outcomes listed in the methods section of an article can be compared with those whose results are reported.
  6. Problems may include: a potential source of bias related to the specific study design used (e.g. lead-time bias or survivor bias); trial stopped early due to some data-dependent process (including formal stopping rules); relevant baseline imbalance between intervention groups; claims of fraudulent behavior; deviations from intention-to-treat (ITT) analysis; (the role of the) funding body. Note: The principles of an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.
  7. Overall judgement of risk of bias per study and per outcome measure, including predicted direction of bias (e.g. favors experimental, or favors comparator). Note: the decision to downgrade the certainty of the evidence for a particular outcome measure is taken based on the body of evidence, i.e. considering potential bias and its impact on the certainty of the evidence in all included studies reporting on the outcome.  

 

 

Evidence table for intervention studies

 

 

Study reference

Study characteristics

Patient characteristics 2

Intervention (I)

Comparison / control (C) 3

 

Follow-up

Outcome measures and effect size 4

Comments

Abd-Elsalam,

2021

 

NCT04403555

Type of study:

RCT

Open-label study

 

Setting:

Tanta and Assiut

University

Hospitals (tertiary hospitals),

between March

and Oct 2020.

 

Country:

Egypt

 

Source of funding:

Not reported in the article.

 

Conflicts of

interest:

All the authors

declare that there are no conflict of

interests.

Hospitalized patients, mildly to moderately affected

 

Inclusion criteria:

• ages 20 to 65

• mildly to moderately affected

COVID‐19 infection

• confirmed by pharyngeal swab PCR

 

Exclusion criteria:

• allergy or contra-indication to study drugs

• pregnant and lactating mother

• patients with cardiac problem

 

N total at baseline:

N = 164

Intervention: 82

Control: 82

 

Important characteristics:

Age, mean (SD):

I: 42.38 y (16.02)

C: 39.38 y (16.92)

Sex, n/N (%) male:

I: 37/82 (45.1%)

C: 45/82 (54.9%)

 

Groups comparable at baseline?

No significant differences between groups on patients’

characteristics and clinical presentation.

Ivermectin

 

a single dose of oral ivermectin tablets (12 mg) every day for 3 days of treatment according to the Egyptian Ministry of Health (MOH) protocol of COVID‐19 treatment.

Ivermectin tablets (Iverzine tablets,

Unipharma) were used in the study

Standard protocol

 

Standard protocol

 of treatment alone for 14

days.

It included paracetamol,

oxygen, fluids (according to

the condition of the patient), empiric antibiotic,

oseltamivir if needed (75

mg/12 h for 5 days), and

invasive mechanical

ventilation with hydrocortisone for severe cases if PaO2 less than 60 mm Hg, O2 saturation less than 90% despite oxygen

or non-invasive ventilation,

progressive hypercapnia,

respiratory acidosis (pH <

7.3), and progressive or

Refractory septic shock

Length of follow up:

1 month

 

Loss to follow-up:

I: 0/82 (0%)

C: 0/82 (0%)

 

All the patients

continued the study

medications to the

end of the duration of

treatment and follow‐

up.

All-cause mortality within

1 month after random, n (%)

I: 3/82 (3.7%)

C: 4/82 (4.9%)

 

Duration of hospitalization

Length of hospital stay (days), mean ± SD

I: 8.82 ± 4.94

C: 10.97 ± 5.28

 

Time to symptom

resolution

Not reported.

 

Invasive respiratory support

Need for mechanical

ventilation, n (%)

I: 3/82 (3.7%)

C: 3/82 (3.7%)

 

Non-invasive mechanical support

Not reported

 

Adverse events

I: 1x nausea; 2x diarrhea

 

Viral clearance

Not reported.

Primary outcome:

All‐cause mortality within 1 month after randomization

Secondary outcomes:

length of hospital stay, need for mechanical ventilation and safety

 

Authors conclusion:

The usage of ivermectin did not achieve significance for any of the endpoints.

However; there was an observed trend to reducing hospital stay in the ivermectin‐treated group.

These findings may suggest using ivermectin as an add‐on therapy to protocols used for the treatment of COVID‐19. However, these results are

needed to be validated in a larger prospective follow‐up study.

Ahmed, 2020

Type of study:

RCT [pilot, double-blind, placebo-controlled]

 

Setting:

single

 

Country:

Bangladesh

 

Conflicts of interest:

‘The authors have no conflicts of interest to declare.’

‘The authors declare that there are no known competing

financial interests or personal relationships that could have

appeared to influence the work described in this paper.’

 

Source of funding:

“this work was supported by the Beximco Pharmaceutical Limited, Bangladesh”

Hospitalized COVID-19 patients; disease severity unclear

 

For the current summary, only intervention group I (ivermectine alone) was included as intervention group.

 

Inclusion criteria:

  • age 18-65 years
  • admitted to hospital within the last 7 days
  • either fever (≥37.5oC); cough or sore throat
  • diagnosed positive for SARS-CoV-2 by rRT-PCR

 

Exclusion criteria:

  • allergic to or had a potential drug-drug interaction for ivermectin or doxycycline
  • chronic illnesses (e.g., ischemic heath disease, heart failure, documented cardiomyopathy, chronic kidney disease, chronic liver disease);
  • received ivermectin and/or doxycycline in the last 7 days;
  • pregnant or lactating;
  • participated in any other clinical trial within last month.

 

N total at baseline:

N = 72

Intervention-I: 23

Control: 23

 

Important characteristics, total group:

Age, mean (SD): 42 years

Sex, female (%): 54%

Time ill before assessment, mean: 3.83 days

 

Fever at enrolment, n/N (%):

I: 1/22 (77.3%)

C: 19/23 (82.6%)

 

Cough at enrolment, n/N (%):

I: 18/22 (81.8 %)

C: 15/23 (65.2%)

 

Sore throat at enrolment, n/N (%)

I: 4/22 (18.2%)

C: 4/23 (17.4%)

 

Unclear whether groups were comparable at baseline

No data per group was provided except for data extracted to this table. Cough (%) at enrolment was 65% in the control group vs. 82% in the intervention groups. It is unclear whether other baseline characteristics differed.

“The pre-treatment characteristics (demographics, clinical history, comorbidity and laboratory values) were comparable among the three treatment groups”

 

Ivermectine or in combination with doxycycline

 

I: oral ivermectin alone (12 mg once daily, for 5 days)

Placebo

 

Standard of care not reported

Length of follow up:

14 days

 

Viral clearance: Nasopharyngeal swabs were obtained to confirm the presence of SARS-CoV-2 using rRT-PCR on the day of enrolment, and then on day 3, 7, and 14. After day 14, patients were followed-up weekly until found test negative.

 

Loss to follow-up:

I: 2/23 (8.7%)

C: 1/23 (4.3%)

Reasons: due to family obligations and unwillingness to test further

All-cause mortality.

Announced in methods, but not reported

 

Invasive respiratory support

Not reported

 

Non-invasive respiratory support

Failing to maintain an SpO2 >93% despite oxygenation; & Days on oxygen support:

None of the patient enrolled required oxygen…”

 

Duration of hospitalization

I: 9.6 days (CI= 7.7 - 11.7)

C: 9.7 days (CI 8.1 - 11.0)

 

Time to symptom resolution

Remission of fever (≥37.5oC) within 7 days.

I: 17/17 (100%)

C: 16/19 (84.2%)

Remission of cough within 7 days.

I: 7/18 (61.1%)

C: 9/15 (40%)

Remission of sore throat within 7 days.

I: 3/4 (75%)

C: 3/4 (75%)

Note: Unclear which patients groups were used to calculate these numbers

 

Safety

Adverse events

“None of the patient enrolled required oxygen or had serious adverse drug events recorded.”

I: 0

C: 0

Discontinuation of the study drug during the trial

Announced in methods, but not reported

 

Virological outcomes

Time tor virological clearance (negative RT-PCR result on nasopharyngeal swab), median (CI)

I:  9.7 days (CI= 7.8 - 11.8)

C: 12.7 days (CI= 11.3 - 14.2)

Day 7

I vs. C: HR 4.1 (CI 1.1 - 14.7)

Day 14

I vs. C: HR 2.3 (CI 0.6 - 9.0)

 

Primary outcomes:

time required for virological clearance (negative nasopharyngeal swab), remission of fever (≥37.5 C) and cough within 7 days.

Secondary outcomes: failure to maintain an SpO2 >93% despite

Oxygenation, days on oxygen support, duration of hospitalization, all-cause mortality, drug safety (adverse events and

discontinuation of study drug)

 

Remarks:

  • No baseline data per group provided
  • No information about disease severity provided.
  • Patients could be hospitalized up to 7 days before enrolment in the study; it was reported that participants were “ill on average 3.83 days before assessment”, but no definition of ‘ill’ was provided.
  • Unclear how missing data were handled and whether analyses were performed according to intention-to-treat protocol
  • The role of funder Beximco Pharmaceutical Limited (BPL) was not described

 

Authors conclusion:

Although the study sample was too small (n=72) to make any solid conclusions, the results

provide evidence of the potential benefit of the early intervention with the drug ivermectin for

the treatment of adult patients diagnosed with mild SARS-CoV-2. First, early intervention

promoted faster viral clearance during disease onset which might have prevented significant

immune-system involvement and speed recovery. Secondly, early intervention reduced the viral load faster, thus may help block disease transmission in the general population. A larger randomized controlled clinical trial of ivermectin treatment appears to be warranted to validate these important findings

 

 

 

Buonfrate, 2022

Type of study:

Phase 2, dose-finding,

randomized,

double-blind,

placebo-controlled trial

 

Setting:

Non hospital based, between

July 31, 2020 and

May 26, 2021

 

Country:

4 centres in the

United States

 

Source of funding:

InsudPharma &

Mundo Sano

donated the study

medication. Alpine Lions Cooperation

contributed to the study. The study was partly funded by the Italian Ministry of Health “Fondi Ricerca Corrente” to IRCCS Sacro Cuore Don

Calabria Hospital.

 

Conflicts of

interest:

None to declare.

 

 

Non-hospitalized patients with

recently diagnosed COVID-19

 

Inclusion criteria:

• age ≥ 18 y

• positive RT-PCR test

(nasopharyngeal swabs)

• COVID-19 Severity Score < 3

• patient able to take oral drugs

 

Exclusion criteria:

• pregnant or lactating women

• suffering from known CNS disease

• patient under dialysis

• any severe medical condition with a prognosis <6 months

• patients under warafin or antiviral treatment

• patients under chloroquine phosphate or hydroxychloroquine

 

N total at baseline:

Randomized: N = 93

Intervention B: N = 29

Intervention C: N = 32

Control A: N = 32

 

Important characteristics:

Age, median (range):

I (B): 47.0 y (31.0-62.0)

I (C): 44.5 y (31.0-55.5)

C (A): 50.0 y (26.0-57.0)

 

Sex, n/N (%) female:

I (B): 14/29 (48.3%)

I (C): 8/32 (25.0%)

C (A): 17/32 (53.1%)

An imbalance in the sex ratio is observed.

Ivermectin with or without placebo

 

I: Intervention B: Single dose ivermectin 600

μg/kg plus placebo for 5 days

 

II: Intervention C: Single dose ivermectin

1200 μg/kg for 5 days

Placebo (A)

Identical in appearance to Ivermectin for 5 days

 

 

Length of follow-up:

30 days

 

Loss-to-follow-up or

incomplete data:

I (B): 3/29 (10.3%)

II (C): 13/32 (40.6%)

C (A): 2/32 (6.2%)

 

Clinical outcomes

Mortality

Not reported

 

Hospitalisation

I (B+C): 4/59 (6.8%)

C: (A): 0/32 (0%)

RR 4.95 [0.27, 89.13]

RD 0.07 [-0.01, 0.15]

 

Time to symptom resolution

Time to clinical resolution*, reported in symptomatic patients; (80 participants); median (IQR) days

I (B): 29 days (IQR 13.5–32.0

II: 14 days (IQR 7–37)

C (A): 14 days (IQR 13–30)

 

Invasive respiratory support

Not reported

Non-invasive respiratory support

Not reported

 

Safety

Concerning adverse event

(hospitalization for

worsening of the disease)

I (B): 1/29 (3.4%)

I (C): 3/32 (9.4%)

C (A): 0/32 (0%)

AEs and SAES are specified in the article.

No SADRS were reported

I: 0

II: 0

C: 0

 

Virological outcomes

Differences in viral load

decline from baseline to 7

days (Log10) (mean, SD)

I (B): 2.5 (2.2), p=0.122

I (C): 2.0 (2.1), p=-0.099

C (A): 2.9 (1.6) ref

I vs. C:

HR 0.69 (95% CI 0.36 to 1.32)

II vs. C:

HR 0.79 (95% CI 0.42 to 1.47)

Primary outcomes:

number of serious adverse drug reactions (SADRs); and change in viral load at day 7

Secondary outcomes:

trend over time in quantitative

viral load at days 7, 14 and 30; time to clinical resolution

(TCR) (if symptomatic); proportion of participants with virological clearance at days 14 and 30; hospitalisation rate; and COVID-19 severity score at days 14 and 30

 

* time from randomisation to clinical resolution or death; clinical resolution not further specified

 

Remarks:

-recruitment was stopped, because of a dramatic drop of cases

-High drop out was observed in the high dosage treatment group due to intolerability

 

Authors conclusion:

-High-dose ivermectin demonstrated safe.

-There was no significant difference in viral load reduction between study arms

-Mild/moderate side effects were more frequent with the highest dose of ivermectin

Chaccour, 2021

Type of study:

RCT; pilot,

double-blind, placebo-controlled

 

Setting:

ER of the Clínica Universidad de Navarra; July 31, 2020 - Sept 11, 2020

 

Country:

Spain

 

Source of funding:

Funding: ISGlobal, Barcelona Institute for Global Health and Clínica Universidad de Navarra;

 

Conflicts of interest

“JLDP reports speaker fees from Pfizer and MSD as well as research

grants from Novartis, outside the scope of the submitted work. No other competing interests were disclosed”

Outpatients attending ER

with symptoms compatible with COVID-19

 

Inclusion criteria:

  • symptoms compatible with COVID-19
  • 18-60y of age
  • Resident of Pamplona basin
  • ≤72 h of fever or cough
  • positive PCR for SARS-CoV-2

 

Exclusion criteria:

  • positive IgG against SARS-CoV-2
  • comorbidities considered risk factors for severe disease
  • COVID-19 pneumonia, as diagnosed by the attending physician and identified in a chest X-ray
  • Known history of ivermectin allergy
  • Hypersensitivity to any component of ivermectin
  • Recent travel history to countries endemic for Loa loa
  • Current use of CYP 3A4 or P-gp inhibitor drugs

 

N total at baseline:

N = 24

Intervention: 12

Control: 12

 

Important characteristics:

Age, median (IQR)[range] (years)

I: 26 (19-36) [18-54]

C: 26 (21-44) [18-54]

Sex, n/N (%) male:

I: 7 (58%)

C: 5 (42%)

BMI, median (IQR) [range] kg/m2

I: 23.5 (19.6-27.8) [18.6-29. 9]

C: 22.9 (21.0-24.8) [19.3-29.9]

 

Groups comparable at baseline?

More females in intervention group.

Ivermectine

 

400 mcg/kg single oral dose or placebo

 

The dose of ivermectin will be given using scales for tailored administration according to their weight, using tablets of 3mg. The individual dose will range from 400 mcg/kg to a maximum of 457 mcg/kg.

 

Placebo

 

Standard of care not described

Length of follow up:

28 days

 

Loss to follow-up:

I: 0:

C: 0

 

Missing data:

Carried over from last observation; seems to concern mostly symptom data; unclear which data and whether proportions were similar between groups

All-cause mortality, 28d

I: 0

C: 0

 

Duration of hospitalisation

Not applicable

 

Time to symptom resolution

Symptoms

Reported in supplement for day 1, 7, 14; described in publication:

“There were no major differences in the evolution of vital signs (Table S3), inflammatory markers (C reactive protein, procalcitonin, ferritin and IL-6) and rest of laboratory parameters of patients in each group (Table S4)”

Progression to severe disease or death during the trial

I: 0/12

C: 0/12

 

Invasive respiratory support

Not reported

Primary outcome

proportion of patients with detectable SARS-CoV-2 RNA by PCR from nasopharyngeal swab at day 7 post-treatment.

Secondary outcomes

viral load at days 4, 7, 14 and 21 post treatment; proportion of patients with symptoms (particularly fever and cough) at days 4, 7, 14 and 21 post-treatment as well as proportion of patients progressing to severe disease or death during the trial; proportion of patients with seroconversion at day 21 post-treatment and proportion of drug-related adverse events

 

Remarks:

  • Relatively young patients (range 18-54y)
  • “In the analysis of the symptoms reported by patients (symptom diary), missing data was carried over from the last data available.”
  • More females in intervention group

 

Authors conclusion:

Among patients with non-severe COVID-19 and no risk factors for severe disease receiving a single 400 mcg/kg dose of ivermectin within 72 h of fever or cough onset there was no difference in the proportion of PCR positives. There was however a marked reduction of self-reported anosmia/ hyposmia, a reduction of cough and a tendency to lower viral loads and lower IgG titers which warrants assessment in larger trials.

Chachar, 2020

Type of study:

RCT; open-label

 

Setting:

Single center; Fatima Memorial Hospital

 

Country:

Pakistan

 

Source of funding:

Not reported

 

Conflicts of interest:

Not reported

 

Outpatients with mild, RT-PCR confirmed COVID-19

 

Inclusion criteria

  • diagnosed with COVID-19 infection
  • RT-PCR test positive for SARSCov-2
  • willing to participate
  • age 18-75 years
  • mild symptoms
  • Ability to take oral medication
  • Willing to adhere to drug intake regimen

 

Exclusion criteria

  • Known severe allergic reactions to Ivermectin
  • Pregnancy or breastfeeding
  • Severe symptoms likely attributed to Cytokine Release Storm
  • Malignant diseases
  • Chronic kidney disease
  • Cirrhosis liver with Child class B or C

 

N total at baseline

N = 50

Intervention: 25

Control: 25

 

Important characteristics:

Age, mean ±SD:

I: 40.60 ± 17y

C: 43.08 ± 14.8y

 

Sex, n/N (%) male:

I: 17/25 (68%)

C: 14/25 (56%)

 

Groups comparable at baseline?

Symptoms at baseline not all comparable between groups (e.g. loss of taste or smell, vomiting, cough)

 

 

Ivermectin

 

Patients were prescribed Ivermectin 12mg stat and then 12 mg after 12 hours and 12mg after 24 hours

No ivermectin

 

Standard of care not described, ‘symptomatic treatment without ivermectin’

 

Length of follow-up:

7 days

 

Loss-to-follow-up & incomplete outcome data:

No loss to FU or missing data reported

Mortality (28-30 day)

Not reported

 

Duration of hospitalization

Not reported.

 

Time to symptom resolution

Asymptomatic at day 7

I: 16/25 (64%)

C: 15/25 (60%)

 

Invasive respiratory support

Not reported.

Primary outcome

Not specified

Secondary outcomes

Not specified

 

Remarks:

-

 

Authors conclusion:

Statistically there was no significant difference between case group who were given ivermectin along with

symptomatic treatment and control group who were only given symptomatic treatment without ivermectin, being

asymptomatic on day 7 at follow up.

Gonzalez, 2022

Type of study:

Double-blind, placebo-controlled, randomized clinical trial

 

Setting:

Hospitalized, August 2020

 

Country:

Mexico

 

Source of funding:

Centenario Hospital Miguel Hidalgo

 

Conflicts of interest:

The authors declare no conflict of interest

 

 

Hospitalized COVID-19 patients without severe respiratory failure.

 

Inclusion criteria:

  • 16 years to 90 years
  • RT-PCR-or antigen test confirmed COVID-19
  • Pneumonia, diagnosed by

 an X-ray or high-resolution chest CT scan

  • Recently established hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heart disease

 

Exclusion criteria:

  • Requiring high oxygen volumes
  • Predictors of a poor response to high-flow oxygen nasal prong therapy
  • Requiring mechanical ventilation

 

N total at baseline:

N = 106*

Intervention: N=36

Control: N=37

 

Important characteristics:

Age, mean (SD):

I: 56 y (16.5)

C: 53.8 y (16.9)

 

Sex, n/N (%) male:

I: 21/36 (58.3%)

C: 23/37 (62.1%)

 

Disease severity

Not reported

 

Groups comparable at baseline?

Yes

 

ivermectin,

12 mg or 18 mg, according to patient weight

 

The dose of ivermectin was 12 mg in patients

weighing less than 80 kg and 18 mg in those above 80 kg

 

All hospitalized patients received pharmacological thromboprophylaxis with low

molecular weight heparin or unfractionated heparin according to local and international

guidelines, dexamethasone (based on the RECOVERY trial)

 

Placebo:

calcium citrate was chosen as a placebo and was administered as

2 tablets every 12 h on the first day, followed by one tablet every 12 h for the following

4 days.

 

All hospitalized patients received pharmacological thromboprophylaxis with low

molecular weight heparin or unfractionated heparin according to local and international

guidelines, dexamethasone (based on the RECOVERY trial)

 

 

 

 

 

 

 

 

Length of follow-up:

28 days

 

Incomplete outcome data & loss-to-follow-up:

Not reported

 

 

Clinical outcomes

Mortality:

I: 5/36 (13.8%)

C: 6/37 (16.2%)

 

Duration of hospitalization

Median (IQR)

I: 6 (4-11)

C: 5 (4-7)

 

Time to symptom resolution

Discharge without respiratory deterioration or death

I: 27/36 (75%)

C: 27/37 (72.9%)

 

Invasive respiratory support

Not reported

 

Non-invasive respiratory support

Not reported

 

Safety

Serious adverse events

Not reported

 

Virological outcomes

Viral clearance

They were unable to determine whether the SARS-CoV-2 PCR tests

became negative, due to the lack of reactants and the minimal usefulness of proving its negativity from a clinical-practical viewpoint.

 

Primary outcome:

  • Median days of hospital stay
  • Rate of respiratory deterioration, requirement of invasive mechanical ventilation or dead

 

Secondary outcome(s):

  • Mean time to negative viral PCR

 

Definitions:

-

 

Remarks:

*33 patients were allocated to group 1 (hydroxychloroquine). This group is not included in this summary of findings table.

 

Patients were classified as high- or low-risk for the development of QT interval prolongation due to hydroxychloroquine according to their electrocardiogram. The QT interval was measured with Bazett’s formula. Patients with an interval of ≥500 ms were randomized

to ivermectin or placebo, while those with an interval of <500 ms were randomized to

ivermectin, hydroxy-chloroquine, or placebo.

 

Authors conclusion:

In non-critically ill, hospitalized patients with pneumonia secondary to COVID-19, the use of hydroxychloroquine or ivermectin did not decrease significantly the number of

hospitalization days, respiratory deterioration, or deaths.

Kishoria, 2020

Type of study:

RCT; open-label

 

Setting:

Single center;

 

Country:

India

 

Source of funding:

Not reported

 

Conflicts of interest:

Not reported

Hospitalized patients with mild, RT-PCR confirmed COVID-19

 

Inclusion criteria

  • men or women,
  • aged ≥ 18 years;
  • tested positive after completion of standard care
  • treatment for SARS-CoV-2 confirmed by RT-PCR assay;
  • mild symptoms or asymptomatic;
  • no comorbidities affecting the patient's prognosis, rendering them at high risk;
  • documented acceptance to participate by means of the execution of the informed consent

 

Exclusion criteria

  • allergy or hypersensitivity to ivermectin or its inactive ingredients, or both;
  • respiratory distress or requiring intensive care;
  • used immunosuppressants (including systemic corticosteroids) in the last 30 days;
  • known HIV infection with CD4 count < 300 cell/L;
  • pregnancy or lactating women;
  • medical conditions such as mal-absorption syndromes affecting proper ivermectin absorption;
  • autoimmune disease or decompensated chronic diseases, or both;
  • uncontrolled, intercurrent diseases including renal impairment, hepatic impairment, symptomatic congestive heart failure, unstable chest angina, or heart arrhythmia;
  • treated in any other study in the previous 30 days;
  • concomitant administration of enzyme inducers (such as carbamazepine) that could affect effectiveness of the drug and people receiving CYP3A4 substrates (such as statins) due to risk of increased toxicity

 

N total at baseline

N = 35 randomized / 32 analyzed

Intervention: 19

Control: 16 / 13

 

Important characteristics:

Age, n (%):

21-40 y

 I: 08(42.2%)

 C: 09(69.2%)

41-60 y

 I: 07(36.8%)

 C: 03(23.1%)

 

Sex, n/N (%) male:

I: 14 (73.7%)

C: 9 (69.3%)

 

Groups comparable at baseline? Patients in the control group are more often younger.

 

Ivermectin + SoC

 

Ivermectin: 12 mg, single dose

 

Standard of care (SoC)

 

SoC included hydroxychloroquine, vitamin C, and paracetamol

Length of follow-up:

6 days

 

Loss-to-follow-up & incomplete outcome data:

Discrepancy between randomized patients (n=35) and patients in analysis (N=32)

Mortality (28-30 day)

Not reported

 

Duration of hospitalization

Discharged at day 6

I: 8/19 (42.2%)

C: 6/13 (46%)

 

Time to symptom resolution

Not reported

 

Invasive respiratory support

Not reported.

Primary outcome

negative throat swab report for

SARS-CoV-2 conducted by RT-PCR after 48 hour

Secondary outcomes

Not specified

 

Remarks:

-trial not registered

-inconsistencies in the report of number of patients; not further explained

 

Authors conclusion:

In summary, this open label randomized study of patients with COVID-19 found that the use of a regimen containing

hydroxychloroquine and ivermectin was associated with no evidence of benefit in comparison to hydroxychloroquine alone.

Krolewiecki, 2020

 

NCT04381884

Type of study:

Pilot, multicenter, randomized, open label, outcome assessor blinded, controlled study.

 

Setting:

4 hospitals in the metropolitan area of Buenos Aires, between May 18 and September 9, 2020

 

Country:

Argentina

 

Source of funding:

This work was supported by grant IP-COVID-19-625 from Agencia Nacional de Promocion de la Investigaci on, el Desarrollo Tecnol ogico y la Innovacion, Argentina and Laboratorio ELEA/Phoenix, Argentina.

 

Conflicts of interest:

All other authors declare no competing interests.

Hospitalized patients with COVID-19

 

Inclusion criteria:

  • Aged 18 to 69 years-old;
  • RT-PCR confirmed infection;
  • Hospitalized and not requiring intensive care;
  • COVID-19 symptoms onset 5 days at recruitment;
  • Absence of use of drugs with potential activity against SARS-CoV-2 (hydroxychloroquine, lopinavir, remdesivir and azithromycin); and those drugs were not permitted during the first week of the trial.

 

Exclusion criteria:

  • The use of immunomodulators within 30 days of recruitment;
  • Pregnancy;
  • Breast feeding;
  • Poorly controlled comorbidities.
  • Patients of child-bearing age (men and women) were eligible if agreed to take effective contraceptive measures during the study period and for at least 30 days after the last study drug administration.

N total at baseline:

N = 45

Intervention: 30

Control: 15

 

Important characteristics:

Age, mean (SD):

I: 42.3 y (12.8)

C: 38.1 y (11.7)

P=0.29

 

Sex, n/N (%) male:

I: 15/30 (50%)

C: 10/15 (66.7%)

P=0.29

 

Disease severity, mean (SD):

Defined by WHO-ordinal scale

3: hospitalized, no oxygen therapy

I: 29/30 (97%)

C: 13/29 (87%)

P=0.20

 

4: oxygen by mask or nasal prongs

I: 14/30 (47%)

C: 6/15 (40%)

P=0.20

 

Groups comparable at baseline?

Yes.

Oral Ivermectin + standard of care

 

Patients in the IVM group received oral treatment for 5 consecutive days with either breakfast or lunch at approximately 24 h intervals. IVM 6 mg ranurated tablets (IVER P, Laboratorios Elea/ Phoenix, Argentina) were used in all cases at a dose of 600 μg/kg/day based on baseline weight rounding to the lower full (6 mg) and half (3 mg) dose.

 

Standard of care included hospitalization of all symptomatic cases, but is not further specified.

Standard of care

 

Standard of care included hospitalization of all symptomatic cases, but is not further specified.

Length of follow-up:

30 days

 

Loss-to-follow-up:

Intervention:

N=1 (3.7%)

Reasons: missed visit on day-30.

 

N=2 withdrew consent (excluded from efficacy analysis).

 

Control:

N=1 (6.7%)

Reasons: discontinued on day-5 (administration of medication not allowed) (included in the efficacy analysis).

 

Incomplete outcome data:

Intervention:

None.

Mortality at day 30 day

No deaths occurred through the study period.

 

Duration of hospitalization

Not reported.

 

Time to symptom resolution

not reported

 

Invasive respiratory support

Not reported.

Primary outcome

difference in SARS-CoV-2 viral load between baseline and day 5

 

Secondary outcomes

clinical evolution at days 7 and 30, relationship between ivermectine plasma concentrations and the primary outcome, and frequency and severity of adverse events

 

Remarks:

The most frequent adverse event and the only experienced by more than 1 case in the IVM group was rash in 3 (10%) cases (all mild, selflimited and lasting approximately 24 h); in the control group, single events of abdominal pain, dizziness, anxiety, anguish, and hyperglycemia (all mild) were reported.

 

The sponsors of the study participated in study design, but had no

role in primary data collection, data analysis, data interpretation,

writing of the report, or the decision to submit for publication.

 

Authors conclusion:

In summary, our findings support the hypothesis that IVM has a concentration dependent antiviral activity against SARS-CoV-2 and provides insights into the type of evaluations to be considered in the assessment of antiviral drugs for the control of COVID-19. Follow-up trials to confirm our findings and to identify the clinical utility of IVM in COVID-19 are warranted.

Lim, 2022

 

NCT04920942

Type of study:

Open-label multicenter randomized controlled clinical trial

 

Setting:

21 sites, between May 31, 2021, and October 25, 2021

 

Country:

Malaysia

 

Source of funding:

Not reported

 

Conflicts of interest:

None

 

 

 

 

 

 

Hospitalized patients with mild or moderate disease at admission

 

Inclusion criteria:

  • SRT-PCR or antigen test confirmed COVID-19 cases
  • <50 years with at least 1 comorbidity
  • Presented with mild to moderate illness (WHO clinical progression scale 2-4) within 7 days from symptom onset

 

Exclusion criteria:

  • Asymptomatic patients
  • Oxygen required patients
  • SPO2 <95% at rest
  • Severe hepatic impairment, acute medical or surgical impairment, concomitant viral infection
  • Pregnancy or breastfeeding
  • Warfarin therapy
  • History of taking ivermectin or any antiviral drugs with reported activity against COVID-19 (i.e. favipiravir, hydroxychloroquine etc).

 

N total at baseline:

N = 500

Intervention: N=250

Control: N=250

 

Important characteristics:

Age, mean (SD):

I: 63.0 y (8.9)

C: 62.0 y (8.4)

 

Sex, n/N (%) male:

I: 111/241 (46.1%)

C: 112/249 (45.0%)

 

 

Disease severity:

Defined by WHO scale 2-4) n/N (%):

Mild:

I: 83/241 (34.4%)

C: 84/249 (33.7%)

 

Moderate:

I: 158/241 (65.6%)

C: 165/249 (66.3%)

 

Groups are comparable at baseline

Ivermectin 0.4mg/kg/day for 5 days

 

+

 

Standard care

The standard

of care for patients with mild to moderate disease consisted

of symptomatic therapy and monitoring for signs of early deterioration

based on clinical findings, laboratory test results,

and chest imaging.

 

Length of follow-up:

28 days

 

Incomplete outcome data & loss-to-follow-up:

Intervention:

N=9 (3.6%)

Reasons: Did not fulfil inclusion criteria (N=2), met exclusion criteria identified after randomization (N=1) or withdrew from study (N=6)

 

232/241 (96.3%) completed 5 doses

 

3 withdrew from study owing to adverse events after taking ivermectin

 

241 included in the modified intention-to-treat analysis

 

Control:

N=1 (0.4%)

Reason: Excluded due to exclusion criteria after randomization

 

249 included in the modified intention-to-treat analysis

 

Clinical outcomes

Mortality (28 day):

Mortality, n/N (%):

I: 3/241 (1.2%)

C: 10/249 (4.0%)

RR 0.31 (95% CI 0.09-1.11). p=0.09

 

Duration of hospitalization

ICU stay, mean (SD):

I: 7.7 days (4.4)

C: 7.3 days (4.3)

P=0.38

 

Time to symptom resolution

Complete symptom resolution at day 5, n/N (%)

I: 122/238 (51.3%)

C: 131/247 (4.0%)

RR 0.97 (95% CI 82-1.15). p=0.72

 

Invasive respiratory support

Mechanical ventilation rate, n/N (%)

I: 4/241 (1.7%)

C: 10/249 (4.0%)

RR 0.41 (95% CI 0.13-1.30). p=0.17

 

Safety

Serious adverse events, n/N (%)

I: 4/241 (1.7%)

C: 1/249 (0.4%)

 

A detailed record of all adverse events is reported in the article.

 

Virological outcomes

Viral clearance

Not reported

Primary outcome:

Proportion of patients who progressed to severe COVID-19

 

Secondary outcome(s):

Time to progression to severe disease, 28-day in-hospital all-cause mortality, mechanical ventilation rate, ICU admission, length of hospital stay after enrolment, adverse events and serious adverse events

Patients were also assessed on day 5 of enrollment for symptom resolution, changes in laboratory test results, and chest radiography findings

 

Definitions:

  • Progression is defined as the hypoxic stage requiring supplemental oxygen to maintain SPO2 95% or greater (Malaysian COVID-19 clinical severity stages 4 or 5; WHO clinical progression scale 5-9)
  • Adverse events and serious adverse events were graded according to the Common Terminology Criteria for Adverse Events version 5.0

 

Remarks:

  • The study was not designed to assess the effects of ivermectin on mortality from COVID-19
  • Open-label trial

 

 

Authors conclusion:

In this randomized clinical trial of high-risk patients with mild to moderate COVID-19, ivermectin treatment during early illness did not prevent progression to severe disease. The study

findings do not support the use of ivermectin for patients with COVID-19.

 

López-Medina, 2021

Type of study:

Single-center, double-blind, randomized, placebo-controlled trial

 

Setting:

Centro de Estudios en Infectología Pediátrica in Cali, between July 15 to December 21, 2020.

 

Country:

Colombia

 

Source of funding:

This study received an unrestricted grant from Centro de Estudios en Infectología Pediátrica (grant ScDi823).

 

Conflicts of interest:

Dr López-Medina reported receiving grants from Sanofi Pasteur, GlaxoSmithKline, and Janssen and personal fees from Sanofi Pasteur during the conduct of the study. Dr López reported receiving grants from Sanofi Pasteur, GlaxoSmithKline, and Janssen and personal fees from Sanofi Pasteur during the conduct of the study. Dr Oñate reported receiving grants from Janssen and personal fees from Merck Sharp & Dohme and Gilead outside the submitted work. Dr Torres reported receiving nonfinancial support from Tecnoquímicas unrelated to this project during the conduct of the study.

COVID patients with mild disease (i.e., being at home or hospitalized but not receiving high-flow nasal oxygen or mechanical ventilation (invasive or noninvasive)

 

Inclusion criteria:

  • positive result from a SARS-CoV-2 reverse transcriptase-polymerase chain reaction or antigen test
  • adult men and non–pregnant or breast-feeding women
  • symptoms began within the previous 7 days
  • mild disease

 

Exclusion criteria:

  • asymptomatic
  • severe pneumonia
  • received ivermectin within the previous 5 days
  • hepatic dysfunction or liver function test results more than 1.5 times the normal level

 

N total at baseline:

N = 398

Intervention: 200

Control: 198

 

Important characteristics:

Age, median (IQR), y:

I: 37 y (29-47.7)

C: 37 y (28.7-49.2)

 

Sex, n/N (%) male:

I: 78/200 (39%)

C: 89/198 (44.9%)

 

Disease severity, n/N (%):

Defined by score at ordinal scale at randomization

1: Not hospitalized and no limitation of activities

I: 123/200 (61.5%)

C: 109/198 (55.0%)

2: Not hospitalized, with limitation of activities,

home oxygen requirement, or both

I: 75/200 (37.5%)

C: 87/198 (43.9%)

3: Hospitalized, not requiring supplemental oxygen

I: 1/200 (0.5%)

C: 1/198 (0.5%)

4: Hospitalized, requiring supplemental oxygen (i.e., not high-flow nasal oxygen nor

mechanical ventilation)

I: 1/200 (0.5%)

C: 1/198 (0.5%)

 

Groups comparable at baseline?

Patients in both groups were balanced in demographic and disease characteristics at baseline.

ivermectin

300 μg/kg of body weight per day of oral ivermectin in solution or the same volume of placebo for 5 days.

 

Ivermectin was provided by Tecnoquímicas SA in bottles of 0.6% solution for oral administration.

 

Patients were asked to take the investigational product on an empty stomach, except on the first study day, when it was administered after screening and randomization procedures took place.

placebo

up to August 26, 2020, the placebo was a mixture of 5%dextrose in saline and 5% dextrose in distilled water, after which placebo was a solution with similar organoleptic properties to ivermectin provided by the manufacturer.

Length of follow up:

21 days

 

Loss to follow-up:

476 patients underwent randomization: 238 randomized to ivermectin, 238 randomized to placebo.

I: 38/238 (16.0%)

Reasons:

Excluded from primary analysis

due to error in labeling from

September 29 to October 15, 2020

C: 40/238 (16.8%)

Reasons:

Error in labeling from September 29 to October 15, 2020 (including 1 who met exclusion criteria identified after randomization)

Clinical outcomes

Mortality at day 21

I: 0/200 (0%)

C: 1/198 (0.5%)

 

Duration of hospitalization

Not reported.

 

Time to symptom resolution

Time to resolution of symptoms

Days, median (IQR)

I: 10 (9-13)

C: 12 (9-13)

Absolute difference -2 (95% CI -4 to 2)

HR 1.07 (95% CI 0.87 to 1.32)

 

Symptoms resolved at day 21

I: 164/200 (82.0%)

C: 156/198 (79.0%)

Absolute difference 3.21 (95%CI -4.58 to 11.01)

OR 1.23 (95% CI 0.75 to 2.01)

 

Invasive respiratory support

Not reported

 

 

Definitions:

*8-category ordinal scale:

0 = no clinical evidence of infection; 1 = not hospitalized and no limitation of activities; 2 = not hospitalized, with limitation of activities, home oxygen requirement, or both; 3 = hospitalized, not requiring supplemental oxygen; 4 = hospitalized, requiring supplemental oxygen; 5 = hospitalized, requiring nasal high-flow oxygen, noninvasive mechanical ventilation, or both; 6 = hospitalized, requiring extracorporeal membrane oxygenation, invasive mechanical ventilation, or both; and 7 = death.

 

Time to recovery was defined as the first day during the 21 days of follow-up in which the patient reported a score of 0.

Primary outcome

time from randomization to complete resolution of symptoms within the 21-day follow-up period

 

Secondary outcomes

proportion of patients with clinical deterioration, clinical conditions on days 2, 5, 8, 11, 15, and 21 (data for days 2 and 15 are not reported), proportion of patients who developed fever, duration of fever since randomization, proportion of patients who died, proportions of patients with new-onset hospitalization in the general ward or intensive care unit or newonset supplementary oxygen requirement for more than 24 hours were combined into a single outcome called escalation of care, frequency of incident cases and duration of escalation of care, adverse events (AEs) leading to treatment discontinuation, and serious AEs

 

Remarks:

  • The primary outcome was originally defined as the time from randomization until worsening by 2 points on the 8-category ordinal scale. Before the interim analysis, it became apparent that the pooled event rate of worsening by 2 points was substantially lower than the initial 18% expectation, requiring an unattainable sample size. Therefore, on August 31, 2020, the principal investigator proposed to the data and safety monitoring board to modify the primary end point to time from randomization to complete resolution of symptoms within the 21-day follow-up period.

 

Deterioration by ≥2 points

in an ordinal 8-point scale was reported as a secondary outcome in the paper.

 

  • The study population was relatively young, with few comorbidities and with liver enzyme levels less than 1.5 times the normal level, so the findings may be generalizable only to such populations.

 

Authors conclusion:

Among adults with mild COVID-19, a 5-day course of ivermectin initiated in the first 7 days after evidence of infection, compared with placebo, did not significantly improve the time to resolution of symptoms. The findings do not support the use of ivermectin for treatment of mild COVID-19, although larger trials may be needed to understand the effects of ivermectin on other clinically relevant outcomes.

Mohan, 2021

 

CTRI/2020/06/026001

Type of study:

Single-center, pilot, double-blind, randomized, placebo-controlled trial

 

Setting:

National Cancer Institute, All India Institute of Medical Sciences, New Delhi, between July 28 and September 29, 2020.

 

Country:

India

 

Source of funding:

The trial was supported by the Science and Engineering Research Board, Department of Science and Technology, Government of India. The funder had no role in study design, data collection, data analysis or writing of the report. The corresponding author had full access to the study data and had the final responsibility for the decision to submit for publication.

 

Conflicts of interest:

None to declare.

Hospitalized patients with non-severe COVID-19

 

Inclusion criteria:

  • age > 18 y
  • admitted at the trial site
  • diagnosed with nonsevere COVID-19, i.e., room air saturation (SpO2) >90%, and with no hypotension or requirement of mechanical ventilation
  • diagnosis of COVID-19 was based on a positive result on either SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) or a rapid antigen test

 

Exclusion criteria:

  • no informed consent given
  • pregnancy or lactation
  • known hypersensitivity to ivermectin
  • chronic kidney disease with creatinine clearance <30 mL/min
  • elevated transaminase levels (>5X upper limit of normal)
  • myocardial infarction or heart failure within 90 days prior to enrolment
  • prolonged corrected QT interval (>450 ms)
  • any other severe comorbidity as per investigator’s assessment
  • enrolment in another clinical trial

 

N total at baseline:

Randomized: N=157

ITT population: N=152

Intervention 1: N=49

Intervention 2: N=51

Control: N=52

 

mITT population: N=125

Intervention 1: N=40

Intervention 2: N=40

Control: N=45

 

Important characteristics:

Age, mean (SD), y:

I1: 36.3 y (10.54)

I2: 34.3 (10.45)

C: 35.3 y (10.52)

 

Sex, n/N (%) male:

I1: 35/40 (57.5%)

I2: 37/40 (92.5%)

C: 39/45 (86.7%)

 

Disease severity, n/N (%):

Mild

I1: 27/40 (67.5%)

I2: 24/40 (60.0%)

C: 29/45 (64.4%)

 

Moderate

I1: 13/40 (32.5%)

I2: 16/40 (40.0%)

C: 16/45 (35.6%)

 

Groups comparable at baseline? Patients in both groups were balanced in demographic and disease characteristics at baseline.

Intervention 1:

Ivermectin 12 mg, single oral dose

 

Intervention 2:

Ivermectin 24 mg, single oral dose + standard care

 

We found that an alcohol-based elixir formulation of Ivermectin at a dose of 400 μg/kg administered after a meal may achieve a plasma Ivermectin concentration >150 ng/mL. A 20 mL dose of elixir formulation consisted of accurately weighted ivermectin (12 or 24 mg) in ethanol (40%v/v) with syrup base which was suitability flavoured and coloured.

Placebo

Length of follow up:

28 days

 

Loss to follow-up or outcome data missing:

I1: 3/52 (6%)

Reasons:

Withdrew consent (n=3)

 

I2: 1/52 (2%)

Reasons:

Withdrew consent (n=1)

 

C: 1/53 (2%)

Reasons:

Withdrew consent (n=1)

Clinical outcomes

Mortality at day 28

I1: 0/49 (0%)

I2: 0/51 (0%)

C: 0/52 (0%)

 

Duration of hospitalization

Discharged from hospital at day 14

I1: 37/40 (92.5%)

I2:38/40 (95%)

C: 39/45 (86.7)%

p = 0.42

 

Time to symptom resolution

Days, mean (SD)

I1: 4.76 (2.44)

I2: 4.26 (2.65)

C: 4.58 (2.94)

p = 0.77

 

Invasive respiratory support

Need for invasive mechanical ventilation

I1: 0/49 (0%)

I2: 0/51 (0%)

C: 0/52 (0%)

Primary outcome

reduction of viral load (estimated from CT value) and conversion to negativity of nasopharyngeal/oropharyngeal RT-PCR on day 5 after intervention

 

Secondary outcomes

qualitative and quantitative results of RT-PCR on day 3 and 7 after intervention; time to clinical resolution; frequency of clinical worsening; clinical status on day 14; and hospital-free days at day 28

 

Definitions:

-

 

Remarks:

-

 

Authors conclusion:

In patients with mild and moderate COVID-19, a single oral administration of Ivermectin did not significantly increase either the negativity of RT-PCR or decline in viral load at day 5 of enrolment compared with placebo.

Okumuş, 2021

Type of study:

Multicenter, single-blind, quasi-randomized, controlled phase 3 trial

 

Setting:

4 tertiary referred Research and Education Hospital, between May 2020 September 2020

 

Country:

Turkey

 

Source of funding:

Afyonkarahisar Health Science University Scientific Research project Coordination Unit Project.

 

Conflicts of interest:

“The authors declare that they have neither financial nor non-financial competing

interests.”

Hospitalized severely ill COVID-19 patients with pneumonia, without SNP mutation in MDR-1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene

 

Inclusion criteria:

  • hospitalized
  • pre-diagnosis of severe pneumonia (one of the following:
    a. Presence of tachypnea ≥ 30/min, peripheral capillary oxygen saturation (SpO2) level < 90% in room air, Partial pressure of oxygen (PaO2)/FiO2 < 300 in oxygen receiving patient;
    b. Presence of specific radiological finding for Covid-19 in lung tomography (bilateral lobular, peripherally located, diffuse patchy ground glass opacities);
    c. Mechanical ventilation requirement;
    d. Acute organ dysfunction findings; patients with SOFA (sepsis-related organ failure assessment) score > 2)

 

Exclusion criteria:

  • Children < 18 years old
  • pregnancy, active breast feeding
  • concurrent autoimmune disease
  • chronic liver or kidney disease
  • immunosuppression
  • SNP mutation in MDR-1/ABCB1 gene and/or haplotypes and mutations of the CYP3A4 gene

 

N total at baseline:

Total: N = 66

Intervention: N = 36 (30 patients without mutations included in analysis)

Control: N = 30

 

Important characteristics:

Age, mean (SD):

I: 58.17 (11.52)

C: 66.23 (13.31)

 

Sex, n/N (%) male:

I: 21/30 (70%)

C: 19/30 (63.3%)

 

Disease severity, SOFA score, mean (SD):

I: 3.12 (1.9)

C: 2.83 (2.1)

 

Mechanic ventilation requirement, n (%)

I: 1/30 (3.3%)

C: 1/30 (3.3%)

 

Groups were comparable at baseline.

Ivermectin + standard of care

 

Ivermectin treatment in the form of a solution prepared for enteral use at 200 microgr/ kg/day (9 mg between 36 and 50 kg, 12 mg between 51 and 65 kg, 15 mg between 66 and 79 kg and 200 microgram/kg in > 80 kg) for 5 days.

 

Standard of care included hydroxychloroquine (2x400mg loading dose followed by 2x200mg, po, 5 days), favipiravir (2x1600mg loading dose followed by 2x600mg maintenance dose, po, total 5 days) and azithromycin (500 mg first day loading dose, followed by 250 mg/day, po, total 5 days).

Standard of care

 

Standard of care included hydroxychloroquine (2x400mg loading dose followed by 2x200mg, po, 5 days), favipiravir (2x1600mg loading dose followed by 2x600mg maintenance dose, po, total 5 days) and azithromycin (500 mg first day loading dose, followed by 250 mg/day, po, total 5 days).

Length of follow up:

10 days (assessment after 5 days of treatment and 5 additional days of follow-up)

 

Loss to follow-up or outcome data missing:

Six (16.7%) patients in the study group were excluded from the study, continuing only the reference treatment after taking the first dose of ivermectin, as a mutation was detected in genetic tests affecting ivermectin metabolism.

Clinical outcomes

Mortality (average of 3 month follow-up)

I: 6/30 (20%)

C: 9/30 (30%)

p = 0.37

 

Duration of hospitalization

Not reported.

 

Time to symptom resolution

Clinical improvement*

At day 5

I: 14/30 (46.7%)

C: 11/30 (36.7%)

P=0.43

 

At day 10

I: 22/30 (73.3%)

C: 16/30 (53.3%)

P=0.10

 

SOFA score – no data provided

“When the mean SOFA scores before treatment and at the end of the follow-up period were compared, a significant decrease was found in the study group (p = 0.009), while an increase was found in the control group (p = 0.88). When the SOFA scores of both groups were compared at the end of the follow-up period, no significant difference was found between them (p = 0.50).”

 

Invasive respiratory support

Not reported.

Primary outcome

clinical responses and drug side effects obtained in patients on the 5th day, at the end of the ivermectin treatment

 

Secondary outcomes

clinical responses and drug side effects obtained in patients on the 5th day after the end of ivermectin treatment (totally 10th day), treatment response, PCR negativity and mortality rates at the end of the follow-up period

 

Definitions:

* Clinical improvement: extubation in mechanically ventilated patients, respiratory rate < 26, SpO2 level in room air > 90%, PaO2 / FiO2 > 300 in patients receiving oxygen, presence of at least two of the 2-point reduction criteria in SOFA-score [inconsistent definition in paper for 5-day and 10-day outcome]

 

Remarks:

  • Quasi-randomized controlled trial
  • Main aim of study (investigate the effectiveness of adding ivermectin to the treatment in patients with severe COVID-19 pneumonia)
  • 16.7% of patients were excluded from the intervention group after the first dose of ivermectin, as the result of the genetic assessment became available
  • Inconsistency in definition of ‘clinical response/improvement’ at day 5 (primary outcome) and 10 after treatment (secondary outcome)
  • Frequency of other medication (hydroxychloroquine, favipiravir, azithromycin) in standard of care is not reported

 

Authors conclusion:

“According to the findings obtained, ivermectin can provide an increase in clinical recovery,

improvement in prognostic laboratory parameters and a decrease in mortality rates even when used in patients with severe COVID-19. Consequently, ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.”

Podder, 2020

Type of study:

Single-center, open-label, quasi-randomized, controlled trial

 

Setting:

Debidwar Upazila Health Complex, Comilla, between May 1 and July 31, 2020.

 

Country:

Bangladesh

 

Source of funding:

This study was self-financed.

 

Conflicts of interest:

None to declare.

Outpatients with mild-to-moderate COVID-19

 

Inclusion criteria:

  • RT-PCR positive
  • mild-to-moderate COVID-19
  • age > 18 y
  • either sex

 

Exclusion criteria:

  • known pre-existing hypersensitivity to ivermectin
  • pregnant and lactating women
  • receiving other antimicrobials or hydroxychloroquine

 

N total at baseline:

Randomized: N=82

Analyzed: N=62

 

Intervention : N=32

Control: N=30

 

Important characteristics:

Age, mean (SD), y:

I: 38.41 y (11.02)

C: 39.97 y (13.24)

 

Sex, n/N (%) male:

I: 23/32 (71.9%)

C: 21/30 (70.0%)

 

Disease severity, n/N (%):

Mild

I: 26/32 (81.3%)

C: 24/30 (80.0%)

 

Moderate

I: 6/32 (18.8%)

C: 6/30 (20.0%)

 

Groups comparable at baseline?

Patients in both groups were balanced in demographic and disease characteristics at baseline.

Ivermectin + standard of care

 

200 μg/kg, single dose, oral

 

Standard of care is not further specified.

Standard of care

 

Standard of care is not further specified.

Length of follow up:

10 days

 

Loss to follow-up or outcome data missing:

After randomization, 20 patients were excluded: 18 patients due to symptoms more than 7 days at presentation and 2 patients due to insufficient data. It is unclear how the exclusion was distributed between the treatment groups.

Clinical outcomes

Mortality

Not reported.

 

Duration of hospitalization

Not reported.

 

Time to symptom resolution

Time to symptom resolution (from date of enrolment)

Days, mean (SD)

I: 5.31 (2.48)

C: 6.33 (4.23)

p > 0.05

 

Time to symptom resolution (from date of onset of illness)

Days, mean (SD)

I: 10.09 (3.24)

C: 11.50 (5.32)

p > 0.05

 

Duration of specific symptoms (i.e., fever, cough, shortness of breath, fatigue, and myalgia) from the date of enrolment is also reported.

 

Invasive respiratory support

Not reported.

Primary outcome

not defined

 

Secondary outcomes

not defined

 

Definitions:

-

 

Remarks:

-

 

Authors conclusion:

Adding ivermectin to usual care in the management of mild to moderate COVID-19 patients did not show any benefit.

Ravikirti, 2021

Type of study:

RCT (double blind)

 

Setting:

All India Institute of Medical Sciences (AIIMS), Patna, India.

All admissions between 1st August and 31st October 2020.

 

Country:

India

 

Source of funding:

Not reported

 

Conflicts of interest:

None.

 

 

 

 

 

 

Hospitalized patients with mild or moderate disease at admission.

 

Inclusion criteria:

  • Age ≥ 18 years;
  • diagnosis of COVID-19;
  • mild or moderate disease on admission.

 

Exclusion criteria:

  • known allergy or adverse drug reaction with ivermectin;
  • unwillingness or inability to provide consent to participate in the study;
  • prior use of ivermectin during the course of current illness;
  • pregnancy and lactation.

 

N total at baseline:

N = 115

Intervention:57

Control: 58

 

Important characteristics:

Age, mean (SD):

I: 50.7 y (12.7)

C: 54.2 y (16.3)

 

Sex, n/N (%) male:

I:40/55 (73%)

C:41/57 (72%)

 

Disease severity, mean (SD):

Defined by

I: 42/55 (76%) mild, 13/55 (24%) moderate disease

C: 46/57 (81%) mild, 11/57 (19%) moderate disease

 

Groups comparable at baseline?

Yes

Ivermectin

 

Ivermectin 12 mg, on day 1 and 2 after their enrolment

 

 

All patients received usual care and treatment by their respective treating teams abiding by the standard treatment guidelines laid out by the institute (not specified)

Placebo tables

 

placebo tablets on day 1 and 2 after their enrolment.

 

 

All patients received usual care and treatment by their respective treating teams abiding by the standard treatment guidelines laid out by the institute (not specified)

Length of follow-up:

10 days

 

Loss-to-follow-up:

Intervention: 2 (4%)

Reasons: 1 lost to follow-up, 1 was administered unblinded ivermectin tablet by the treating team on day 2, hence excluded.

 

Control: 1 (2%)

Reasons: 1 was administered unblinded ivermectin tablet by the treating team on day 2, hence excluded.

 

Incomplete outcome data:

Intervention: 23 (40%)

Reasons: 23 no or inconclusive report

[9 discharged before 6th day; 2 sample not sent for unknown reason; 9 sample lost; 3 report inconclusive

 

Control: 13 (22%)

Reasons: 13 no or

inconclusive report: [3 discharged before 6th day; 1 died; 2 sample not sent for

unknown reason; 3 sample lost; 4 report inconclusive]

 

Clinical outcomes

Mortality (28-30 day)

not reported

 

Mortality (in-hospital)

I: 0/55 (0%)

C: 4/57 (7%)

 

Duration of hospitalization

Discharged at day 10

I: 44/55 (80%)

C: 42/57 (74%)

 

Time to symptom resolution

Symptom free at day 6

I: 46 (84%)

C: 51 (90%)

 

Respiratory support

Invasive ventilation

I: 1/55 (2%)

C: 5 /57 (9%)

 

Safety

Adverse events

No adverse events attributable to ivermectin were reported during this trial.

 

Virological outcomes

Viral clearance

% negative PCR at day 6

I: 13/55 (24%)

C: 18/57 (32%)

Primary outcome:

Negative RT-PCR report on day 6.

Secondary outcomes:

Symptom status on day 6, discharge status on day 10, requirement of ICU support, invasive mechanical ventilation, and final treatment outcome (death/discharge) during hospital stay.

 

Definitions:

Definition severity:

Mild: No evidence of breathlessness or hypoxia (normal saturation); Moderate: Breathlessness and/or hypoxia (saturation 90-94% on room air), respiratory rate of 24 or more and no features of severe disease (defined by the Ministry of Health and Family Welfare (MOHFW), Government of India (GOI) guidelines)

 

Remarks:

Role of pharmaceutical company is unclear (Ivermectin tablets were procured from the learning resource allowance of the principal investigator. Placebo tablets were provided by Sun Pharma Pvt. Ltd.)

 

Authors conclusion:

Inclusion of ivermectin in treatment regimen of mild to moderate COVID-19 patients could not be recommended with certainty based on our study results as it had shown only marginal benefit in successful discharge from the hospital with no other observed benefits. Larger, multicentre RCTs should be planned to provide a clearer answer.

 

Reis, 2022

Type of study:

Double-blind, randomized, placebo-controlled, adaptive platform trial (TOGETHER)

 

Setting:

Outpatient with SARS-CoV-2 infection, between March 23, 2021, and August 6, 2021

 

Country:

12 public health clinics, Brazil

 

Source of funding:

FastGrants and the Rainwater Charitable Foundation

 

Conflicts of interest:

Conflicts of interest were transparently and extensively reported

 

 

Outpatients with SARS-COV-2 infection

 

Inclusion criteria:

  • ≥18 years
  • presentation to an outpatient care setting with an acute clinical condition consistent with Covid-19 within 7 days after symptom onset
  • Confirmed COVID-19 by PCR or another rapid test
  • Patients over 18 years of age and with at least ONE of the following criteria

a. Age 50³ years (do not need any of the other criteria)

b. Diabetes mellitus requiring oral medication or insulin

c. Hypertension requiring at least 01 oral medication for treatment

d. Known cardiovascular diseases (heart failure, congenital heart disease, valve disease, coronary artery disease, myocardiopathy under treatment, clinically manifest heart diseases with clinical repercussions)

e. Lung disease symptomatic and/or under treatment

(emphysema, fibrosing diseases)

f. Patients with symptomatic asthma requiring chronic use of

agents for symptom control.

g. Smoking

h. Obesity, defined as BMI > 30 kg/m2 on weight and height

information provided by the patient;

i. Transplant Patients

j. Patient with stage IV chronic kidney disease or on dialysis.

k. Immunosuppressed patients/ in use of cortico-therapy (equivalent to at least 10 mg prednisone per day) and/or immunosuppressive therapy)

l. Patients with a history of Cancer in the past 05 years or

currently undergoing oncological treatment

 

Exclusion criteria:

  • Patients with an acute respiratory condition
  • Taking serotonin reuptake inhibitors
  • Pregnant/locating
  • Known allergies to the study drug

 

N total at baseline:

N = 3515

Intervention: N=679

Control: N=679

2157 participants were assigned to other treatment groups

 

Important characteristics:

Age, median (IQR):

I: 49 y (39-57)

C: 49 y (37-56)

 

Sex, n/N (%) male:

I: 296/679 (43.6%)

C: 271/269 (39.9%)

 

Disease severity

Not reported

 

Groups comparable at baseline?

Yes

ivermectin

at a dose of 400 µg per kilogram of body weight

for 3 days

 

+ standard care for COVID-19 provided by health care professionals in Brazil

 

 

 

 

Placebo for 3 days¹

 

 

 

 

 

+ standard care for COVID-19 provided by health care professionals in Brazil

 

 

 

 

Length of follow-up:

28 days

 

Incomplete outcome data & loss-to-follow-up:

Intervention:

679 Were included in the intention to-

treat analysis (100%)

 

674 Were included in the modified

intention-to-treat analysis (99.3%)

 

624 Were included in the per-protocol

analysis (91.9%)

 

Control:

679 Were included in the intention to-

treat analysis

(100%)

 

675 Were included in the modified

intention-to-treat analysis (99.4%)

 

288 Were included in the per-protocol

Analysis (42.4%)¹

 

Clinical outcomes

Mortality (day 28)

I: 21/679 (3.1%)

C: 24/679 (3.5%)

RR: 0.88 (0.49-1.55)

 

Duration of hospitalization (for any cause)

I: 79/679 (11.6%)

C: 95/679 (14%)

RR: 0.83 (0.63-1.10)

 

Time to symptom resolution

Median no. of days to clinical recovery*:

I: 14 (11-14)

C: 14 (11-14)

RR: 1.05 (0.88-1.24)

 

Invasive respiratory support

I: 19/679 (2.8%)

C: 25/679 (3.7%)

RR: 0.77 (0.43-1.36)

 

Non-invasive respiratory support

Not reported

 

Safety

Serious adverse events

Grade 3 or more

I: 79/679 (11.6%)

C: 92/679 (13.5%)

 

Virological outcomes

Viral clearance

Day 3

I: 11/148 (7.4%)

C: 17/170 (10.0%)

RR: 0.76 (0.36-1.52)

 

Day 7

I: 36/142 (25.4%)

C: 42/165 (25.5%)

RR: 1.00 (0.68-1.46)

Primary outcome:

  • Composite outcome was hospitalization due to coronavirus disease 2019 (Covid-19) within 28 days after randomization or an emergency department visit due to clinical worsening of Covid-19 (defined as the participant remaining under observation for >6 hours) within 28 days after randomization.

 

Secondary outcome(s):

  • Viral clearance at day 3 and 7
  • Hospitalization for any cause
  • Time to hospitalization
  • Duration of hospitalization
  • Time to emergency visit lasting more than 6 hours
  • Time to clinical recovery (WHO scale)
  • Death from any cause
  • Time to death
  • Receipt of mechanical ventilation
  • Number of days with mechanical ventilation
  • Health-related quality of life
  • Percentages of patients who adhered to the assigned regimen
  • Adverse reactions

 

Definitions:

*Clinical recovery was assessed with the use of the World Health Organization clinical progression scale

 

Remarks:

Only the results in the 3-day ivermectin group as compared with the concurrent placebo group are reported in this article.

 

¹Participants in the

placebo group received placebo for 1, 3, 10, or 14 days, comparable to the active-treatment groups in the trial. Although

all the participants who had been assigned to receive any placebo were included in the intention-to-treat

population, only those in the 3-day placebo groups were included in the per-protocol population.

 

Authors conclusion:

Treatment with ivermectin did not result in a lower incidence of medical admission

to a hospital due to progression of Covid-19 or of prolonged emergency department

observation among outpatients with an early diagnosis of Covid-19.

Shahbaznejad, 2021

Type of study:

multicenter, randomized, double-blind, RCT

 

Setting:

2 referral tertiary hospitals

 

Country:

Iran

 

Source of funding:

Not reported

 

Conflicts of interest:

None.

 

 

 

 

 

Hospitalized COVID-19 patients, children and adults

 

Inclusion criteria:

  • age > 5 years
  • weight > 15 kg
  • hospitalized
  • COVID-19 diagnosis, by any of the following: (1) positive result on COVID-19 reverse-transcription polymerase chain reaction; (2) clinical symptoms of COVID-19, with a history of contact with a patient with COVID-19; and/or (3) abnormalities on chest computed tomography (CT) compatible with COVID- 19 (ground-glass opacity, halo sign, reversed halo sign, and patchy infiltration).

 

Exclusion criteria:

  • history of chronic liver and/or renal disease;
  • receipt of treatment with warfarin, an angiotensin-converting enzyme inhibitor, or a angiotensin II receptor antagonist;
  • acquired immunodeficiency
  • pregnant or breast-feeding

 

N total at baseline:

Randomized:

N = 69

Intervention: 35

Control: 38

Included in analysis:

I: 35

C: 34

 

Important characteristics:

Age, mean ±SD (min, max):

I: 47.63 ±22.20 (5.5, 85.0)

45.18 ±23.11 (5.0, 86.0)

Sex, n/N (%) male:

I: 18 (51.4)

C 18 (52.9)

Disease severity, mean (SD):

Need Ventilator

I: 2 (5.7)

C: 1 (2.9), p= 1

Severe COVID-19

I: 13 (37.1)

C: 18 (52.9), p= 0.19

 

Duration of symptoms before

admission (days), mean ±SD (Min, Max)

I: 6.21 ±3.60 (1, 15)

C: 6.38 ±2.86 (2, 15), p= 0.72

 

Groups comparable at baseline? Yes, except for loss of appetite, insomnia, rales and arthralgia, which occurred more often in the intervention group

Ivermectin

 

single oral dose (0.2 mg/kg) of ivermectin utilizing 3-mg oral tablets, or a multiple thereof, on the first day of admission, at the

following weight-based doses: 15 to 24 kg, 3 mg; 25 to 30 kg, 6 mg; 36 to 50 kg, 9 mg; 51 to 80 kg, 12 mg; and > 80 kg, 0.2 mg/kg

 

All of the participants received appropriate antibiotics and/or supplemental oxygen as indicated.

 

+ standard of care

Standard of care

 

= supportive medical treatment for COVID-19 according to the national protocols of Iran at the time of this study (including hydroxychloroquine and/or lopinavir/ ritonavir)

 

All of the participants received appropriate antibiotics and/or supplemental oxygen as indicated.

Length of follow up:

7 days

 

Loss to follow-up:

I: 0/0 (0%)

Reasons: -

C: 4/38 (10.5%)

Reasons: ‘withdrawn’

 

 

Clinical outcomes

Mortality (28-30 day)

Not reported; sample size reported to be too small

“In the ivermectin group, a 78-year-old woman with a history of diabetes mellitus and heart failure died. She was critically ill at the time of admission and died within the first 24 hours.”

 

Duration of hospitalization

Duration of hospital stay

I: 7.1 (0.5) (95% CI 6.1–8.1)

C: 8.4 (0.6) (95% CI 7.2–9.5), p= 0.016

 

Time to symptom resolution

Clinical improvement* after baseline,

 

Duration of symptoms

I: 4.2 (0.3) (95% CI 3.6–4.8)

C: 5.2 (0.3) (95% CI 4.6–5.8), p= 0.023

 

Also reported: duration of separate symptoms, such as fever, chills, cough.

 

Respiratory support

Oxygen needed

I: 10/35 (28.6%)

C: 9/34 (26.5%)

P=0.84

Invasive mechanical ventilation needed

I: 2/35

C: 1/34

 

Safety

Adverse events

I: 0

C: 0

“No potential adverse events, including wheezing, itching, skin rash, edema, hypotension or liver toxicity were observed in the patients of either group”

 

Virological outcomes

Viral clearance

not reported

 

 

Primary outcome:

Clinical improvement after baseline

Secondary outcomes:

Time to improvement of chief symptoms, hospitalization duration, duration of supplemental oxygen with non-invasive ventilations, prevalence of mortality, drug-induced adverse events, changes in assessed laboratory values over time.

 

 

Definitions:

Clinical improvement: defined as resolving a patient’s baseline status on persistent and continuous cough (persistent cough for > 1 hour, or ≥3 coughing episodes in 24 hours, that interferes with activities of daily living and the ability to work) and tachypnea in addition to increasing oxygen saturation to > 94%.

 

Remarks:

  • procedures, concealment of randomization sequence, blinding not clearly described
  • Results inconsistent between text and table
  • Ivermectin was distributed by Europhartech (Lempdes, France).

 

Authors conclusion:

“A single dose of ivermectin was well-tolerated in symptomatic patients with COVID- 19, and important clinical features of COVID- 19 were improved with ivermectin use, including dyspnea, cough, and lymphopenia. Further studies with larger sample sizes, different drug dosages, dosing intervals and durations, especially in different stages of the disease, may be useful in understanding the potential clinical benefits ivermectin.“

 

 

 

Vallejos, 2021

 

NCT04529525

Type of study:

Randomized, double-blind, placebo-controlled trial.

 

Setting:

Ministry of Public Health of the Province of Corrientes.

 

Country:

Argentina.

 

Source of funding:

None.

 

Conflicts of interest:

The authors declare that they have no competing interests.

 

 

 

 

 

 

Outpatients with early COVID-19

 

Inclusion criteria:

  • >18 years of age;
  • residing in the province of Corrientes at the time of diagnosis with confirmed RT-PCR test for SARS-CoV-2 detection in the last 48 hours;
  • woman of childbearing age, should be using a contraceptive method of proven efficacy and safety;
  • ≥ 48 kg body weight

 

Exclusion criteria:

  • requiring current home oxygen;
  • requiring hospitalization for COVID-19 at the time of diagnosis;
  • history of hospitalization for COVID-19;
  • pregnant or breastfeeding woman;
  • known allergy to ivermectin or components of ivermectin or placebo tablets;
  • mal-absorptive syndrome;
  • presence of any other concomitant acute infectious disease;
  • known history of sever liver disease;
  • recent or expected need for dialysis.
  • concomitant use of hydroxychloroquine or chloroquine or antiviral drugs due to a viral pathology other than COVID-19 at time of admission was prohibited as was the use of ivermectin ≤ 7 days before randomization
  • participation in study that involved administration of a drug ≤ 30 days.

N total at baseline:

N = 501

Intervention: N = 250

Control: N = 251

 

Important characteristics:

Age, mean (SD):

I: 42.58 y (15.29)

C: 42.40 y (15.75)

 

Sex, n/N (%) female:

I: 111/250 (44.4%)

C: 126/251 (50.2%)

 

Disease severity:

Not reported: Lastly, we did not include any scale to determine the severity of the patients who were enrolled.”

 

Groups comparable at baseline?

Yes.

 

Ivermectin plus standard of care

 

The dose of ivermectin used was the approved dose in Argentina for the treatment of other diseases, such as parasitic diseases, and it was staggered according to weight. Those weighing up to 80 Kg received 2 tablets of 6 mg (mg) each at inclusion and another 2 tablets of 6 mg each 24 h after the first dose (total 24 mg). Those weighing more than 80 kg and up to 110 kg received 3 tablets of 6 mg each at inclusion and another 3 tablets of 6 mg each 24 h after the first dose (total 36 mg). Those weighing more than 110 kg received 4 tablets of 6 mg each at inclusion and another 4 tablets of 6 mg each 24 h after the first dose (total 48 mg)

 

+

 

Standard of care

Placebo plus standard of care

 

Individuals randomized to placebo received the equivalent number of placebo tablets to the ivermectin weight-based dosage, at baseline and again after 24 h.

 

+

 

Standard of care:

The SOC was in accordance with the

recommendations of the Argentine Ministry of Health

Length of follow-up:

30 days after the final visit.

 

Loss-to-follow-up:

Intervention:

In the ivermectin group, 249 patients had 100% compliance and 1 had 50% compliance.

 

Control:

In the placebo group, 248 patients had 100% compliance, 2 patients had 50% compliance and 1 patient had 0% compliance.

 

* Considering that an intention-to-treat analysis was performed, all 501 patients were included for the analysis of primary and secondary outcomes. There were no arm crossovers.

 

Incomplete outcome data:

None.

 

Clinical outcomes

(All-cause) mortality (28-30 day)

I: 4/250 (1.60%)

C: 3/251 (1.20%)

OR 1.34 (95% CI 0.30 to 6.07)

P=0.70

 

Requiring hospitalization

I: 14/250 (5.60%)

C: 21/251 (8.37%)

OR 0.65 (95% CI 0.32 to 1.31)

P=0.227

 

Time to hospitalization days (in those who were hospitalized), median (IQR)

I: 3.5 (3 to 5)

C: 3 (2 to 5)

P=0.59

 

Time to symptom resolution

Not reported.

 

Respiratory support

Invasive mechanical ventilatory support, n/N (%)

I: 4/250 (1.60%)

C: 3/251 (1.20%)

OR 1.34 (95% CI 0.30 to 6.07)

P=0.70

 

Safety

Adverse events

I: 45/250 (18.00%)

C: 53/251 (21.11%)

P=0.60

 

no serious adverse

events were observed

 

*specific adverse events were reported in the publication.

 

Virological outcomes

Viral clearance

Negative nasal swab day 3, n/N (%)

I: 113/250 (47.08%)

C: 120/251 (49.79%)

OR 0.90 (95% CI 0.63 to 1.28)

 

Negative nasal swab day 12, n/N (%)

I: 212/250 (89.08%)

C: 221/251 (92.47%)

OR 0.76 (95% CI 0.45 to 1.27)

P=0.29

Primary outcome:

Hospitalization

Secondary outcomes:

Time to hospitalization, use of mechanical ventilation support (MVS), time to invasive MSV, negative nasal swabs D3, D12, dialysis, ivermectin safety, all-cause mortality

 

 

Definitions:

Hospitalization was defined as a stay of at least 24 h in a health institution, in any of its services,

at any point from randomization until the end of

study visit.

 

Ivermectin safety was defined as frequency of adverse events

 

Remarks:

-

 

Authors conclusion:

In the IVERCORCOVID19 trial, in patients with a positive COVID-19 nasal swab by RT-PCR technique in the last 48 h, ivermectin in a staggered dose according to the patient’s weight for 2 days had no significant effect on preventing hospitalization of patients with COVID19. No significant differences were observed in secondary outcomes such as the time elapsed from study enrollment to hospitalization in those who required it. Additionally, no significant differences were observed in the use of invasive mechanical ventilatory support, the requirement for dialysis, negative nasal swabs at 3 and 12 days after study enrollment, or in all-cause mortality. Patients who received ivermectin required invasive mechanical ventilatory support earlier. The use of ivermectin was not associated with increased adverse events.

 

 

 

 

Notes:

  1. Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
  2. Provide data per treatment group on the most important prognostic factors [(potential) confounders]
  3. For case-control studies, provide sufficient detail on the procedure used to match cases and controls
  4. For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders

 

Autorisatiedatum en geldigheid

Laatst beoordeeld  : 03-10-2022

Laatst geautoriseerd  : 03-10-2022

Geplande herbeoordeling  :

Initiatief en autorisatie

Initiatief:
  • Federatie Medisch Specialisten
  • Stichting Werkgroep Antibioticabeleid
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
  • Nederlandse Vereniging voor Klinische Geriatrie
  • Nederlandse Vereniging voor Medische Microbiologie
  • Nederlandse Vereniging van Ziekenhuisapothekers
  • Nederlandse Vereniging voor Intensive Care
  • Patiëntenfederatie Nederland

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut). Deze ondersteuning werd gefinancierd uit de Kwaliteitsgelden Medisch Specialisten (SKMS). De werkgroep werd gefinancierd uit een VWS subsidie.

De financiers hebben geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodules is in 2020 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de behandeling van patiënten met COVID-19.

 

In 2020 is een multidisciplinair expertiseteam behandeling ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van het expertiseteam behandeling) die betrokken zijn bij de zorg voor patiënten met COVID-19. Dit expertiseteam fungeerde als stuurgroep, welke opdracht heeft gegeven tot het ontwikkelen van de module, alsmede fungeerde als klankbordgroep.

 

Werkgroep

  • Dr. Marjolein Hensgens, internist-infectioloog, Afdeling Infectieziekten, UMC Utrecht en LUMC Leiden (Stichting Werkgroep Antibiotica Beleid)
  • Drs. Emilie Gieling, apotheker, Afdeling Klinische Farmacie, UMC Utrecht.
  • Prof. Dr. Dylan de Lange, intensivist, Afdeling Intensive Care, UMC Utrecht.
  • Dr. Wim Boersma, longarts, Afdeling Longziekten, Noordwest Ziekenhuisgroep, Alkmaar.
  • Dr. Paul van der Linden, apotheker, Afdeling Klinische Farmacie, Tergooi MC, Hilversum (Stichting Werkgroep Antibiotica Beleid).
  • Prof. Dr. Bhanu Sinha, arts-microbioloog, Afdeling Medische Microbiologie & Infectiepreventie, UMCG, Groningen (Stichting Werkgroep Antibiotica Beleid).
  • Dr. Mark de Boer, internist-infectioloog, Afdelingen Infectieziekten en Klinische Epidemiologie, LUMC, Leiden (Stichting Werkgroep Antibiotica Beleid).
  • Tot 1-11-2021 tevens deel van de werkgroep: Dr. Albert Vollaard, internist-infectioloog, LCI, RIVM

 

Stuurgroep (expertiseteam Behandeling COVID-19)

  • Dr. L.M. van den Toorn (voorzitter), longarts, Erasmus Medisch Centrum (Erasmus MC), NVALT
  • Dr. M.G.J. de Boer, internist-infectioloog, Leids Universitair Medisch Centrum (LUMC), SWAB/NIV)
  • Drs. A.J. Meinders, internist-intensivist, St. Antonius Ziekenhuis, NVIC
  • Prof. dr. D.W. de Lange, intensivist-toxicoloog, Universitair Medisch Centrum Utrecht (UMC Utrecht), NVIC
  • Dr. C.H.S.B. van den Berg, infectioloog-intensivist Universitair Medisch Centrum Groningen (UMCG), NVIC
  • Dr. S.U.C. Sankatsing, internist-infectioloog, Diakonessenhuis, NIV
  • Dr. E.J.G. Peters, internist-infectioloog, Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Drs. M.S. Boddaert, arts palliatieve geneeskunde, Leids Universitair Medisch Centrum (LUMC), IKNL
  • Dr. P.L.A. Fraaij, kinderarts-infectioloog, Erasmus Medisch Centrum (Erasmus MC), Sophia Kinderziekenhuis, NVK
  • Dr. E. van Leeuwen, gynaecoloog, Amsterdam University Medical Centers (Amsterdam UMC), NVOG
  • Dr. J.J. van Kampen, arts-microbioloog, Erasmus Medisch Centrum (Erasmus MC), NVMM
  • Dr. M. Bulatović-Ćalasan, internist allergoloog-immunoloog en klinisch farmacoloog, Universitair Medisch Centrum Utrecht (UMC Utrecht), Amsterdam University Medical Centers (Amsterdam UMC), NIV
  • Drs. A.F.J. de Bruin, anesthesioloog-intensivist, St. Antonius Ziekenhuis, NVA
  • Drs. A. Jacobs, klinisch geriater, Catharina Ziekenhuis, NVKG
  • Drs. B. Hendriks, ziekenhuisapotheker, Leids Universitair Medisch Centrum (LUMC), NVZA
  • Drs. M. Nijs, huisarts, NHG
  • Dr. S.N. Hofstede, senior adviseur, Kennisinstituut van Medisch Specialisten

 

Meelezer

  • Drs. K. (Klaartje) Spijkers, senior adviseur patiëntenbelang, Patiëntenfederatie Nederland, Utrecht

 

Met ondersteuning van:

  • dr. S.N. Hofstede, senior adviseur, Kennisinstituut van Medisch Specialisten
  • dr. L.M.P. Wesselman, adviseur, Kennisinstituut van Medisch Specialisten
  • dr. D. Nieboer, adviseur, Kennisinstituut van Medisch Specialisten
  • drs. A.L.J. (Andrea) Kortlever - van der Spek, adviseur, Kennisinstituut van Medisch Specialisten
  • M. Griekspoor MSc., junior adviseur, Kennisinstituut van Medisch Specialisten

  • drs. I. van Dusseldorp, senior literatuurspecialist, Kennisinstituut van Medisch Specialisten

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

 

Werkgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

De Lange

1. Afdelingshoofd Nationaal Vergiftigingen Informatie Centrum (NVIC) van het UMC Utrecht (0,6 fte)
2. Intensivist, afdeling Intensive Care, UMC Utrecht (0,4 fte)

Secretaris Stichting Nationale Intensive Care Evaluatie (Stichting NICE), onbezoldigd.

Geen

Geen actie nodig

De Boer

Internist-Infectioloog, klinisch epidemioloog, senior medisch specialist, Leids Universitair Medisch Centrum, afdeling Infectieziekten

- Voorzitter Stichting Werkgroep Antibioticabeleid (onkostenvergoeding)
- Voorzitter NIV-COIG commissie Immuniteit en Infectieziekten (beperkt honorarium)
- Sectieredacteur Infectieziekten Nederlands Tijdschrift voor Geneeskunde (onbetaald)
- Lid FMS Expertiseteam behandeling COVID-19 (onbetaald)

Geen

Geen actie nodig

Sinha

Arts-microbioloog/hoogleraar, Universitair Medisch Centrum Groningen (voltijd) (zie ook https;//www.rug.nl/staff/b.sinha/)

- SWAB-bestuur: secretaris [onbetaald; vacatiegeld voor instelling]
- SWAB redactiegroep Leidraad/RL Medicamenteuze behandeling van patiënten met COVID-19 (infectie met SARS-CoV-2) [onbetaald]
- Verschillende functies in meerdere UMCG commissies [onbetaald]

- Projectsubsidie EU (Cofund): deelprojecten, cofinanciering
- Projectsubsidie PUSH: deelprojecten, cofinanciering
- Projectsubsidie Stichting Beatrixoord
- Projectsubsidie Cross Border Institute (RUG): deelproject
- Projectsubsidie Data Federation Hub (RUG)
- Projectsubsidie Interreg (via instelling): deelproject
- Geen m.b.t. het onderwerp van de leidraad/richtlijn

 

 

Mogelijk boedbeeldfunctie SWAB

Geen actie nodig

Van der Linden

Ziekenhuisapotheker
Afdeling klinische farmacie
Tergooi

Penningmeester SWAB, vacatiegeld
METC UMCU, betaald

Geen

Geen actie nodig

Vollaard

Internist-infectioloog, Landelijke Coordinatie Infectieziektebestrijding, RIVM

Arts voor ongedocumenteerde migranten, Dokters van de Wereld, Amsterdam (onbetaald)

Geen

Geen actie nodig

Gieling

Ziekenhuisapotheker - Klinisch Farmacoloog, UMC Utrecht

Lid OMT Nederlandse Vereniging voor Ziekenhuisapothekers (onbetaald)

Geen

Geen actie nodig

Boersma

Longarts Noordwest Ziekhuisgroep

Hoofd research afdeling longziekten

Lid sectie infectieziekten NVALT, onbetaald
Lid workgroup repiratory infections group 10.1 ERS, onbetaald
LId EMBARC streering committee, onbetaald

Eenmalige digitale deelname aan adviesraad MSD Pneumovax over Pneumococcal disease, betaald

 

Geen actie nodig

Hensgens

Internist-infectioloog, UMC Utrecht (0.8 aanstelling, waarvan nu 0.4 gedetacheerd naar LUMC)

Internist-infectioloog, LUMC (via detachering, zie boven)

Geen

Geen

Geen actie nodig

 

Stuurgroep

 

Achternaam stuurgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Van den Toorn (voorzitter)

Voorzitter NVALT
Longarts in Erasmus MC

Geen

Geen

Geen actie nodig

De Boer

Internist-Infectioloog, senior medisch specialist, LUMC, afdeling infectieziekten

- Voorzitter Stichting Werkgroep Antibioticabeleid (onkostenvergoeding)
- Voorzitter NIV-COIG commissie Immuniteit en Infectieziekten (beperkt honorarium)
- Sectieredacteur Infectieziekten Nederlands Tijdschrift voor Geneeskunde (onbetaald)
- Lid FMS Expertiseteam behandeling COVID-19 (onbetaald)

Geen

Geen actie nodig

Meinders

Internist-intensivist, St.-Antonius ziekenhuis, Nieuwegein

commissie werk
geen betaalde nevenfunctie of relatie industrie

Geen

Geen actie nodig

De Lange

Afdelingshoofd Nationaal Vergiftigingen Informatie Centrum (NVIC) van het UMC Utrecht
Intensivist, afdeling Intensive Care, UMC Utrecht

secretaris Stichting Nationale Intensive Care Evaluatie (Stichting NICE) (onbetaald)

Geen

Geen actie nodig

Van den Berg

Infectioloog-intensivist, UMCG

Geen

Geen

Geen actie nodig

Sankatsing

Internist-infectioloog/internist-acute geneeskunde, Diakonessenhuis, Utrecht

- Bestuurslid Nederlandse Vereniging van Internist-Infectiologen (NVII) (onbetaald).
- Lid Commissie Richtlijnen Nederlandse Internisten Vereniging (NIV) (betaald).
- Lid Werkgroep Richtlijn Sepsis II en III van de FMS (betaald).
- Lid Regionaal Coördinatieteam van het Regionaal Zorgnetwerk Antibioticaresistentie Utrecht (betaald).

Geen

Geen actie nodig

Peters

Internist - aandachtsgebieden infectieziekten en Acute Geneeskunde Amsterdam UMC, locatie Vumc
Opleider Infectieziekten Vumc
Plaatsvervangend Hoofd Infectieziekten Amsterdam UMC

Wetenschappelijk Secretaris International Working Group on the Diabetic Foot (onbetaald)
Voorzitter Werkgroep Behandeling Gewrichtsprotheseinfecties voor Stichting Werkgroep Antibioticabeleid (onbetaald)

Geen

Geen actie nodig

Boddaert

Medisch adviseur bij Integraal Kankercentrum Nederland (IKNL) en Palliatieve Zorg Nederland (PZNL)

Arts palliatieve geneeskunde in LUMC

Geen

Geen

Geen actie nodig

Fraaij

Kinderarts infectioloog- immunoloog, Erasmus MC-Sophia, Rotterdam
Klinische wetenschapper, Viroscience, ErasmusMC, Rotterdam

Bestuur Stichting Infecties bij Kinderen (onbetaald)

deelname aan RECOVER, European Union's Horizon 2020 research

Geen actie nodig

Van Leeuwen

Gyaecoloog Amsterdam Universitair Medisch Centra
Bestuurder Stichting Prenatale Screening Amsterdam en Omstreken (SPSAO)

Geen

Geen

Geen actie nodig

Van Kampen

Arts-microbioloog, afdeling Viroscience, Erasmus MC

- associate editor antimicrobial resistance & infection control (onbetaald)
- lid sectie virusdetectie SKML (onbetaald)

- lid antibioticacommissie Erasmus MC (onbetaald)
- plaatsvervangend lid infectiecommissie Erasmus MC (onbetaald)

1. Mede uitvinder patent: 1519780601-1408/3023503

2. R01AI147330 (NIAID/NH) (HN onderzoek

(1+2 niet gerelateerd aan COVID-19)

 

 

 

 

 

 

Geen actie nodig

Bulatovic

Internist allergoloog-immunoloog en klinische farmacoloog, UMC Utrecht en Diakonessenhuis Utrecht
Onderzoeker Amsterdam Medisch Centrum

Functie 1: arts
Functie 2: onderzoeker
(Beide betaald)

Geen

Geen actie nodig

De Bruin

Anesthesioloog - Intensivist St. Antonius ziekenhuis Nieuwegein en Utrecht
Sectie voorzitter IC&PACU NVA

Geen

Geen

Geen actie nodig

Jacobs

Klinisch geriater en klinisch farmacoloog

Geen

Geen

Geen actie nodig

Hendriks

Ziekenhuisapotheker farmaceutische patiëntenzorg, afd. Kiinische Farmacie en

Toxicoiogie, Leids Universitair Medisch Centrum

Lid SWAB werkgroep surveillance antibioticagebruik, onbetaald

Lid SWAB richtlijncommissie antibiotica allergie, onbetaald

Geen

Geen actie nodig

Nijs

Huisarts

Geen

Geen

Geen actie nodig

Hofstede

Senior adviseur Kennisinstituut van Medisch Specialisten

Geen

Geen

Geen actie nodig

 

Meelezer

 

Achternaam

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Spijkers

Senior adviseur patiëntenbelang

Voorzitter Stichting Samen voor Duchenne
Lid Community Advisory Board for Duchenne

Geen

Geen actie nodig

 

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door een afgevaardigde patiëntenvereniging in de klankbordgroep. De verkregen input is meegenomen bij het opstellen van de module. De conceptrichtlijn is tevens voor commentaar voorgelegd aan de Patiëntenfederatie Nederland en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Werkwijze

Van leidraad naar richtlijnmodules

Bij aanvang van de pandemie in 2020 was het onduidelijk of bestaande of nieuwe medicijnen een relevante bijdrage konden leveren aan het herstel van patiënten geïnfecteerd met het SARS-CoV-2. Vandaar dat eind februari 2020 werd aangevangen met de eerste versie van de leidraad ‘Medicamenteuze behandeling voor patiënten met COVID-19 (infectie met SARS–CoV-2)’, welke begin maart 2020 online beschikbaar werd gesteld op de website van de SWAB (https://swab.nl/nl/covid-19). Sindsdien werd het adviesdocument op wekelijkse basis gereviseerd en indien nodig op basis van nieuwe publicaties van onderzoek aangepast. Het initiatief en de coördinatie hiertoe werden genomen door de SWAB Leidraadcommissie, ondersteund door het kennisinstituut van de Federatie Medisch Specialisten en een brede klankbordgroep waarbinnen de betrokken specialisten(verenigingen) zijn vertegenwoordigd. In september 2021 is gestart met het doorontwikkelen van de leidraad naar richtlijnmodules.

 

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

 

Knelpuntenanalyse en uitgangsvragen

Tijdens de COVID-19 pandemie zijn knelpunten op verschillende manieren geïnventariseerd:

1. De expertiseteams benoemde de knelpunten in de zorg voor patiënten met COVID-19.

2. Er is een mailadres geopend (covid19@demedischspecialist.nl) waar verschillende partijen knelpunten konden aandragen, die vervolgens door de expertiseteams geprioriteerd werden.

3. Door de Federatie van Medisch Specialisten zijn webinars georganiseerd waarbij vragen konden worden ingestuurd. Deze vragen zijn na afloop van de webinars voorgelegd aan de expertiseteams en geprioriteerd.

 

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

 

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur en de beoordeling van de risk-of-bias van de individuele studies is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Wanneer mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

 

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

 

GRADE

Definitie

Hoog

  • er is hoge zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Redelijk

  • er is redelijke zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Laag

  • er is lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.

Zeer laag

  • er is zeer lage zekerheid dat het ware effect van behandeling dichtbij het geschatte effect van behandeling ligt;
  • de literatuurconclusie is zeer onzeker.

 

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

 

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE methodiek.

 

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

 

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

 

Sterke aanbeveling

Zwakke (conditionele) aanbeveling

Voor patiënten

De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.

Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.

Voor behandelaars

De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.

Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.

Voor beleidsmakers

De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.

Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

 

Organisatie van zorg

Bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen.

 

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

 

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

 

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

 

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

 

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

 

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

 

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. http://richtlijnendatabase.nl/over_deze_site/over_richtlijnontwikkeling.html

 

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

 

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Zoekverantwoording

Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Volgende:
Langdurige klachten en revalidatie na COVID-19