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 measure^g

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 6^th 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)

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.