Hydroxychloroquine - hospitalized

Abd-Elsalam, 2020

Type of study: 

A multicenter randomized controlled study 

Setting: 

Tertiary referral centers 

Country: 

Egypt 

Source of funding: 

None. 

Inclusion criteria: 

• Patients with SARS-CoV-2 infection (both genders). 

Exclusion criteria: 

• Allergies/contraindication to HCQ;
• Pregnant and lactating females;
• Patients with cardiac problems. 

N total at baseline: 

N = 194 

Intervention: 97 

Control: 97 

Important characteristics: 

Age, mean (SD):

I: 40.35y (18.65) 

C: 41.09y (20.07) 

P=0.80 

Sex, n/N (%) male: 

I: 56/97 male (57.7%) 

C: 58/97 male (59.8%) 

P=0.77 

Hydroxychloroquine

Patients received HCQ 400 mg twice daily (in day 1) followed by 200 mg tablets twice daily added to the standard of care treatment adopted by the Egyptian Ministry of health for 15 days. 

Standard of care

Patients received only the standard of care treatment adopted by the national Ministry of Health for 15 days.

Length of follow up

28 days

Mortality, 28d

Death 

I: 6/97 (6.1%) 

C: 5/97 (5.1%) 

P=0.76

OR 0.824 (95% CI 0.243 to 2.797), p=0.757

Hospitalization

Duration to hospital discharge; Mean (SD) 

I: 11.04 (2.71) 

C: 11.27 (2.19) 

P=0.52 

Need for transfer to ICU

I: n=11/97 (11.3%) 

C: n=13/97 (13.4%) 

P=0.83

Respiratory support

Need for mechanical ventilation

I: 4/97 (4.1%)

C: 5/97 (5.2%)

P = 0.75

Time to symptom resolution

Duration to clinical improvement; Mean (SD) 

I: 9.43 (1.87) 

C: 9.52 (2.94) 

P=0.80 

Disease severity (after 28 days), n (%) 

Recovered 

I: n=52/97 (53.6%) 

C: n=33/97 (34.0%) 

Mild 

I: n=23 (23.7%) 

C: n=39 (40.2%) 

Moderate 

I: n=8 (8.2%) 

C: n=11 (11.3%) 

Severe 

I: n=8 (8.2%) 
C: n=9 (9.2%) 

Death 

I: n=6 (6.1%) 

C: 5 (5.1%) 

Safety

Not reported

Viral clearance 

Time to negative PCR; Mean (SD) 

I: 17.01 (2.98) 

C: 17.64 (2.45) 

P= 0.11

Remarks: 

-definition of ‘clinical improvement’ not described

Authors conclusion: In conclusion, our trial adds extra evidence from Egypt that HCQ may not be beneficial as a treatment for COVID-19. 
 

Chen, 2020

Type of study:

RCT; open-label

Setting:

11 public hospitals between April 1 and May 31.

Country:

Taiwan

(northern, central, and southern).

Source of funding:

Research grant from

the Hospital and Social Welfare Organizations

Administration

Commission,

Ministry of Health and Welfare.

Taiwan Biotech Co.

Ltd.: donation of

investigational

products.

The authors declare no conflicts of interests.

Non-hospitalized COVID-19 patients

Inclusion criteria:

• Age 20–79 years;
• COVID-19 diagnosis (confirmed by pharyngeal real-time RT-PCR for SARS-CoV-2)

Exclusion criteria:

• severe illness (respiratory distress, oxygen supplementation, and evidence of infiltration according to chest roentgenography);
• documented history of hypersensitivity to quinine derivatives;
• retinal disease;
• hearing loss;
• severe neurological or mental illness;
• pancreatitis;
• lung disease;
• liver disease (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3× the normal upper limit);
• kidney disease (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 according 151 to MDRD or CKD-EPI);
• hematological disease;
• cardiac conduction abnormalities at electrocardiographic (ECG) screening with long QT syndrome or QTcF interval > 450 msec for males and > 470 msec for females according to Fridericia’s correction at screening;
• known HIV infection;
• active hepatitis B or C without concurrent treatment (positive for hepatitis B [HBsAg and HBeAg] or hepatitis C ribonucleic acid [RNA] titer > 800,000 156 IU/mL);
• (m) G6PD;
• psychiatric disorders and alcohol/ substance dependence/abuse that may jeopardize patient safety;
• pregnant or breastfeeding woman.

N total at baseline:

N = 33

Intervention: 21

Control: 12

Important characteristics:

Age, mean (SD):

I: 33.0 (12.0)

C: 32.8 (8.3)

Sex, n/N (%) male:

I: 11/21 (52.4)

C: 8/12 (66.7)

Groups comparable at baseline.

Hydroxychloroquine + standard of care (SOC):

HCQ 400 mg twice for 1 d and HCQ 200 mg twice daily for 6 days +SOC Enrollees were randomized within 4 days of diagnosis.

SOC

Stratified by mild or moderate illnesses within 4 days of diagnosis.

*mild clinical COVID-19 symptoms: supportive treatment

*moderate clinical COVID19 symptoms: antimicrobial therapy

(1) ceftriaxone 2 g daily for 7 days ± azithromycin 500 mg on day 1 and 250 mg on days 2–5; or (2) levofloxacin 750 mg daily for 5 d; or

(3) levofloxacin 500 mg daily; or (4) moxifloxacin 400 mg daily for 7–14 days for subjects allergic to ceftriaxone or azithromycin or according to physician discretion. Oseltamivir 75 mg b.i.d. will be administered for 5 days to subjects presenting with concomitant influenza A or B infection.

Follow-up

From randomization up to 14 days.

Loss to follow-up

2 in the HCQ group and 1 in the SOC group had withdrawn consents before the first dose was administered.

Mortality, 14d

I: 0/21

C: 0/12

Duration of hospitalization

Discharge rate by day 14: announced but not reported

Respiratory support

Not reported

Time to symptom resolution

Clinical recovery (resolution of symptoms, not further specified) by day 14

I: 6/21, 28.6%

C: 5/12, 41.7%

p-value: 0.51

Safety – adverse events

Serious adverse events:

No severe adverse events were reported

Severe QTc prolongation:

No severe QTc prolongation was noted.

Viral clearance

Time to negative rRT-PCR assessments from randomization to hospital day 14 (median)

I: 5 days (95% CI 1-9 days)

C: 10 days (95% CI 2-12 days)

p-value: 0.40

Proportion of negative viral rRT-PCR on hospital day 14 (%)

I: 17/21 (81.0)

C: 9/12 (75.0)

p-value: 0.36

Off-quarantined by day 14

I: 19.0%

C: 16.7%

p-value: not reported

Remarks:

One (4.8%) in the HCQ group and two (16.7%) in the SOC group were concomitantly administered azithromycin.

Authors conclusion:

HCQ failed the primary endpoint of shortening the viral clearance interval.

A retrospective observational study was performed as well by the authors: review of medical registers (n=37). The retrospective study also demonstrated that HCQ conferred no therapeutic benefit to the COVID-19 cases investigated.

Horby, 2020

(RECOVERY trial)

Type of study:

Randomized, open

label, controlled

trial (RECOVERY

trial)

Setting:

Multi-centre, 176

Hospitals

Country:

United Kingdom

Source of funding:

NIHR grant, NIHR

Oxford Biomedical

Research Centre,

Wellcome, the Bill

and Melinda Gates

Foundation, the

Department for

International

Development,

Health Data

Research UK, the

Medical Research Council Population

Health Research

Unit, the NIHR

Health Protection

Unit in Emerging

and Zoonotic

Infections, and NIHR

Clinical Trials Unit

Support Funding.

Authors received

funding from

several parties.

Inclusion criteria:

Clinically suspected or laboratory confirmed COVID-19 infection and no medical history that might, in the opinion of the

attending clinician, put the patient at significant risk by

participation in the trial. Initially, recruitment was limited to patients ≥ 18 years, but this limit was removed.

Exclusion criteria:

Patients with known prolonged

electrocardiograph QTc interval.

(Co-administration with medications that prolong the QT

interval was not a contraindication but it was

advised to check QT interval by

performing an ECG).

N total at baseline:

N = 4716

Intervention: 1561

Control: 3155

Important characteristics:

Age, mean (SD):

I: 65.2 (15.2)

C: 65.4 (15.4)

P= not reported

Sex, n/N (%) male:

I: 960/1561 (61.5)

C: 1974/3155 (62.6)

P= not reported

Respiratory support — no. (%)

No oxygen received

I: 362/1561 (23.2)

C: 750/3155 (23.8)

Oxygen only

I: 938/1561 (60.1)

C: 1873/3155 (59.4)

Invasive mechanical ventilation

I: 261/1561 (16.7)

C: 532/3155 (16.9)

Groups comparable at baseline.

Hydroxychloroquine + usual care

200mg tablet containing 155mg base equivalent. Patients received a loading dose of 4 tablets (800 mg)

at zero and 6 hours,

followed by 2 tablets (400 mg) starting at 12 hours after the initial dose and then every 12 hours for

the next 9 days or until discharge (whichever occurred earlier).

Usual care alone

A online follow-up form was to be completed when participants were discharged, had died or at 28 days after randomization (whichever occurred earlier). Further

analyses at 6 months.

Follow-up information was complete for 4619 (98%) of the randomized patients.

Mortality, 28 days (n/N/%)

I: 421/1561(27.0)

C: 790/3155 (25.0)

Rate Ratio (95%CI): 1.09

(0.97 to 1.23)

P=0.15

Stratified for baseline respiratory support

No oxygen received

 I: 58/362 (16.0)

 C: 99/750 (13.2)

 RR 1.24 (0.89−1.73)

Oxygen only

 I: 253/938 (27.0)

 C: 475/1873 (25.4)

 RR 1.08 (0.93−1.26)

Invasive mechanical ventilation

 110/261 (42.1)
 C: 216/532 (40.6)

 RR 1.03 (0.81−1.30)

Duration of hospitalization

Discharge within 28 days (n/N/%)

I: 931/1561 (59.6)

C:1983/3155 (62.9)

Rate Ratio (95%CI): 0.90

(0.83 to 0.98)

P= not reported

Time to symptom resolution

Not reported

Respiratory support

only reported in composite with death

Invasive mechanical ventilation

I: 128/1300 (9.8) C: 225/2623 (8.6)

RR 1.15 (0.93–1.41)

Safety

Cardiac-related events:

Any major cardiac arrhythmia, including : Supraventricular tachycardia, Ventricular tachycardia or fibrillation and Atrioventricular block requiring intervention, info on those with complete FU forms:
I: 60/735 (8.2%)

C: 90/1420 (6.3%)

Remarks:

RECOVERY is a large, pragmatic, randomized, controlled platform trial

designed to provide rapid and robust assessment of the impact of readily

available potential treatments for COVID-19 on 28-day mortality. This paper published the preliminary results on hydroxychloroquine.

From 12 May 2020, extra information was recorded on the occurrence of new major cardiac arrhythmia.

Since preliminary data showed no beneficial effect of hydroxychloroquine,

enrolment of participants was closed on 5 June and the preliminary result for the primary outcome was made public. Investigators were advised that any patients currently taking

hydroxychloroquine as part of the study should discontinue the treatment.

Authors conclusion:

The findings indicate that hydroxychloroquine is not an effective treatment for hospitalized patients with COVID-19 but do not address its use as prophylaxis or in patients with less

severe SARS-CoV-2 infection managed

in the community.

Lyngbakken, 2020

Type of study:

single center, two-arm, open label, group-sequential, pragmatic randomized controlled trial

Setting:

Single-center

Country:

Norway

Source of funding:

The authors declare no competing interests.

Inclusion criteria:

• >18 years old;
• SARS-CoV-2 positive

Exclusion criteria:

• Need of admission to ICU on hospital admission;
• History of psoriasis;
• Reduced hearing/tinnitus;
• Visual impairment;
• Known adverse reaction to hydroxychloroquine sulfate;
• Pregnancy
• Prolonged corrected QT interval (>450 ms).

N total at baseline:

N = 53

Intervention: N = 27

Control: N = 26

Important characteristics:

Age, median (IQR):

I: 56 (41 to 72)

C: 69 (51 to 74)

P= not reported

Sex, n/N (%) male:

I: 19/27 (70.4%)

C: 16/26 (61.5%)

BMI in kg/m² (range):

I: 25.6 (23.9 to 29.4)

C: 27.6 (24.2 to 33.0)

Groups comparable at baseline? Yes

hydroxychloroquine sulfate (at a dose of 400 mg twice daily for 7 days) + standard care.

Standard care alone.

30 days

Mortality, 28-30 day

Mortality, 30d, n/N (%)

I: 1/27 (3.9%).

C: 0/26 (0%)

Duration of hospitalization

Not reported

Time to symptoms resolution

Change in degree of illness as quantified; change in NEWS2 (National Early Warning Score 2)-score from randomization to 96 h (higher score indicates worse condition):

I: marginal mean change 0.47

[95% CI −0.58 to 1.53]

C: 0.29

[95% CI −0.88 to 1.46]

Diff between groups 0.18 [95% CI −1.40 to 1.76]

Respiratory support

Clinical status at 7-point ordinal scale* at 14 days

I:

 1: 1 (3.8%)

 2: 0

 3: 1 (3.8%)

 4: 0

 5: 1 (3.8%)

 6: 3 (11.5%)

 7: 20 (76.9%)

C:

 1: 1 (4.0%)

 2: 1 (4.0%)

 3: 0

 4: 2 (8.0%)

 5: 0

 6: 2 (8.0%)

 7: 19 (76.0%)

Cumulative odds ratio 1.11 [95% CI 0.31 to 4.01]

Safety

Adverse events; included visual disturbances, gastrointestinal discomfort, diarrhea, headache, nausea, or dizziness

I: 125

C: 112

Serious adverse events, n (%)b

I: 5 (18.5%)

C: 6 (23.1%)

No patient had >1 SAE. SAEs included acute respiratory distress syndrome (n = 1), pneumonia (n = 2), respiratory failure (n = 7), and urinary tract

infection (n = 1).

Viral clearance

Rate of reduction in SARS-CoV-2 viral load; log10 RNA copies/mL/24 h

I: 0.24 (95% CI 0.03 to 0.46)

C: 0.14 (95% CI -0.10 to 0.37)

MD= 0.11 (95% CI= -0.21 to 0.43).

Definitions

Clinical status at 7-point ordinal scale:

1. dead, 2. hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation, 3. hospitalized, on noninvasive ventilation or high flow oxygen devices, 4. hospitalized, requiring supplemental oxygen, 5. hospitalized, not requiring supplemental oxygen, 6. not hospitalized, but unable to resume normal activities, 7. not hospitalized, with resumption of normal activities

Remarks:

Because of rapidly decreasing

incidence of COVID-19 in Norway, the trial was prematurely stopped by the trial sponsor on May 25, 2020.

Authors conclusion:

In conclusion, therapy with hydroxychloroquine did not impact SARS-CoV-2 viral kinetics in patients admitted to hospital with moderately severe COVID-19. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2.

Pan, 2020

(WHO SOLIDARITY trial)

Type of study:

RCT (open-label, non-blinded)

Setting & country:

405 hospitals in 30 countries; WHO Solidarity Trial

Source of funding:

Funded by the World Health Organization;

ISRCTN Registry nr, ISRCTN83971151; ClinicalTrials.gov nr, NCT04315948.)

N total at baseline:

N = 11,330

Hydroxychloroquine arm

I: 947

C: 906

Important characteristics:

Age, n/N (%):

I:

<50y: 335/947(35.4%)

50-69y: 410/947(43.3%)

≥70y: 202/947 (21.3%)

C:

<50y: 317/906 (35.0%)

50-69y: 396/906 (43.7%)

≥70y: 193/906 (21.3%)

Sex, n/N (%) male:

I: 574/947 (60.6%)

C: 535/906 (59.1%)

Respiratory support

I:

No suppl. Oxygen at entry:

345/947(36.4%)

Suppl. Oxygen at entry

517/947 (54.6%)

Already receiving ventilation

85/947 (9.0%)

C:

No suppl. Oxygen at entry:

341/906 (37.6%)

Suppl. Oxygen at entry

483/906 (53.3%)

Already receiving ventilation

82/906 (9.2%)

Previous days in hospital

I:

0 days: 296/947 (32.2%)

1 day: 317/947 (33.5%)

≥2 days: 334/947 (35.3%)

C:

0 days: 281/906 (31.0%)

1 day: 312/906 (34.4%)

≥2 days: 313/906 (34.5%)

Hydroxychloroquine

Oral; 4 tablets at hour 0, 4 tablets at hour 6,

and, starting at hour 12, two tablets twice daily for 10 days. Each tablet contained 200 mg of

hydroxychloroquine sulfate (155 mg of hydroxychloroquine

base per tablet; a little-used alternative

involved 155 mg of chloroquine base per

tablet).

Discontinued for futility on June 19, 2020

Taking trial drug midway through scheduled duration*:

I: 95%

C: 6%

Use of non-study drug, n/N (%)s:

Corticosteroids

I: 140 (14.8%)

C: 140 (15.5%

Convalescent plasma

I: 7 (0.7%)

C: 3 (0.3%)

Anti-IL-6 drug

I: 21 (2.2%)

C: 18 (2.0%)

Non-trial interferon

I: 2 (0.2%)

C: 1 (0.1%)

Non-trial antiviral

I: 62 (6.6%)

C: 54 (6.0%)

Standard of care

Length of follow up:

28 days, or up to discharge

Loss to follow-up:

I: 7/954 (0.7%)

Reasons: no or unknown consent

C: 3/909 (0.3%)

Reasons: no or unknown consent

Mortality, 28-30 day

All-cause in-hospital mortality,

regardless of whether death occurred before or after day 28:

I: 104/947 (10.2%)

C: 84/906 (8.9%)

RR=1.19 (0.89-1.59),

Adjusted** HR=1.14 (0.89-1.46),

All-cause in-hospital mortality, stratified by ventilation at randomization:

Ventilated: HR 1.26 (95% CI 0.76-2.10)

Not ventilated: HR 1.16 (95% CI 0.82-1.65)

Duration of hospitalization

Hospitalized, not discharged:

Percentage of patients (rather than number of patients) ever reported as discharged who were still in the hospital:

Day 7, %

I: 64%

C: 54%

Day 14

I: 23%

C: 20%

Day 21

I: 11%

C: 10%

Time to symptoms resolution

Not reported

Respiratory support

Initiation of mechanical ventilation, in those not receiving ventilation at baseline:

I: 75/862 (8.7%)

C: 66/824 (8.0%)

RR 1.09 (95% CI 0.79 to 1.49)

Safety – adverse events

Not reported

Viral clearance

Not reported

Also reported:

Composite death or initiation ventilation:

I: 150/947 (15.5%)

C: 131/906 (14.3%)

RR 1.10 (95% CI 0.88 to 1.36)

Publication: RR 1.11 [0.87-1.42]

Definitions/information:

Taking trial drug midway through scheduled duration, %, calculated only among patients who died or were discharged alive, % patients who were taking the trial drug midway through its

scheduled duration (or midway through the time from entry to death or discharge, if this was shorter).

*Adjusted model all-cause mortality: some overlap between the 4 control groups; an exploratory sensitivity analysis used multivariate Cox regression to fit all 4 treatment effects simultaneously; adjusted for several prognostic factors (age, sex, diabetes, bilateral lung lesions at entry (no, yes, not imaged at entry), and respiratory support at entry (no oxygen, oxygen but no ventilation, ventilation).

Authors conclusion:

These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little

or no effect on hospitalized patients with Covid-19, as indicated by overall mortality,

initiation of ventilation, and duration of hospital stay.

Self, 2020

Type of study:

Double blind RCT

Setting:

Multicenter, April 2, 2020, and June 19, 2020, at 34 hospitals in the US within the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network

Country:

United States of America

Source of funding:

National Heart, Lung, and Blood Institute

Inclusion criteria:

• hospitalized COVID-19 patients for less than 48 hours
• laboratory-confirmed SARS-CoV-2 infection
• symptoms of respiratory illness for less than 10 days

Exclusion criteria:

• more than 1 dose of hydroxychloroquine or chloroquine in the prior 10 days
• QTc interval greater than 500 ms
• Prior receipt or planned administration of select medications that prolong the QTc interval
• Seizure disorder

N total at baseline:

N = 479

Intervention: 242

Control: 237

Important characteristics:

Age, median (IQR):

I: 58 y (45-69)

C: 57 y (43-68)

Sex, n (%) male:

I: 135 (55.8%)

C: 132 (55.7%)

COVID Outcomes Scale, mean (SD):

Defined by patient’s clinical status (1-7), mild to severe.

2: Hospitalized, receiving ECMO or invasive mechanical ventilation

I: 13 (5.4)

C: 19 (8.0)

3: Hospitalized, receiving noninvasive ventilation or nasal high-flow oxygen

I: 28 (11.6)

C: 27 (11.4)

4: Hospitalized, receiving supplemental oxygen without positive pressure or high flow

I: 116 (47.9)

C: 108 (45.6)

5: Hospitalized, not receiving supplemental oxygen

I: 85 (35.1)

C: 83 (35.0)

Groups comparable at baseline? Yes

400 mg of hydroxychloroquine sulfate in pill form twice a day for the first 2 doses and then 200 mg in pill form twice a day for the subsequent 8 doses, for a total

of 10 doses over 5 days

Matching placebo in the same dosing frequency

Length of follow up:

28 days

Loss to follow-up:

I: 0 (0%)

C: 0 (0%)

Mortality, 28-30 day

All-cause mortality,

28 days, n (%):

 I: 25/242 (10.4%)

 C: 25/237 (10.6%)

 Absolute difference: -

 0.2% (95% CI -5.7 to

 5.3%);

 aOR: 1.07 (95% CI 0.54

 to 2.09)

14 days

 I: 18 (7.5)

 C: 14 (5.9)

 Diff 1.5 (−2.9 to 6.0)

Duration of hospitalization

Hospital-free days through 28 days, median (IQR)

I: 21 (11 to 24)

C: 20 (10 to 24)

Diff 1 (−1 to 3)

aOR 1.17 (0.85 to 1.61)

Time to symptoms resolution

Time to recovery, defined as time to reach COVID Outcome Scale category 5, 6, or 7; median (IQR)

I: 5 (1 to 14)

C: 6 (1 to 15)

Respiratory support

Clinical status after randomization

Assessed; 7-point WHO scale*, median (IQR)

14 days

I: 6 (4 to 7); C: 6 (4 to 7)

Diff 0

aOR 1.02 (0.73 to 1.42)

28 days

I: 6 (6 to 7); C: 6 (6 to 7)

Diff 0 (−1 to 1)

aOR 0.97 (0.69 to 1.38)

Clinical status at day 28

Hospitalized with oxygen

I: 9 (3.7); C: 10 (4.2)

3: Noninvasive ventilation or high-fow nasal cannula

I: 0

C: 0

Invasive mechanical ventilation or ECMO

I: 11 (4.5); C: 12 (5.1)

Oxygen-free days, through 28 days, median (IQR)

I: 21 (0 to 27)

C: 20 (0 to 27)

Ventilator-free days, through 28 days, median (IQR)

I: 28 (28 to 28)

C: 28 (28 to 28)

Safety – adverse events

Systematically collected safety events, n (%):

Cytopenia

I: 92 (38); C: 87 (36.7)

AST or ALT ≥2 times upper limit of normal

I: 50 (20.7); C:65 (27.4)

Cardiac arrest treated with CPR

I: 10 (4.1); C: 4 (1.7)

Symptomatic hypoglycemia

I: 10 (4.1); C: 8 (3.4)

Ventricular tachyarrhythmia

I: 5 (2.1); C: 6 (2.5)

Seizure

I: 1 (0.4); C: 0

SAE

I: 18 in 14 (5.8%) patients

C: 12 in 11 (4.6%) patients

Diff 1.1 (−3.0 to 5.2)

Viral clearance

Not reported

Definitions

7-point WHO scale for clinical status:

1, death; 2, hospitalized, receiving extracorporeal

membrane oxygenation (ECMO) or invasive mechanical

ventilation; 3, hospitalized, receiving noninvasive mechanical

ventilation or nasal high-flow oxygen therapy; 4, hospitalized,

receiving supplemental oxygen without positive

pressure or high flow; 5, hospitalized, not receiving supplemental

oxygen; 6, not hospitalized and unable to perform

normal activities; and 7, not hospitalized and able to perform

normal activities.

Adjusted OR:

Used covariables: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization

Remarks:

• “On June 19, 2020, enrollment was stopped for futility based on recommendations from the DSMB after it reviewed information both internal and external to the trial. Enrollment was stopped at the fourth interim analysis, which included 371 patients with primary outcome data and an additional 108 patients who had not reached 14 days after randomization for primary outcome assessment. At that time, trial data did not meet the prespecified threshold for futility (defined as >90% probability of an aOR < 1.1 for the primary outcome) but demonstrated an 81% probability for an aOR less than 1.1”

Authors conclusion:

Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly

improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Tang,

2020

Type of study:

multicentre, randomised, parallel, open

label trial

Setting:

16 government designated

covid-19 treatment centres in three provinces (Hubei, Henan, and Anhui); 11 to 29 February 2020

Country:

China

Source of funding:

Multiple funding.
Described in detail; see manuscript

Inclusion criteria:

• age ≥18 years
• RT-PCR confirmed ongoing SARS-CoV-2 infection in upper or lower respiratory tract
• willingness to participate, consent not to be enrolled in other clinical trials during the study period

Not mandatory: pneumonia on chest CT

Exclusion criteria:

• Severe conditions (e.g. malignancies, heart, liver, or

kidney disease or poorly controlled metabolic diseases

• unsuitability for oral administration
• pregnancy or lactation
• allergy to HCQ
• cognitive impairments or poor mental status, disabling cooperation
• severe hepatic and renal impairment or receipt of

continuous renal replacement therapy, haemodialysis,

or peritoneal dialysis.

N total at baseline: 150

Intervention: 75

Control: 75

Important characteristics:

Age, mean±SD:

I: 48.0 ± 14.1

C: 44.1 ± 15.0

Sex, n/N (%) male:

I: 42/75 (56%)

C: 40/75 (53%)

Days from disease onset to randomisation, mean±SD:
I: 16.0±9.9

C: 17.1±11.1

Groups comparable at baseline.

Also described: exposure history, treatment before randomisation, vital signs, comorbidities, laboratory parameters

Standard care

+

hydroxychloroquine

(HCQ)

HCQ: start within

24 hours after randomisation,

Day 1-3: loading dose 1200 mg daily for three days

From day 4 on: maintenance dose 800 mg daily

Treatment duration: 2 weeks in mild to moderate disease, 3 weeks in severe disease

In case of adverse events related to HCQ as adjusted

by investigators, the dose of HCQ was adjusted.

Standard care

Follow-up duration:

28 days

Loss to follow-up:

none

Mortality, 28-30 day

I: 0; C: 0

“… and no patients died during follow-up.”

Duration of hospitalization

Not reported

Time to symptoms resolution

Alleviation of symptoms*; probability alleviation day 28 days

I: 59.9%, (95% CI 45.0 - 75.3)

C:66.6% (95% CI 39.5 - 90.9)

Diff –6.6% (95% CI –41.3 - 28.0)

Time to alleviation, days, Median:

I: 19; C: 21

HR 1.01, 0.59 to 1.74

P=0.97

“As the trial was stopped early and only two patients with severe

disease were enrolled, results on clinical improvement are not presented.”

Respiratory support

Not reported

Safety – adverse events

Safety (based on actual exposure)

Duration HCQ treatment, days, median (range):

I: 14 (1-22)

C: n.a.

Adverse events, n/N (%):

I: 21/70 (30%)

C: 7/80 (9%)

Serious adverse events, n/N (%):

I: 2 /70 (3%)

(1xupper respiratory tract infection, 1x disease progression

C: 0

Viral clearance

SARSCoV-2 negative conversion at 28 days:

I: 85.4% (95% CI 73.8 - 93.8)

C: 81.3% (95% CI 71.2 - 89.6)

Mean diff: 4.1% (95% CI -10.3% to 18.5%).

Median time to negative conversion, days:

I: 8 (95% CI 5 – 10)

C: 7 (95% CI 75 – 8)

HR: 0.85, (95% CI 0.58 to 1.23) P=0.34

Definitions:

Alleviation of symptoms* was defined as resolving from fever to an axillary temperature of 36.6°C or below, normalisation of SpO2 (>94% on room air), and disappearance of respiratory symptoms including nasal congestion, cough, sore throat, sputum production, and shortness of breath

Remarks:

• This was a RCT, open-labelled.
• Data regarding viral clearance and alleviation of symptoms were analysed according to intention-to-treat protocol.
• Almost all patients had mild to moderate disease (only 2/150 severe)
• “After a two round extensive review of the efficacy and safety data generated from the interim analysis, the IDMC endorsed an early termination of the trial. Members of the committee all agreed that the data from the trial are important for clinicians, the public, and the government to avoid inappropriate use of hydroxychloroquine in the clinical management of covid-19, particularly in areas with overwhelming patient numbers.”
• Longer follow-up period (supplem. Data) shows results consistent with reported results

Authors conclusion:

Administration of hydroxychloroquine did not result in a significantly higher probability of negative

conversion than standard of care alone in patients admitted to hospital with mainly persistent mild to

moderate covid-19. Adverse events were higher in hydroxychloroquine recipients than in non-recipients.

Ulrich, 2020 (TEACH)

Type of study:

Multicenter, double-blind, randomized clinical trial

Setting:

NYU Langone Health (Tisch Hospital and Kimmel Pavilion, NYU Langone—Brooklyn Hospital, and

NYU Winthrop Hospital), NYC Health and Hospitals / Bellevue Hospital Center (BHC), and State University of New York (SUNY) Downstate Medical Center.

Country:

USA

Source of funding:

This work was supported by the New York University Grossman School of Medicine. R.J.U. is supported in part by the NYU CTSA grant (TL1 TR001445) from the National Center for Advancing Translational Sciences (NCATS) and the New York State Empire Clinical Research Investigator Program (ECRIP). M.J.M. and V.R. are supported by the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) grant (UM1 AI148574). J.A.D. is supported by National Institutes of Health Fogarty grants (D43 TW010046, D43 TW010562, and D43 TW011532). This research was supported in part by an NYU CTSA grant (UL1 TR001445) from the National Center for Advancing Translational Sciences, National Institutes of Health. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors have no relevant financial disclosures. All authors: no reported conflicts of interest. All authors have

submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Conflicts that the editors consider relevant to the content of the manuscript

have been disclosed.

Hospitalized patients with COVID-19

Inclusion criteria:

• At least one COVID-19 symptom (eg, fever, cough, dyspnea, nausea, diarrhea, myalgia, anosmia, dysgeusia);
• The subject’s (or legally authorized representative’s) written informed consent.

Exclusion criteria:

• Subjects who met the primary end point at enrolment;
• Patients who had received any doses of HCQ or chloroquine (CQ) within 30 days;
• Patients who were unable to take oral medications;
• Patients who were allergic to HCQ or CQ;
• Patients who had a baseline corrected QT (QTc) interval >500 ms;
• Patients who were on concomitant therapy with antiarrhytmic medications (flecainide, amiodarone, digoxin, procainamide, propafenone, thioridazine, or pimozide);
• Patients who had a history of cardiac arrest retinal disease, or glucose-6-phosophate dehydrogenase deficiency.

N total at baseline:

N = 128

Intervention: 67

Control: 61

Important characteristics:

Age, mean (SD):

I: 66.5 (16.4) years

C: 65.8 (16.0) years

P=0.804

Sex, n/N (%) male:

I: 45/67 (67.2%)

C: 31/61 (50.8%)

P=0.089

Disease severity, median (IQR) Defined by COVID-19 severity score

3: Hospitalized, on non-invasive ventilation or high-flow nasal cannula

I: 14/67

C: 7/61

Total: 21/128

4: Hospitalized, on supplemental oxygen

I: 26/67 (38.8%)

C: 36 (59.0%)

Total: 62/128)

5: Hospitalized, not on O2, requiring ongoing medical care

I: 26/67

C: 17/61

Total: 43/128

6: Hospitalized, not on O2, not requiring ongoing care

I: 1/67 (1.5%)

C: 1/61 (1.6%)

Total: 2/128 (1.6%)

P=0.777

Symptom duration (days since symptom onset)

I: 6.50 (6.00)

C: 7.00 (10.0)

P=0.091

Groups comparable at baseline.

Hydroxychloroquine sulfate 400 mg by mouth 2 times per day (day 1) and 200 mg by mouth 2 times per day (days 2-5). The 5-day course was based on in vitro projections to optimize HCQ tissue levels against SARS-CoV-2.

Placebo (calcium citrate 400 mg by mouth 2 times per day (day 1) and 200 mg by mouth 2 times per day (days 2-5). The 5-day course was based on in vitro projections to optimize HCQ tissue levels against SARS-CoV-2.

Length of follow up:

30 days.

Loss to follow-up:

I: n/N (%)

Reasons:

C: n/N (%)

Reasons:

Mortality, 28-30 day

Mortality (day 14), n/N (%)

I: 3/67 (4.5%)

C: 5/61 (8.2%)

Total: 8/128)

P=0.350

Mortality (day 30), n/N (%)

I: 7/67 (10.4%)
C: 6/61 (9.8%)

Total: 13/128 (10.2)

P=1.000

Duration of hospitalization

Length of stay – admission to discharge, mean (SD)

I: 9.75 (10.3)

C: 6.80 (5.92)

Total: 8.34 (8.59)

P=0.053

Time to symptoms resolution

(fever-free days), mean (SD)

I: 6.40 (0.94)

C: 6.31 (1.33)

Total: 6.36 (1.13)

P=0.631

Respiratory support

Clinical improvement (COVID-severity score at day 14), n/N (%)

1: death

I: 3/67 (4.5%)

C: 5/61 (8.2%)

Total: 8/128 (6.2%)

2: Ventilator or ECMO

I: 2/67 (3.0%)

C: 0/61 (0%)

Total: 2/128 (1.6%)

3: Hospitalized, on NIV or high-flow nasal

I: 7/67 (10.4%)

C: 2/61 (3.3%)

Total: 9/128 (7.0%)

4: Hospitalized, on supplemental oxygen

I: 4/67 (6.0%)

C: 1/61 (1.6%)

Total: 5/128 (3.9%)

5: Hospitalized, not on O2, ongoing medical care

I: 2/67 (3.0%)

C: 0/61 (0%)

Total: 2/128 (1.6%)

6: Hospitalized, not on O2, not requiring ongoing care

I: 1/67 (1.5%)

C: 2/61 (3.3%)

Total: 3/128 (2.3%)

7: Outpatient, no limitation on activities or home O2

I: 13/67 (19.4%)

C: 18/61 (29.5%)

Total: 31/128 (24.2%)

8: Outpatient, no limitation on activities

I: 28/67 (41.8%)

C: 29/61 (47.5%)

Total: 57 (44.5%)

Unknown:

I: 7/67 (10.4%)

C: 4/61 (6.6%)

Total: 11/128 (8.6%)

O2-supplementation-free days, mean (SD)

I: 4.63 (2.44)

C: 4.43 (2.40)

Total: 4.53 (2.41)

P=640

Mechanical ventilation, n/N (%)

day 14

I: 5/67 (7.5%)

C: 4/61 (6.6%)

Total: 9/128 (7/0%)

P=1.000

day 30

I: 5/67 (7.5%)

C: 3/61 (4.9%)

Total: 8/128(6.2%)

P=0.778

Safety – adverse events

Cardiac-related events:

(Arrhythmia, cardiac arrest)

I: 0

C: 0

Total No. of patients with AE, n(%)

I: 38/67 (56.7)

C: 36/61 (59.0)

P=.933

Of which possibly related to study treatment

I: 7 (10.4)

C: 4 (6.6)

P=.639

AEs included GI symptoms, rash, headache

Total No. of events

I: 63

C: 59

Viral clearance

Not reported

Definitions:

-

Remarks:

-

Authors conclusion:

Therapies against SARS-CoV-2 are urgently needed to improve COVID-19 morbidity and mortality. This double blind, placebo-controlled randomized trial did not suggest that HCQ is beneficial in preventing severe outcomes or improving clinical scores among non-ICU hospitalized patients with COVID19. Treatment with HCQ was associated with a slight QTc interval prolongation, increased D-dimer, and a trend toward increased length of stay. However, our findings are limited due

to a relatively small sample size, and larger randomized trials are needed.

Hydroxychloroquine – non-hospitalized

Mitjà,

2020

Type of study:

open-label, randomized, controlled trial

Setting:

Multicenter, 3 health administrative regions in Catalonia

Country:

Spain

Source of funding:

This work was mainly supported by the crowdfunding campaign JoEmCorono (https://www.yomecorono.com/) with the contribution of over 72,000 citizens and corporations. The study also received financial support from Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®).

Inclusion criteria:

• patients aged ≥ 18 years
• mild symptoms of Covid-19 (i.e., fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like-illness) for < 5 days before enrolment
• non-hospitalized
• positive PCR test for SARS-CoV-2 in the baseline nasopharyngeal swab.

Exclusion criteria:

• moderate-to-severe Covid-19 disease (e.g., required hospitalization),
• any condition that might preclude following the study procedures safely (e.g., mental disability),
• known allergy or hypersensitivity to study drugs,
• known retinal and severe liver or renal diseases,
• history of cardiac arrhythmia,
• known QT prolongation or other diseases that could be exacerbated by study drugs (e.g., psoriasis),
• active treatment with medications that are contraindicated with study drugs, or
• known HIV infection.
• pregnant or breastfeeding

N total at baseline:

N = 293

Intervention: 136

Control: 157

Important characteristics:

Age, mean (SD):

I: 41.6 (12.4)

C: 41.7 (12.6)

P=not reported

Sex, n/N (%) male:

I: 98/136 (72.1%)

C: 103/157 (65.6%)

P=not reported

Groups comparable at baseline?

Yes

Hydroxychloroquine

HCQ - Dolquine®, 800 mg on day 1, followed by 400 mg once daily for six days)

Usual care

No treatment aside from usual care

28 days

Mortality, 28d

I: 0

C: 0

“No patients required mechanical ventilation or died during the study period.”

Hospitalization

I: 5.9%, 8/136

C: 7.1%, 11/157

RR 0.75 [95% CI 0.32; 1.77]).

Time to symptom resolution,

Complete resolution of symptoms* within 28 days, median

I: 10.0, IQR 4–18

C: 12.0 days, IQR 6–21)

log-rank-test for survival analysis p = 0.38

Respiratory support

Mechanical ventilation

I: 0

C: 0

“No patients required mechanical ventilation or died during the study period.”

Safety (in safety population)

at least one AE during, 28d FU

I: 121/169 (72.0%)

C: 16/184 (8.7%) The most frequent treatment-related AEs among participants given HCQ were gastrointestinal (e.g., diarrhea, nausea, and abdominal pain) and nervous system disorders (e.g., drowsiness, headache, and metallic taste).

SAE

I: 8/169 (4.7%)

C: 12/184 (6.5%)

Of which none related to HCQ.

Viral clearance

Viral RNA load in nasopharyngeal swab, reduction from baseline, mean difference:

Day 3

I: 1.41 Log10 copies/mL

C: -1.41 Log10 copies/mL

(difference [d] 0.01 [95% CI –0.28; 0.29])

Day 7

I: –3.44 Log10 copies/mL

C: 3.37 Log10 copies/mL

(d –0.07 [–0.44; 0.29]).

Definitions:

*Resolution of symptoms was assessed sequentially

using a symptoms questionnaire designed to gather information on the type of symptom and last

day experienced; complete resolution was considered when no Covid-19-related symptoms were

reported at all.

Remarks:

- Initially, the protocol included the use of HCQ and cobicistat-boosted darunavir (DRVc) combined treatment, but it was adapted to HCQ alone after the recommendation of the pharmaceutical company not to use DRVc for the treatment of Covid-19 due to lack of activity in-vitro and the negative results in human clinical trials of closely related HIV protease inhibitors.

Authors conclusion:

- Compared with usual care, early treatment with HCQ failed to reduce the RNA viral load in nasopharyngeal swabs after 3 and 7 days of treatment and shorten the time to complete resolution of symptoms in adults with PCR-confirmed mild Covid-19.

- Our results indicate no impact on viral burden up to 7 days nor symptoms resolution or hospitalization rate up to 28 days following diagnosis. The added value of our study is the randomized-controlled design and the use of the agreed minimal outcome set for Covid-19 clinical trials, including RT-PCR to conclusively determine the viral burden. Our findings provide the scientific community and policymakers with essential insights on the inefficacy of HCQ as a therapeutic candidate for SARS-CoV-2, at least in similar settings and conditions to ours.

Omrani, 2020 (Q-PROTECT)

Type of study:

RCT (parallel)

Setting:

two units of Qatar’s national healthcare system, Hamad

Medical Corporation (HMC). The first was the Emergency Department (ED) at HMC’s tertiary hospital, Doha’s Hamad General Hospital (HGH). The second unit was a 3500-bed quarantine facility 20 miles north of Doha, at Umm Qarn

Country:

Qatar

Source of funding:

The study was supported by internal institutional funds of the Hamad Medical Corporation (government health service of the State

of Qatar).

Conflict of interest

The authors have no financial or personal relationships with other people or organizations that could represent a conflict of interest.

SARS-CoV-2 PCR-positive males and females with mild or no symptoms.

Inclusion criteria:

• Hospitalization;
• Tachypnoea (respirations >29/minute);
• Hypoxemia (pulse oximetry on room air <93%);
• Treatment was also recommended for any patient with chest X-ray abnormality who had risk factors of older age (>60); Immunocompromise;

Comorbidity (e.g. diabetes or hypertension)

Exclusion criteria:

• Retinal or macular disease;
• Psoriasis;
• Hepatic or renal disease;
• Porphyria;
• Glucose-6-dehydrogenase (G6PD) deficiency;
• QT-interval prolongation;
• Hypersensitivity;
• HC or AZ;
• Pregnancy;
• Laboratory assessment revealed low levels of potassium or magnesium, or elevated creatine or transaminases.

N total at baseline:

N = 456

Intervention-1: 152

Intervention-2: 152

Control: 152

Important characteristics:

Age, median (IQR):

I-1: 42 years (38-48)

I-2: 40 years (31-47)

C: 41 years (31-47)

Sex, n/N (%) male:

I-1: 150/152 (98.7%)

I-2: 149/152 (98.0%)

C: 150/152 (98.7%)

Disease severity, median (IQR): Symptoms at enrolment, Patient-reported fever

I-1: 46 (30.3%)

I-2: 51 (33.6%)

C: 52 (34.2%)

Respiratory symptoms

I-1: 37 (24.3%)

I-2: 36 (23.7%)
C: 34 (22.4%)

Groups comparable at baseline? Yes

Hydroxychloroquine

Intervention-1:

Oral hydroxychloroquine plus oral azithromycin (500 mg day one, 250 mg daily on days two through five)

Intervention-2:

Oral hydroxychloroquine (600 mg daily for one week)

Placebo

Length of follow up:

21 days

Loss to follow-up:

• 432 participants had all three symptom assessment follow-ups at day 7, 14 and 21.
• 439 participants had symptom assessment at day 7.
• 438 patients had symptom assessment at day 14 and 21.

Reasons for loss to follow-up

• Dropping out at participants request.
• Hospitalization.
• Transfer to military hospital

Unavailability for contact.

Mortality, 28d

Not reported.

Mortality other:

Not reported

Duration of hospitalization

Not reported.

Time to symptom resolution

Symptomatic day one and:

Asymptomatic day 7

I-1: 56 of 70 (80.0%, 68.7-88.6%)

I-2: 55 of 69 (79.7%, 68.3-88.4%)

C: 52 of 59 (88.1%, 77.1-95.1%)

P=0.377

Asymptomatic day 14

I-1: 66 of 69 (95.7%, 87.8-99.1%)

I-2: 64 of 69 (92.8%, 83.9-97.6%)

C: 58 of 60 (96.7%, 88.5-99.6%)

P=0.716

Asymptomatic day 21

I-1: 67 of 69 (97.1%, 89.9-99.6%)

I-2: 68 of 69 (98.6%, 92.2-100.0%)

C: 56 of 60 (93.3%, 83.8-98.2%)P=0.299

Respiratory support

Not reported

Safety

QT prolongation

>30 msec

I-1: 37 (24.3%; 17.8-32.0%)

I-2: 31 (20.4%; 14.3-27.7%)

C: 13 (8.8%; 4.8-14.6%)

p= 0.001

>60 msec

I-1: 5 (3.3%; 1.1-7.5%)

I-2: 4 (2.6%; 0.76.6%)

C: 2 (1.4%; 0.2-4.8%) p=0.641

Viral clearance

Virologic cure, defined as (PCR-negative status), n/N (%) (95% CI)

day six

I-1: 16/152 (10.5%) (95% CI= 6.1 to 16.5%)

I-2: 19/149 (12.8%) (95% CI= 7.9 to 19.2%)

C: 18/147 (12.2%) (95% CI= 7.4 to 18.7%)

P=0.821

day 14

I-1: 30/149 (20.1%) (95% CI= 14.0 to 27.5%)

I-2 42/146 (28.8%) (95% CI= 21.6 to 36.8%)

C: 45/143 (31.5%) (95% CI= 24.0 to 39.8%)

P=0.072

Increase in cycle threshold from day one to day six, median (IQR) (95% CI)

I-1: 7.2 (3.9 to 11.5) (95% CI= 6.1 to 8.8)

I-2: 7.5 (3.4 to 11.5) (95% CI= 5.7 to 8.8)

C: 8.0 (4.1 to 11.7) (95% CI= 7.3 to 9.0)

P=0.634

Definitions:

-

Remarks:

Authors conclusion:

The lessons of Q-PROTECT must be considered in light of the trial strengths and weaknesses, the medication risks and benefits, and the existing evidence base. Taking all of these factors into account, the

investigators conclude that HC±AZ shows no sign of usefulness in the population studied, and that there is low likelihood of undiscovered drug benefits outweighing therapeutic risks.

Skipper, 2020

Type of study:

Randomized, double-blind, placebo-controlled trial

Setting:

Internet-based trial across the United States and Canada

(40 states and 3 provinces).

Country:

USA and Canada

Source of funding:

By Steve Kirsch, Jan and David Baszucki, the Minnesota Chinese Chamber of Commerce, the Alliance of Minnesota Chinese Organizations, and the University of Minnesota

Foundation. Authors were supported by several funds. Apotex Canada and Rising Pharmaceuticals in

the United States provided a donation of some of the hydroxychloroquine

tablets used.

Inclusion criteria:

• non-hospitalized adults
• ≤ 4 days of symptoms
• PCR-confirmed SARS-CoV-2 infection or compatible symptoms after a high-risk exposure to a person with PCR-confirmed COVID-19 within the past 14 days.

Exclusion criteria:

• Age < 18 years
• Hospitalized
• received certain medications,
• met other safety exclusion criteria.

N total at baseline:

N = 423

Intervention: 212

Control: 211

Important characteristics:

Age, median (IQR):

I: 41 (33–49)

C: 39 (31–50)

P=not reported

Sex, n/N (%) male:

I: 89/212 (42%)

C: 96/211 (45%)

P=not reported

Groups comparable at baseline?

Yes

Hydroxychloroquine

800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours

later, then 600 mg (3 tablets) once daily for 4 more days (5

days in total).

Medication adherence

I: 77% (157 of 203)

Placebo

Placebo tablets of folic acid, 400 mcg, were prescribed as an identical regimen for the control group. In Canada, the placebo tablets were lactose.

Medication adherence

C: 86% (166 of 194)

Length of follow up

14 days

Mortality, 28d

Not reported

Mortality, other

Death, 14d

I: 1 (non-hospitalized)

C: 1 (hospitalized)

Hospitalization

Hospitalisation, 14d

I: 4/212

C: 10/211 (of which 2 not related to study)

Total events hospitalization or death, 14 d

I: 5

C: 10

P = 0.29

Respiratory support

Not reported

Time to symptom resolution

Change in symptom severity score over 14 days;

on a 10-point VAS

I: -2.6 points (SE 0.12)

C: -2.33 points (SE 0.12)

(absolute difference,

-0.27 points [95% CI, -0.61 to 0.07 points]; P = 0.117)

Safety

Adverse events

I: 43% [92 of 212]

C: 22% [46 of 211];

P < 0.001.

Serious adverse events

I: 0

C: 0

Viral clearance

Not reported

Remarks:

-participants with no data were excluded from analyses (5.3%)

-also probable COVID-19 patients were included. Only 58% of participants received SARS-CoV-2

testing because of severe U.S. testing shortages.

-primary outcome was changes after interim analyses

Authors conclusion:

- Hydroxychloroquine

did not substantially reduce symptom severity or prevalence over time in nonhospitalized persons

with early COVID-19. This trial may not inform whether an effect would be observed in populations at higher

risk for severe COVID-19. Further randomized controlled clinical trials are needed in early COVID-19.

- Hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.

Barratt-Due, 2021

Type of study:

Independent, add-on RCT to WHO Solidarity trial, an open-label, adaptive RCT

Setting:

23 hospitals, between 28 March and 5 October 2020

Country:

Norway

Source of funding:

National Clinical Therapy Research, no role in RCT

Conflicts of interest:

JTA reports grant from South-Eastern Norway Regional Health Authority. ABD reports paid lecture by Allergan Norden AB and participation in advisory board meeting SANOFI-AVENTIS Norwy. SGD reports grant from Research Council of Norway. FLJ reports funding from Oslo University Hospital and Helse SørØst. MT reports participation in European advisory board for Eli Lilly and coordinator of National reference group on COVID-19 treatment in Norway.

Hospitalized patients with confirmed SARS-CoV-2 infection

Inclusion criteria:

• ≥18 years
• SARS-CoV-2 confirmed by PCR
• Hospitalized (ward or intensive care)

Exclusion criteria:

• Severe comorbid conditions with life expectancy <3 months
• Aspartate aminotransferase or alanine aminotransferase levels >5x normal upper limit
• Rate-corrected QT interval > 470 ms
• Pregnancy or breastfeeding
• Acute occurrence comorbid condition >7 days before inclusion
• Known intolerance to study drugs
• Participation confounding trial
• Concomitant medications interfering with study drugs

N total at baseline:

N = 181

Remdesivir: n=42

Hydroxychloroquine: n=52

Control remdesivir: n=57

Control HSQ: n=54

(some controls were in both groups)

Important characteristics:

Age, mean (SD): 59.8 (15.3)

R: 59.7 y (16.5)

CR: 58.1 y (15.7)

H: 60.3 y (13.3)

CH: 59.2 y (16.4)

Sex, n/N (%) male:

R: 29/42 (69%)

CR: 43/57 (75%)

H: 31/52 (60%)

CH: 34/54 (63%)

Disease severity, mean (SD):

Defined by Viral load (log₁₀ count/1000 cells)

R: 1.6 (1.6)

CR: 2.3 (1.8)

H: 2.3 (1.5)

CH: 2.0 (1.5)

Anti-SARS-CoV-2 antibodies, seroconverted (RDB ≥5) n/N (%)

R: 14/42 (42.4%)

CR: 18/57 (46.2%)

H: 15/52 (42.9%)

CH: 20/54 (54.1%)

Groups are not comparable on baseline regarding sex, comorbid conditions, ICU admission, P-F ratio less than 40 kPa, ACE and ARB medication, LDH level, D-dimer level, AST level, ALT, level.

R: standard of care plus 200 mg intravenous remdesivir on day 1, 100 mg daily up to day 9

H: standard of care plus 800 mg oral hydroxychloroquine 2x day on day 1, 400 mg 2x day up to day 9

All study treatment were discontinued at discharge.

Standard of care according to WHO guidelines recommending systemic steroids

Length of follow-up: 3 months

Loss-to-follow-up:

R: 9 (21%)

• n=1: no post-randomization data
• n=3: death
• n=3: loss to follow-up
• n=2: other

CR: 9 (16%)

• n=1: no post-randomization data
• n=1: voluntary discontinuation
• n=4: death
• n=1: loss to follow-up
• n=2: other

H: 13 (24%)

• n=2: no post-randomization data
• n=5: voluntary discontinuation
• n=4: death
• n=1: loss to follow-up
• n=1: other

CH: 8 (15%)

• n=1: voluntary discontinuation
• n=2: death
• n=1: loss to follow-up
• n=4: other

Incomplete outcome data:

Missing data due to discharge or participant withdrawal were imputed with best outcome. Not reported how many.

Clinical outcomes

Mortality (28 day)

R: 2.4 (0.1; 10.1)

CR: 5.2 (1.3-13.1)

RD: -2.9 (-10.3; 4.5)

H: 7.5 (2.4; 16.7)

CH: 1.8 (0.1; 7.6)

RD: 5.8 (-2.2; 13.7)

Mortality (60 day)

R: 7.1 (1.8; 17.5)

CR: 5.3 (1.3; 13.1)

RD: 1.9 (-7.8; 11.6)

H: 7.5 (2.4; 16.7)

CH: 1.8 (0.1; 7.6)

RD: 5.8 (-2.2; 13.7)

In-hospital mortality

R: 7.1 (1.8; 17.5)

CR: 7.0 (2.2; 15.6)

RR: 1.0 (0.2; 4.6)

H: 7.5 (2.4; 16.7)

CH: 3.6 (0.6; 10.6)

RR: 2.2 (0.4; 10.8)

Duration of hospitalization

Not reported

Admission to ICU during hospitalization

R: 19.0 (9.2; 32.6)

CR: 19.3 (10.5; 30.8)

RD: -0.3 (-15.9; 15.4)

H: 22.6 (12.8; 35.0)

CH: 16.1 (8.1; 27.1)

RD: 6.6 (-8.2; 21.4)

Time to symptom resolution

Not reported

Respiratory support

Mechanical ventilation

R: 9.5 (3.1; 20.8)

CR: 7.0 (2.2; 15.6)

RD: 2.5 (-8.6; 13.6)

H: 15.1 (7.2; 26.3)

CH: 10.7 (4.4; 20.5)

RD: 4.4 (-8.2; 17.0)

Time to receipt mechanical ventilation

RR R vs CR: 1.4 (0.4; 5.8)

RR H vs CH: 2.1 (0.7; 6.2)

Duration of mechanical ventilation

Reported in appendix figure 1

Safety

Adverse events n/N (%)

R: 34/42 (81%)

H: 26/52 (50%)

C: 33/87 (n=38%)

Serious adverse events n/N (%)

R: 13/42 (31%)

H: 12/52 (23%)

C: 20/87 (n=23%)

Virological outcomes

Viral clearance

Not reported

Viral load

Reported in a figure 2 and appendix figure 2

Subgroup analysis based on symptom duration before hospitalization, the presence of ARS-CoV-2 antibodies, high or low viral load at hospital admission, degree of inflammation, and age were performed.

Definitions: not applicable

Remarks:

• Randomization to remdesivir started on 7 April 2020. Hydroxychloroquine was removed on 8 June 2020. The trial was stopped on 5 October because of low mortality, potential adverse events and little effect of remdesivir.
• 185 were randomly assigned, 4 excluded due of absence of post-randomization information
• The groups are not well balanced, see table 1
• No blinding was performed
• Some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other, giving a partial overlap of the 2 control groups.

Authors conclusion:

The overall lack of effect of remdesivir and HCQ on the clinical course of patients hospitalized for COVID-19 was accompanied by a paucity of effect on SARS-CoV-2 viral clearance in the oropharynx. Our findings question the antiviral potential of these drugs in hospitalized patients with COVID-19.

Arabi, 2021

Type of study:

Randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP).

Setting:

187 sites across 11 countries.

Country:

United States of America, Canada, France, Germany, Ireland, Netherlands, Portugal, United Kingdom, Saudi Arabia, Australia, New Zealand.

Source of funding:

Supported by the European Union;

See the full-text publication of the study for the full description.

Conflicts of interest:

See the full-text publication of the study for the full description.

NCT02735707

Severe COVID-19 ICU patients

Inclusion criteria:

• 18 years or older;
• Admitted with suspected or confirmed COVID-19;
• Receiving respiratory or cardiovascular organ failure support in an intensive care unit.

Exclusion criteria:

• If death was deemed to be imminent during the next 24 hours and one or more of the patients, substitute decision-maker, or attending physician are not committed to full active treatment;
• Expected to be discharged from hospital the same day or the following day;
• More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection;
• Previous participation in this REMAP-CAP within the last 90 days;
• Presence of any of the following exclusion criteria: known hypersensitivity to lopinavir-ritonavir and hydroxychloroquine, (2) receiving lopinavir-ritonavir or hydroxychloroquine as a usual medication prior to this hospitalization, (3) known human immunodefciency (HIV) infection (an exclusion criterion from receiving lopinavir-ritonavir), (4) severe liver failure (an exclusion criterion from lopinavir-ritonavir), (5) known or suspected pregnancy, (6) receiving amiodarone as a usual medication prior to this hospitalization or any administration of amiodarone within the 72 h prior to the assessment of eligibility (an exclusion criterion from lopinavir-ritonavir), (7) high clinical risk of sustained ventricular dysrhythmia.

N total at baseline:

N = 694; analysed: N = 677

Intervention 1: N = 255; N = 249

Intervention 2: N = 50; N = 49

Intervention 3: N = 27 ; N = 26

Control: N = 362; N = 353

Important characteristics:

Age, mean (SD):

Intervention 1: 61 y (13)

Intervention 2: 56.3 y (13)

Intervention 3: 60.3 y (8.9)

Control: 60.8 y (12.9)

Sex, n/N (%) male:

Intervention 1: 182/254 (71.7%)

Intervention 2: 35/50 (70%)

Intervention 3: 19/27 (70.4%)

Control: 252/362 (69.6%)

Disease severity, mean (SD):

Defined by APACHE II score, median (IQR)

Intervention 1: 13.0 (8 to 18)

Intervention 2: 12.5 (7.8 to 20.2)

Intervention 3: 14 (10.2 to 20.8)

Control: 13 (8 to 19)

Groups comparable at baseline?

Yes.

Lopinavir-ritonavir, hydroxychloroquine,

combination therapy of lopinavir-ritonavir and hydroxychloroquine

Lopinavir-ritonavir was administered for 5 days minimum, up to a maximum of 14 days or until ICU discharge whichever occurred frst. Lopinavir–ritonavir was administered at a dose of 400 mg of lopinavir and 100 mg of ritonavir every 12 h. For patients with a gastric tube who were unable to swallow tablets, lopinavir-ritonavir (at the same dose) was administered as a 5-ml suspension every 12 h or alternatively as two dissolved tablets or four crushed tablets (double dose), noting that systemic absorption is reduced by approximately 50% for crushed tablets

Hydroxychloroquine

Hydroxychloroquine was administered as two loading doses of 800 mg, 6-h apart, followed 6 h later by 400 mg 12 hourly for 12 doses. Tis dose regimen was supported by pharmacokinetic modelling and by guidance regarding safety from clinicians with experience with the use of hydroxychloroquine for the treatment of severe malaria. If a patient was unable to swallow, crushed hydroxychloroquine tablets were administered via an enteral tube.

Combination therapy

Combination of Lopinavir-ritonavir and hydroxychloroquine.

No antiviral agents against COVID-19

Length of follow-up:

90 days

Loss-to-follow-up:

Intervention 1:

N = 6 (%)

Reasons: not reported.

Intervention 2:

N = 1 (%)

Reasons: not reported.

Intervention 3:

N = 1 (%)

Reasons: not reported.

Control:

N = 9 (%)

Reasons: not reported.

Incomplete outcome data:

None.

Clinical outcomes

In-hospital deaths, n/N (%)

Intervention 1: 88/249 (35.3%)

Intervention 2: 17/49 (34.7%)

Intervention 3: 13/26 (50.0%)

Control: 106/353 (30.0%)

90-day survival (time-to-event analysis), adjusted HR (95% CI)

Intervention 1: aHR 0.83 (95% CI 0.65 to 1.07)

Intervention 2: aHR 0.71 (95% CI 0.45 to 0.97)

Intervention 3: aHR 0.58 (95% CI 0.36 to 0.92)

Control: 1

Duration of hospitalization

Time to hospital discharge, adjusted HR, median (95% CI)

Intervention 1: aHR 0.83 (95% CI 0.68 to 0.99)

Intervention 2: aHR 0.76 (95% CI 0.56 to 0.97)

Intervention 3: aHR 0.63 (95% CI 0.42 to 0.89)

Control: 1

Time to ICU discharge, adjusted HR, median (95% CI)

Intervention 1: aHR 0.87 (95% CI 0.72 to 1.07)

Intervention 2: aHR 0.74 (95% CI 0.52 to 0.94)

Intervention 3: aHR 0.63 (95% CI 0.44 to 0.89)

Control: 1

Time to symptom resolution

WHO scale at day 14, adjusted HR, median (95% CI)

Intervention 1: aHR 0.85 (95% CI 0.68 to 0.99)

Intervention 2: aHR 0.76 (95% CI 0.56 to 0.97)

Intervention 3: aHR 0.63 (95% CI 0.42 to 0.89)

Control: 1

Respiratory support

Progression to invasive mechanical ventilation, ECMO, or death, restricted to those not intubated at baseline, n/N (%); adjusted OR, median (IQR)

Intervention 1: 89/176 (50.6%); aOR 0.75

Intervention 2: 17/24 (70.8%); aOR 0.58 (95% CI 0.24 to 1)

Intervention 3: 11/14 (78.6%); aOR 0.42 (95% CI 0.16 to 0.95)
Control: 107/239 (44.8%); aOR 1.00.

Cardiovascular support-free days, median (IQR); adjusted OR (95% CI)

Intervention 1: 14 (-1 to 21); aOR 0.66 (95% CI 0.49 to 0.89)

Intervention 2: 13 (-1 to 19); aOR 0.60 (95% CI 0.39 to 0.86)

Intervention 3: -1 (-1 to 14); aOR 0.39 (95% CI 0.22 to 0.69)

Control: 18 (-1 to 21); aOR 1.00.

Respiratory support-free days, median (IQR); adjusted OR (95% CI)

Intervention 1: 3 (-1 to 15); aOR 0.75 (95% CI 0.56 to 0.99)

Intervention 2: 0 (-1 to 9); aOR 0.64 (95% CI 0.4 to 0.92)

Intervention 3: -1 (-1 to 7); aOR 0.47 (95% CI 0.27 to 0.83)

Control: 5 (-1 to 16); aOR 1.00.

Safety

Serious adverse events

Patients with ≥1 serious adverse events, n/N (%); adjusted OR (95% CI)

Intervention 1: 13/255 (5.1%); aOR 0.55 (95% CI 0.24 to 1.22)

Intervention 2: 3/50 (6.0%); aOR 0.65 (95% CI 0 to 2.38)

Intervention 3: 1/27 (3.7%); aOR 0.97 (95% CI 0.24 to 4.79)

Control: 12/362 (3.3%)l aOR 1.00.

Serious ventricular arrhythmia or sudden unexpected death, n/N (%); adjusted OR (95% CI)

Intervention 1: 6/239 (2.5%); aOR 1.30 (95% CI 0.56 to 3.28)

Intervention 2: 2.49 (4.1%); aOR 0.88 (95% CI 0.27 to 3.55)

Intervention 3: 2/26 (7.7%); aOR 0.62 (95% CI 0.18 to 2.60)

Control: 10/345 (2.9%); aOR 1.00.

Virological outcomes

Viral clearance

Not reported.

Definitions:

- Organ support included the provision of invasive mechanical ventilation, non-invasive mechanical ventilation, high-flow nasal cannulae with a flow rate of at least 30 L per minute and a fractional inspired oxygen concentration of 0.4 or higher, or the infusion of vasopressor or inotropes for shock.

Remarks:

-

Authors conclusion:

In conclusion, among critically ill patients with COVID-19, treatment with lopinavir-ritonavir, hydroxychloroquine, or combination therapy resulted in worse outcomes compared to no COVID-19 antiviral therapy

Schwartz, 2021

Type of study:

randomized, double-blind, placebo-controlled

trial

Setting:

community-based in Alberta, with enrolment beginning April 15, 2020 and paused on May 22, 2020

Country:

Canada

Source of funding:

Calgary Health Trust, the University of Calgary, Alberta Innovates Health Solutions, Alberta Health Services and the Alberta Government provided funding. Hydroxychloroquine and matching placebo were provided by Apotex. Funders had no role in trial design, interpretation or publication decisions.

Conflicts of interest:

Conflicts of interest were transparently and extensively reported. Most importantly, the last author (MH) reports that Apotex Pharma provided the drug and placebo for the current trial as an in-kind contribution to the study. He was the main contact with Apotex Pharma and has no other relationship with the company; there were no obligations attached to this donation of drug and placebo.

Community-dwelling individuals with confirmed COVID-19

Inclusion criteria:

• Adults
• SARS-CoV-2 infection confirmed by RT-PCR from a nasopharyngeal or pharyngeal swab within the previous 4 days
• symptom onset within the previous 12 days
• ≥ 1 risk factor for severe disease

Exclusion criteria:

• hospitalized
• pregnant or breastfeeding
• unable to swallow pills
• unable to comply with the medical regimen
• used hydroxychloroquine, chloroquine, lumefantrine, mefloquine or quinine within the previous 30 days

N total at baseline:

Randomized: N = 148

Intervention: N = 111

Control: N = 37

Important characteristics:

Age, mean (SD):

I: .46.7 y (11.5)

C: .46.9 y (11.0)

Sex, n/N (%) male:

I: 65/111 (58.6%)

C: 17/37 (45.9%)

Participants in the intervention group less often had diabetes or asthma. Also, they less often had shortness of breath, malaise, myalgias, coryza, dysgeusia and diarrhea, but more often had nausea; unclear whether these differences are statistically significant.

hydroxychloroquine 800 mg orally in divided doses on day 1 followed by 200 mg twice daily for 4 days (12 tablets over 5 days)

placebo

Length of follow-up:

30 days

Loss-to-follow-up:

Based on the information presented in the flow chart (Fig. 2), no participants were lost to follow-up in the ITT population. However, the table of results (Tab. 2) shows that for most of the outcomes data was missing for ≥ 1 participants; the PP population consisted of 74/111 patients in the intervention group, and 31/37 patients in the control group.

Incomplete outcome data:

Mortality within 30 days

I: 0/111 (0%)

C: 0/37 (0%)

Admission to ICU within 30 days

I: 1/111 (0.9%)

C: 0/37 (0%)

Hospitalization within 30 days

I: 1/111 (0.9%)

C: 0/37 (0%)

Time to symptom resolution

Days, median

I: 22/111 (19.8%)

C: 2/37 (5.4%)

Development of severe disease,

defined as the composite of hospitalization, invasive mechanical ventilation or death within 30 days

I: 1/111 (0.9%)

C: 0/37 (0%)

The safety population consisted of 91/111 patients in the intervention group and 33/37 patients in the placebo group who took at least 1 tablet of the study drug.

Primary outcome was the development of severe disease, defined as the composite of hospitalization, invasive mechanical ventilation, or death within 30 days.

Clinical outcomes

Mortality

Mortality within 30 days

I: 0/111 (0%)

C: 0/37 (0%)

Duration of hospitalization

Admission to ICU within 30 days

I: 1/110 (0.9%)

C: 0/37 (0%)

Hospitalization within 30 days

I: 4/110 (3.6%)

C: 0/37 (0%)

Time to symptom resolution

Time to COVID-19 recovery

Days, median

I: 14 (95%CI: 10-20); data available for 89/111 participants

C: 12 (95%CI: 7-18); data available for 35/37 participants

p = 0.3

Respiratory support

Not reported.

Other

Development of severe disease,

defined as the composite of hospitalization, invasive mechanical ventilation or death within 30 days

I: 4/110 (3.6%)

C: 0/37 (0%)

p = 0.6

Disposition at day 30

Recovered vs. Ongoing symptoms, not hospitalized vs. Unknown, not hospitalized or deceased

I: 67/110 (60.9%) vs. 23/110 (20.9%) vs. 20/11020/ (18.2%); missing for 1 patient

C: 29/37 (78.4%) vs. 5/37 (16.2%) vs. 2/37 (5.4%)

Safety

Serious adverse events within 30 days

I: 3/91 (3.3%)

C: 0/33 (0%)

p = 0.6

Emesis within 30 days

I: 5/91 (5.5%)

C: 0/33 (0%)

p = 0.3

Virological outcomes

Viral clearance

Not reported.

Definitions:

-

Remarks:

The trial recruited only 10% of the target sample size, stopping early because of a report on hydroxychloroquine safety (that was subsequently retracted) and a rapid decline in disease prevalence coinciding with control of the first wave of the COVID-19 pandemic.

Authors’ conclusion:

There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered.

Ader, 2021

Type of study:

RCT, phase 3 open-label

(DisCoVeRY)

Setting:

30 sites in France and 2 in Luxembourg, between March 22nd and June 29th.

Country:

France and Luxembourg

Source of funding:

The study was founded by Programme Hospitalier de Recherche Clinique (PHRC-20-0351)

 (Ministry of Health), from the DIM One Health Île-de-France (R20117HD), and from REACTing, a French multi-disciplinary collaborative network working on emerging infectious diseases. The funding sources had no role in the analysis of the data nor in the decision of publication.

Conflicts of interest:

F.R. reports personal fees from Gilead Sciences, personal fees from MSD, personal fees from Pfizer, personal fees from TheraTechnologies, personal fees from ViiV Healthcare, outside the submitted work. F.G. reports grants from BioMerieux, personal fees and non-financial support from Gilead, non-financial support from Corevio, outside the submitted work. G.P.reports grants and personal fees from Gilead Sciences, grants and personal fees from Merck, grants and personal fees from ViiV Healthcare, grants and personal fees from TheraTechnologies, outside the submitted work. K.L. reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Y.Y. has nothing to disclose. He has been a board member receiving consultancy fees from ABBVIE, BMS, Gilead, MSD, J&J, Pfizer, and ViiV Healthcare, however all these activities have been stopped in the 03 past years. F.L. reports personal fees from Gilead personal fees and non-financial support from MSD, non-financial support from Astellas, non financial support from Eulmedica, outside the submitted work. A.K. reports personal fees from Baxter, personal fees from Aspen, personal fees from Aguettant, outside the submitted work. S.N. reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomérieux, personal fees from BioRad, outside the submitted work. F.D. reports personal fees from Gilead, outside the submitted work. J.N. reports non448 financial support from MSD France, non-financial support from GILEAD Sciences, personal fees from PASCALEO, outside the submitted work. J.M. reports non-financial support from GILEAD, outside the submitted work. A.M. reports personal fees from MSD, personal fees from GILEAD, personal fees from JANSSEN, personal fees from Viiv Healthcare, outside the submitted work. M.H. reports grants from Fonds Erasme- COVID-Université Libre de Bruxelles, grants from Belgian health Care Knowledge Center, during the conduct of the study; personal fees from Gilead advisory board on education on invasive fungal infections, personal fees from Pfizer: moderator for session on Isavuconazole, outside the submitted work. D.C. reports personal fees from Gilead, grants and personal fees from Janssen, outside the submitted work. C.B. reports personal fees from Da Volterra, personal fees from Mylan

Pharmaceuticals, outside the submitted work. F.M. reports grants from Sanofi, grants and personal fees from Da Volterra, outside the submitted work. All other authors have nothing to disclose.

Hospitalized patients, peripheral oxygen saturation ≤94% (moderate) or requiring supplemental oxygen (severe)

Inclusion criteria:

adults (≥ 18-year-old)

a PCR-proven (< 72 hours) SARS-CoV-2 infection

 pulmonary rales or crackles with a peripheral oxygen saturation ≤94% or requiring supplemental oxygen

Exclusion criteria:

Enrolment in another investigative trial

Use of other antivirals

N total at baseline:

N = 583

Intervention:

-L/r: 145

-L/r + IFN: 145

-HCQ: 145

Control: 148

Important characteristics:

Age, median [IQR]:

L/r: 63 [55-71]

L/r + IFN: 64 [53-71]

HCQ: 65 [55-71]

C: 62 [52-71]

Sex, n/N (%) male:

L/r: 106/145 (73.1%)

L/r + IFN: 103/145 (71.0%)

HCQ: 104/145 (71.7%)

C: 105/148 (70.9%)

Baseline severity of COVID-19, n/N (%):

Moderate disease (receiving low-flow supplemental oxygen or not requiring oxygen)

L/r: 94/145 (64.8%)

L/r + IFN: 91/145 (62.8%)

HCQ: 93/145 (64.1%)

C: 94/148 (63.5%)

Severe disease (requiring non-invasive ventilation or high-flow oxygen devices, invasive mechanical ventilation or ECMO)

L/r: 51/145 (35.2%)

L/r + IFN: 54/145 (37.2%)

HCQ: 52/145 (35.9%)

C: 54/148 (36.5%)

Groups comparable at baseline?

Not reported.

-lopinavir/ritonavir (L/r) (400 mg lopinavir and 100 mg ritonavir

234 orally twice on day for 14 days) + SoC

- lopinavir/ritonavir plus IFN-ß-1a (L/r + IFN) (44 µg of subcutaneous IFN-ß-1a on days 1, 3, and 6 +SoC

-hydroxychloroquine (HCQ) (400 mg orally,

236 twice on day 1 as a loading dose followed by 400 mg once daily for 9 days + SoC

Supportive treatments corticosteroids, anticoagulants or immunomodulatory agents were allowed

Standard of care (Soc)

Supportive treatments corticosteroids, anticoagulants or immunomodulatory agents were allowed.

Length of follow up:

29±3 days

Loss to follow-up:

L/r: 1/145 (0.7%)

Reason: did not receive at least one dose of intervention.

L/r + IFN: 1/145 (0.7%)

Reason: did not receive at least one dose of intervention.

HCQ: 2/145 (1.4%)

Reason: did not receive at least one dose of intervention.

C: 0/148 (0%)

All analyses were stratified by severity at randomization, and adjusted effect measures are reported.

Clinical outcomes

Mortality (within 28 days), n (%)

Moderate subgroup

L/r: 4 (4.3%)

L/r + IFN: 4 (4.4%)

HCQ: 6 (6.5%)

C: 5 (5.3%)

Severe subgroup

L/r: 10 (19.6%)

L/r + IFN: 13 (24.1%)

HCQ: 5 (9.6%)

C: 7 (13.0%)

L/r vs control: OR=1.24 (0.55 to 2.82) [P=0.60]

L/r + IFN vs control: OR=1.51 (0.69 to 3.34) [P=0.30]

HCQ vs control: OR=0.93 (0.40 to 2.20) [P=0.88]

Duration of hospitalization

Time to hospital discharge within 29 days

L/r vs control: HR=0.77 (0.58 to 1.02) [P=0.07]

L/r + IFN vs control: HR=0.72 (0.54 to 0.96) [P=0.026]

HCQ vs control: HR=0.83 (0.62 to 1.10) [P=0.20]

Time to symptom resolution

Clinical status at 7-point ordinal scale* at day 15

L/r vs control: OR=0.83 (0.55 to 1.26) [P=0.39]

L/r + IFN vs control: OR=0.69 (0.45 to 1.04) [P=0.08]

HCQ vs control: OR=0.93 (0.62 to 1.41) [P=0.75]

Clinical status at 7-point ordinal scale* at day 29

L/r vs control: OR=0.93 (0.62 to 1.41)

[P=0.74]

L/r + IFN vs control: OR=0.76 (0.50 to 1.15) [P=0.19]

HCQ vs control: OR=1.16 (0.77 to 1.75)

[P=0.49]

Respiratory support

Ventilator-free days until day

29

L/r vs control: LSMD=-0.98 (-2.96 to 1.00) [P=0.33]

L/r + IFN vs control:LSMD=-2.01

(-4.03 to 0.00) [P=0.05]

HCQ vs control: LSMD=0.09 (-1.93 to 2.10) [P=0.93]

Safety

Adverse events, n/N (%)

Any adverse events

L/r: 119/144 (82.6%); p=0.02

L/r + IFN: 117/144 (81.3%); p=0.04

HCQ: 109/143 (76.2%); p=0.35

C: 105/148 (70.9%)

Any serious adverse events

L/r: 76/144 (52.8%); p=0.02

L/r + IFN: 78/144 (54.2%); p=0.01

HCQ: 63/143 (44.1%); p=0.34

C: 57/148 (38.5%)

Virological outcomes

Viral clearance

The slope of the decrease of the viral loads in Nasopharyngeal swab (NPS)over time was not significantly affected by any of the investigational treatments. No significant difference in the proportion of participants with detectable viral loads at each sampling time was observed in the NPS nor in the lower respiratory tract (LRT) specimens.

Also available:

Secondary efficacy outcome measures were the clinical status at day 29 and the time to an improvement of 2 categories as measured on the 7-point ordinal scale or hospital discharge until day 29, the time to National Early Warning Score 2 (NEWS2) ≤2 or hospital discharge until day 29, the time to hospital discharge until day 29, oxygenation- and ventilator-free days until day 29, 29-day mortality, and the SARS-CoV-2 detection and quantitative normalized viral loads. Trough plasma concentrations of lopinavir, ritonavir and hydroxychloroquine were measured at days 1 and 3. Secondary safety outcomes included the cumulative incidence of any grade 3 or 4 AE, or of any serious adverse event (SAE, according to the DAIDS Table

264 for Grading the Severity of Adult and Paediatric Adverse Events, v2.1, July 2017) and the proportion of patients with a premature suspension or discontinuation for any reason of the investigational treatments.

Definitions:

*7-point ordinal scale of the WHO Master Protocol (v3.0, March 3, 2020):

1. Not hospitalized, no limitation on activities; 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6. Hospitalized, on invasive mechanical ventilation or ECMO; 7. Death.

Remarks:

Based on interim analyses (see Supplementary Appendix), enrolment in the hydroxychloroquine arm was prematurely stopped on June 17th , and enrolment in lopinavir containing arms was stopped on June 29th 2020 (futility and safety concerns).

The trial was performed in the early phase of the COVID-19 pandemics and the SoC underwent substantial changes over time

Authors conclusion:

In patients admitted to hospital with COVID-19, lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine were not associated with clinical improvement at day 15 and day 29, nor reduction in viral shedding, and generated significantly more SAEs in lopinavir/ritonavir-containing arms. These findings do not support the use of these investigational treatments for patients hospitalized with COVID-19.

Réa‑Neto, 2021

Type of study:

RCT (open-label)

Setting:

6 hospitals in Curitiba, Brazil

April 16 to August 06, 2020

Country:

Brazil

Source of funding:

Not reported.

Conflicts of interest:

No competing interest.

clinicaltrials.gov nr, NCT04420247,

“Retrospectively

Registered”

Patients admitted to ICU

Inclusion criteria:

• Age ≥ 18 with flu symptoms (runny nose, dry or productive cough, sore throat and/or fever) associated with:
• clinical need for supplemental oxygen for dyspnea,
• pulse oxygen saturation≤94% on room air,
• pulmonary CT findings compatible with COVID-19
• the necessity of mechanical ventilation (MV) and a diagnosis of SARS-CoV-2 infection confirmed by molecular analysis or RT-PCR performed at admission

Exclusion criteria:

• History of cardiopathy or any kind of arrhythmia
• psoriasis
• seizure
• G6PD deficiency
• myasthenia gravis
• ALT/AST > 5* ULN
• creatinine clearance < 30 ml/min/1.73 m2
• pregnancy or lactation
• known Clq/HClq allergy

N total at baseline:

N = 142

Intervention: 71

Control: 71

The modified intention-to-treat analysis: N=105

I: 53

C: 52

Important characteristics:

Age, mean (SD):

I: 54.7 y (12.1)

C: 52.8 y (12.6)

Sex, n/N (%) male:

I: 36/53 (67.9%)

C: 34/52 (65.4%)

Disease severity:

according to ventilatory support

Intensive mechanical ventilation at baseline, no. (%):

I: 9/53 (17)

C: 10/52 (19.2)

Score on nine-point ordinal scale*, no. (%)d

3: I: 1 (1.9), C: 0 (0)

4: I: 43 (81.1), C:42 (80.8)

5: I: 0 (0), C: 0 (0)

6: I: 1 (1.9), C: 3 (5.8)

7: I: 8 (15.1), C: 7 (13.5)

Groups were comparable at baseline, with the exception of the number of patients with hypertension (I: 19 vs. C: 21), DM (I: 11 vs. C: 16) and Immunocompromised state (I: 2 vs. C: 4). No p values reported.

Chloroquine or hydroxychloroquine for 5 days plus standard treatment

Chloroquine:

450 mg twice a day on day 1 and 450 mg once daily from days 2-5

Hydroxychloroquine: 400 mg twice a day on day 1 and 400 mg once daily from days 2-5

standard treatment only

Length of follow up:

28 days

Loss to follow-up:

I: 0/53 (0%)

C: 1/52 (1.9%)

The modified intention-to-treat analysis was restricted to 105 patients.

Results also reported for Clq and HClq separately (see supplement of article)

Clinical outcomes

Mortality (28 day)

I: 16 (30%)

C: 10 (19%)

(Difference (95% CI):1.57 (0.79 to 3.13), p= 0.236)

RR 1.57 [95% CI 0.79 to 3.13], p=0.196

Duration of hospitalization

ICU LOS (Length of stay) among survivors, median (IQR), days:

I: 3.5 (1–12)

C: 3 (0–7)

(Difference (95% CI):1 (− 2.6 to 4.6), p= 0.368)

Hospital LOS among survivors, median (IQR), days:

I: 7.5 (5–16)

C: 7 (4–12)

(Difference (95% CI): 1 (− 2.9 to 4.9), p= 0.257)

Time to symptom resolution

Not reported

Respiratory support

Mechanical ventilation -free days, median (IQR), days:

I: 25 (3–28)

C:28 (4–28)

(Difference (95% CI): − 3 (− 11.7 to 5.7), p= 0.236)

Invasive mechanical ventilation incidence, no (%):

I: 18 (41)

C: 8 (19)

(Difference (95% CI): 2.15 (1.05 to 4.40), p= 0.03)

WHO 9-point ordinal score*, n(%):

day 14

Score 0 : I: 11 (20.8) C: 22 (42.3)

Score 1: I: 5 (9.4) C: 6 (11,5)

Score 2: I: 10 (18.9) C: 6 (11.5)

Score 3: I: 0 (0) C: 0 (0)

Score 4: I: 6 (11.3) C: 2 (3.8)

Score 5: I: 2 (3.8) C: 3 (5.8)

Score 6: I: 3 (5.7) C: 3 (5.8)

Score 7: I: 6 (11.3) C: 3 (5.8)

Score 8: I: 10 (18.9) C: 7 (13.5)

OR (95% CI): 2.41 (1.17 to 4.93; odds for worse clinical condition)

P=0.016

Day 28

OR 2.47 (1.15-5.30), p= 0.020

Safety

Arrhythmias, no (%)

I: 4/68 (5.9)

C: 1/70 (1.9)

(Difference (95% CI): 3.92 (0.45 to 33.9), p= 0.176)

One patient in the Clq/HClq group stopped treatment on the third day owing to severe arrhythmia

Virological outcomes

Not reported.

Also available: Coagulopathy incidence, Acute renal dysfunction incidence, clinical status on days 5, 7, 10 and 28.

Primary outcome:

Clinical status measured on day 14 after randomization with a WHO 9-point ordinal scale.

Secondary outcomes:

all-cause mortality; invasive MV use; the incidence of acute renal dysfunction in 28 days; clinical status of patients on days 5, 7, 10 and 28

Definitions:

*WHO Score on nine-point ordinal scale:

(0) non-hospitalized and no clinical or virological evidence of infection; (1) non-hospitalized and no limitation on activities; (2) non-hospitalized, but with limitation on activities; (3) hospitalized, but not requiring supplemental oxygen; (4) hospitalized and on oxygen via mask or nasal prongs; (5) hospitalized, on non IVM or high-flow oxygen or pressure support ventilation in weaning mode; (6) hospitalized, intubated and on MV; (7) hospitalized on MV and additional organ support (renal replacement therapy, vasoactive drugs or extracorporeal membrane oxygenation), and (8) dead

Remarks:

Open-label trial;

The trial was stopped before reaching the planned sample size due to harmful effects; Retrospectively

Registered protocol.

Authors conclusion:

In conclusion, the addition of Clq/HClq to standard care in patients admitted to the hospital with severe COVID-19 resulted in clinical worsening and higher incidences of IMV and renal dysfunction, even though there was no difference in mortality. According to these findings, the use of Clq/HClq in patients with more severe forms of COVID-19 pneumonia is strongly contraindicated, and these results can inform clinical practice and guidelines.

Reis, 2021

Type of study:

RCT

TOGETHER Trial

Setting:

local public health authorities in Brazil, participants enrolled between June 2 and September 30, 2020.

Country:

Brazil

Source of funding:

The trial was supported by the Bill and Melinda Gates Foundation. The funder had no role in the design and conduct of the study; collection,

management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflicts of interest:

None reported by the authors.

High-risk adult outpatients (see inclusion criteria)

Inclusion criteria:

• 18 years or older
• reported less than 8 days since onset of flulike symptoms or chest computerized tomography scan consistent with COVID-19
• at least one additional criterion for high risk:

aged 50 years or older;

presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, or emphysema; diabetes requiring oral

medication or insulin; hypertension requiring treatment; known cardiovascular diseases (congestive heart failure of any etiology, documented coronary artery disease, clinically manifest miscellaneous heart disease); symptomatic lung disease on chronic treatment; history of transplantation; obesity

(body mass index 30 [calculated as weight in kilograms divided by height in meters squared]);

immunocompromised status due to disease (eg, those living with HIV with a CD4 T-cell count of <200 cells/mm3

, confirmed malignant neoplasm); immunocompromised status due to medication

(eg, people taking 10 mg or more of prednisone equivalents a day); and patients with cancer

Exclusion criteria:

• use of any of study drugs in 30 days prior to screening
• clinical evidence of progression of COVID-19 (ie, use of oxygen supplementation; arterial oxygen saturation less than 94%; use of noninvasive positive-pressure ventilation support)
• history of known lifethreatening cardiac arrhythmias;
• long QT syndrome
• known allergy to study drugs

N total at baseline:

N = 685

Intervention hydro: 214

Intervention lopi-rito: 244

Control: 227

Important characteristics:

Age, median (IQR):

I hydro: 53 y (18-84)

I lopi-rito: 54 y (18-94)

C: 53 y (18-80)

Sex, n/N (%) male:

I hydro: 92/214 (43.0 %)

I lopi-rito: 110/244 (45.1%)

C: 106/227 (46.7 %)

Participants with multiple risk factors, n/N (%)

I hydro: 121/214 (56.5%)

I lopi-rito: 134/244 (54.9%)

C: 134/227 (59.0%)

Groups comparable at baseline?

With respect to covariates of age, body mass index, and comorbidities, the groups were generally well balanced.

hydroxychloroquine group

 loading dose of 800 mg at the time of randomization and then 400 mg in daily doses at 8:00 AM for 9 days.

lopinavir-ritonavir group

a loading dose of 800 mg of lopinavir and 200 mg of ritonavir at

the first 2 intakes, followed by 400 mg of lopinavir and 100 mg of ritonavir every 12 hours for the next 9 days.

placebo group

corresponding tablets of inert material (talc). Placebo bottles were matched for the same number of tablets as active hydroxychloroquine

(placebo of hydroxychloroquine) and active lopinavir-ritonavir (placebo of lopinavir-ritonavir).

Length of follow up:

90 days

Loss to follow-up:

I hydro: 16/214 (7.5%)

Reasons:

-7 Did not receive assigned

Treatment

-9 Had adhered <80% to assigned treatment

I lopi-rito: 44/244 (18.0%)

Reasons:

-12 Did not receive assigned

Treatment

-32 Had adhered <80% to

assigned treatment

C: 19/227 (8.4%)

Reasons:

-7 Did not receive assigned

Treatment

-12 Had adhered <80% to

assigned treatment

At the end of the trial, 79 participants (11.5%) did not complete all phases of the study. The lopinavir-ritonavir intervention group had 44 participants

(18%) who did not complete the study, which was more than either of the other 2 groups.

Clinical outcomes

Mortality

At the end of the trial, we recorded 3 fatalities, 1 in the placebo group and 2 in the lopinavir-ritonavir

intervention group.

Duration of hospitalization

COVID-19 hospitalization, n/N (%)

I hydro: 8/214 (3.7)

HR 0.76 (95% CI 0.30-1.88)

I lopi-rito: 14/244 (5.7)

HR 1.16 (955 CI 0.53-2.56)

C: 11/227 (4.8)

HR 1 [reference]

Time to hospitalization, median (IQR), d

I hydro: 4.8 (1.40-6.12)

I lopi-rito: 3.6 (2.50-4.76)

C: 2.4 (0.76-3.20)

All-cause hospitalization, n/N (%)

I hydro: 11/214 (5.1)

HR 0.96 (95% CI 0.42-2.17)

I lopi-rito: 16/244 (6.6)

HR 1.22 (95% CI 0.58-2.57)

C: 12/227 (5.3)

HR 1 [reference]

Time to hospitalization, median (IQR), d

I hydro: 3.8 (1.88-6.43)

I lopi-rito: 3.1 (2.31-4.75)

C: 2.2 (0.79-3.12)

Time to symptom resolution

WURSS Scale (Wisconsin Upper Respiratory Symptom Survey)

We found no difference in the resolution of combined symptoms using the WURSS scale between either hydroxychloroquine and placebo or lopinavir-ritonavir and placebo, or for individual symptoms.

Respiratory support

Not reported.

Safety

Adverse events

Any Treatment-Emergent Adverse Events (TEAE), n/N (%)

I hydro: 46/207 (22.2)

I lopi-rito: 92/232 (39.7)

C: 46/220 (20.9)

Serious TEAE, n/N (%)

I hydro: 11 (5.3)

I lopi-rito: 20 (8.6)

C: 12 (5.5)

Virological outcomes

Virological clearance

Defined as 1 negative swab since

Baseline.

In the mixed-effect logistic model, the clearance for the hydroxychloroquine (odds ratio [OR], 0.91; 95% CI, 0.82-1.02) and lopinavir-ritonavir (OR, 1.04; 95% CI, 0.94-1.16) groups did not differ in comparison with the control group.

Neither hydroxychloroquine nor lopinavir-ritonavir showed difference in viral clearance across all prespecified subgroups based on ITT analysis.

Remarks:

The independent DSMB, based on interim analysis results, made the decision to stop enrollment to the hydroxychloroquine and lopinavir-ritonavir groups because of a low number of emerging events. This study reports on the final results inclusive of patients who had been randomized to hydroxychloroquine or lopinavir-ritonavir between the time of data-cut for interim analysis to the time of the DSMB meeting.

Authors conclusion:

This randomized clinical trial found no clinical benefit to support the use of either

hydroxychloroquine or lopinavir-ritonavir in an outpatient population. This adds to the growing

evidence that these drugs should not be used for the treatment of COVID-19. While evidence

emerges to evaluate these drugs as prophylaxis, as treatment for both outpatients and inpatients,

hydroxychloroquine and lopinavir-ritonavir do not appear to confer any clinical benefit.

Gupta, 2021a

Type of study:

Open-label randomized controlled trial with unblinded assessment.

Setting:

Tertiary care centre of Indian Armed Forces Medical Services located in a metropolitan city.

Country:

India.

Source of funding:

No information.

Conflicts of interest:

All authors have none to declare.

Patients with moderate to severe COVID-19 infections who require hospitalized care.

Inclusion criteria:

• Patients who were COVID-19 positive based on real time reverse transcription polymerase chain reaction (rRT PCR);
• Patients who were symptomatic for the disease for <5 days;
• Patients who were willing to participate in the trial and satisfied at least two of the following four criteria: (i) oxygen saturation (SaO₂) less than 95% as measured by digital pulse oximetry; (ii) respiratory rate more than 20/min; (iii) pulse rate more than 90/min or; (iv) imaging evidence of lung infection in the form of reticulonodular opacities, ground glass opacities, consolidation or acute respiratory distress syndrome.

Exclusion criteria:

• Patients who were 14 years or less in age.

N total at baseline:

N = 110

Intervention: N=55

Control: N=55

Important characteristics:

Age, mean (SD):

I: 57.8 y (12.6)

C: 57.3 y (14.1)

P=0.72

Sex, n/N (%) male:

I: 43/55 (76.8%)

C: 37/55 (68.5%)

P=0.20

Disease severity, mean (SD):

Defined by SOFA score at admission (SD)

I: 2.6 (1.7)

C: 2.4 (1.6)

P=0.56

Groups comparable at baseline?

Yes.

Hydroxychloroquine + standard of care

Patients in the HCQ arm received the drug as per the following schedule: 400 mg twice on day 1, followed by 400 mg once daily from day 2 today 5.

Standard of care

Standard of care included intravenous (IV) antibiotics to cover respiratory pathogens, IV dexamethasone at a dose of 4 mg every 8 h for 5 days and subcutaneous low-molecular-weight heparin(LMWH) enoxaparin in dose of 40 mg (0.4 ml) once a day for 5days.

Length of follow-up:

Four days.

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Clinical outcomes

Mortality (28-30 day), n/N (%)

I: 10/55 (18.2%)

C: 2/55 (3.6%)

P=0.01

Duration of hospitalization

Days of hospitalization, mean (SD)

I: 13.89 (5.85)

C: 13.67 (5.83)

P=0.98

Time to symptom resolution

Days to normalization of SaO₂, mean (SD)

I: 6.54 (4.48)

C: 7.59 (5.06)

P=0.26

Respiratory support

Days on oxygen, mean (SD)

I: 8.49 (6.38)

C: 7.98 (5.45)

P=0.26

Number of needing ventilator, n/N (%)

I: 10/55 (18.2%)

C: 4/55 (7.27%)

P=0.09

Days from admission to ventilator, mean (SD)

I: 4.90 (4.88)

C: 1.5 (2.38)

P=0.18

Days on ventilator, mean (SD)

I: 8.33 (8.60)

C: 8.75 (3.09)

P=0.37

Safety

Adverse events

Not reported.

Virological outcomes

Viral clearance

Not reported.

Definitions:

SOC: Standard of care included intravenous (IV) antibiotics to cover respiratory pathogens, IV dexamethasone at a dose of 4 mg every 8 h for 5 days and subcutaneous low-molecular-weight heparin(LMWH) enoxaparin in dose of 40 mg (0.4 ml) once a day for 5days.

Remarks:

-

Authors conclusion:

In conclusion, in the rapidly changing world of COVID-19therapeutics, our open-label, parallel group, unblinded ran-domized control trial suggests that HCQ does not change outcomes in moderate to severe COVID-19 infection. It sup-ports some of the other observational studies and trials con-ducted in the last few months. We could not comment on thetoxicity of HCQ as trial was not designed to assess it. Thestrength of our trial is that it was randomized and therandomization was good as seen by the well matched baselinecharacteristics; we recruited more patients than our calcu-lated sample size and this helped us perform the adjustedanalysis without losing the strength of the study and ouroutcomes were both clinical and laboratory based. The chieflimitation of our trial is that there was no blinding atrandomization or at assessment. Our trial is relevant becauseit is one of the first few from India. It will help clinicians in notprescribing a drug which does not change outcomes in mod-erate to severe COVID-19 infection and may be potentiallytoxic. It will help policy makers in closing the chapter on arepurposed drug which had gained a lot of popularity and spotlight at the beginning of the pandemic.

Dubée, 2021

HYCOVID trial

Type of study:

RCT; double-blind, placebo-controlled

Setting:

48 hospitals in France and the Principality of Monaco; April 2 to May 21, 2020

Start: April 1, 2020

Suspended: May 26, 2020

Stopped: June 9, 2020

Country:

France, Monaco

Source of funding:

This work was supported by a grant from the French Ministry of Health through a national call for proposals for therapeutic trials on COVID-19. The trial also received an exceptional donation from the Pays de la Loire region and from the Angers Loire Métropole conurbation . None of the funding organizations played any role in the trial design, data collection, analysis of results, or writing of the manuscript.

Conflicts of interest:

The authors have declared that there are no conflicts of interest in relation to this work.

Mild-to-moderate COVID-19 patients; almost all hospitalized (99%), with (60%) or without supplemental oxygen (severely ill patients requiring oxygen therapy needed > 3L / min or ICU admission excluded)

Inclusion criteria:

• Men and non-pregnant women; aged ≥18 years
• diagnosis of COVID-19 confirmed by positive

SARS-CoV-2 RT-PCR on a nasopharyngeal swab

within 2 days or chest-CT

• ≥1 of the following risk factors for worsening: (i) need for supplemental oxygen to reach a peripheral capillary oxygen saturation of more than 94% (SpO2 >94%) or a ratio of oxygen partial pressure to fractional inspired oxygen less than or equal to 300 mmHg (PaO2/FiO2 ≤300 mmHg); (ii)
• age ≥75 years; (iii) age 60-74 years and presence of ≥ 1 of following comorbidities: obesity (body mass index ≥30 kg/m2), arterial hypertension requiring treatment, or diabetes mellitus requiring treatment

Exclusion criteria:

• requiring > 3 L/min of oxygen to reach an SpO2 of 94%
• clinical condition necessitating admission to ICU
• negative SARS-CoV-2 RT-PCR
• short-term life-threatening comorbidity (life expectancy <3 months),
• any condition contraindicating hydroxychloroquine treatment (known hypersensitivity or allergy, retinopathy, concomitant treatment associated with a risk of ventricular arrhythmias, use of medications that are contraindicated with hydroxychloroquine and cannot be replaced or stopped during the trial)
• conditions associated with an increased risk of adverse event

N total at baseline:

Randomized: N = 250

 Intervention: 125

 Control: 125

In analysis:

 I: 123

 C: 124

Important characteristics:

Median age (IQR) – yr

I: 76 (60-85)

C: 78 (57-87)

Male sex – no. (%)

I: 65 (52.0)                 

C: 56 (44.8)

Median time (IQR) from onset of symptoms to inclusion – days

I: 5 (3-9)

C: 5 (3-8)

Score on ordinal scale – no. (%)

1. Ambulatory, no limitation of activity                   

I: 1 (0.8)

C: 1 (0.8)

2. Ambulatory, limitation of activity                   

I: 1 (0.8)

C: 0 (0.0)

3. Hospitalized, no oxygen therapy       

I: 46 (36.8)

C: 50 (40.0)

4. Hospitalized, oxygen therapy (≤3 L/min)

I: 77 (61.6)

C: 74 (59.2)

Groups comparable at baseline.

Hydroxychloroquine + standard care

Hydroxychloroquine (200 mg tablets, orally) at a dose of two tablets twice daily on the first day followed by one tablet twice daily for 8 days (total hydroxychloroquine dose of 4 g) plus standard care

Placebo + standard care

Matching placebo at a dose of two tablets twice daily on the first day followed by one tablet twice daily for 8 days plus standard care

Length of follow up:

28 days days

Loss to follow-up:

I: 2/125 (1.6%)

Reason: withdrew consent

C: 1/25 (0.8%)

Reason: withdrew consent

Incomplete data:

Clinical status data are missing at Day 14 and 28 for

two patients in each group; not further described

Clinical outcomes

Mortality - day 28

I: 6 (4.8)

C: 11 (8.9)

RR 0.54 (0.21–1.42)

Mortality other: day 14

I: 6 (4.8)

C: 6 (4.9)

RR 0.99 (0.33–2.99)

Duration of hospitalization

‘not reported’

Time to symptom resolution

Clinical evolution; WHO 9-point Ordinal Scale for Clinical Improvement for COVID-19*; RR (95% CI); definitions:

absence of deterioration: stability or decrease of at least one point on the

ordinal scale;

clinical improvement: decrease of at least one point on the ordinal scale;

recovery: score of 0, 1, or 2

Day 14      

 Absence of deterioration             

 I: 112 (90.3)              

 C: 111 (90.2)             

 RR 1.01 (0.93–1.09)

 Clinical improvement            

 I: 84 (67.7)                 

 C: 81 (65.9)                

 RR 1.01 (0.86–1.18)

 Recovery

 I: 71 (57.3)                 

 C: 68 (55.3)                

 RR 1.03 (0.83–1.27)

Day 28      

 Absence of deterioration             

 I: 115 (92.7)              

 C: 112 (91.1)             

 RR 1.02 (0.95–1.10)

 Clinical improvement            

 I: 98 (79.0)                

 C: 93 (75.6)                

 RR 1.03 (0.90–1.16)

 Recovery

 I: 91 (73.4)                 

 C: 84 (68.3)                

 RR 1.06 (0.91–1.24)

Respiratory support

Use of intubation and mechanical ventilation                  

Day 14

I: 3 (2.4)

C: 3 (2.4)

RR 0.99 (0.20–4.82)

Day 28      

I: 3 (2.4)

C: 4 (3.3)

RR 0.74 (0.17–3.26)

Safety

Adverse events

I: 124

C: 120

Any adverse event - no. of patients (%)

I: 70 (56.5%)

C: 61 (50.8)

Adverse event leading to discontinuation of treatment - no. of patients (%)

I: 4 (3.2)

C: 2 (1.7)

 Of which: cardiac rhythm or

 conduction disorders: I: 4; C: 1

 Skin rash: I: 0; C: 1

Serious adverse event - no. of patients (%)

I: 3 (2.4)

C: 4 (3.3)

 Of which: cardiac rhythm or

 conduction disorders: I: 3; C: 3

 Rash: I: 0; C: 1

Virological outcomes

Viral clearance

Positive SARS-CoV-2 RT-PCR

Day 5       

I: 75/103 (72.8)

C: 73/100 (73.0)      

RR 1.00 (0.84–1.18)

Day 10     

I: 52/91 (57.1)

C: 47/83 (56.6)        

RR 1.01 (0.78–1.31)

Definitions:

WHO Ordinal Scale for Clinical Improvement:

0: patient uninfected, no clinical or virological signs of infection; 1: patient at home, without limitation of activities; 2: patient at home, with limitation of activities; 3: patient hospitalized without oxygen therapy; 4: patient with oxygen therapy by mask or nasal prongs; 5: patient under non-invasive ventilation or high-flow oxygen; 6: patient under invasive mechanical ventilation; 7; patient under invasive mechanical ventilation and additional organ support, including vasopressors, renal replacement therapy, and extracorporeal membrane

oxygenation; 8: death.

Remarks:

-trial prematurely stopped

Authors conclusion:

In this underpowered trial involving mainly older patients with mild-to-moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo.

Brown, 2020

Type of study:
RCT

Setting:
13 Hospitals in Utah

Country:
USA

Source of funding:
Heart and Lung Research Foundation, Intermountain Research and Medical Foundation, and Office of the Associate Vice President for Research, University of Utah Health Sciences.

Hospitalized COVID-19 patients with symptomatic laboratory-confirmed COVID-19, within 1-0 days of a positive test for COVID-19.

Inclusion criteria:
Trial protocol met de exacte inclusie criteria kan ik niet vinden.

Exclusion criteria:
Ethical reasons (e.g., prisoners) or for safety reasons (e.g., known long QT, seizure disorder, renal or liver failure).

N total at baseline:
N = 85
Intervention: 42
Control: 43

Important characteristics:
Age, median (IQR):
I: 51y (42-60)
C: 58y (43-68)

Sex, n/N (%) female:
I: 19/42 (44%)
C: 14/43 (33%)

[Disease severity], median (IQR):

Mechanical ventilation
I: N = 4 (9%)
C: N = 5 (12%)

Hospitalized, some oxygen (%)
I: 24 (56%)
C: N = 23 (55%)

Hospitalized, no oxygen (%)
I: N = 6 (14%)
C: N = 6 (14%)

Mechanical ventilation & other organ support
I: N = 2 (5%)
C: N = 2 (5%)

Hydroxychloroquine sulfate was administered orally as a loading dose of 400mg twice on the first day followed by 200mg twice daily for the following 4 days (total dose 2.4gm) or until discharge or death

Azithromycin was administered orally as a loading dose of 500mg on the first day, followed by 250mg daily for the next 4 days (total dose 1.5gm) or until discharge or death.

Length of follow up:
28 days

Loss to follow-up:
None

Clinical outcomes
Median posterior odds ratio (95% credible intervals) from proportional odds model

*An OR >1 favors azithromycin over hydroxychloroquine for this comparison.
*An OR <1 favors azithromycin over hydroxychloroquine for this comparison.

28-day mortality
Too few events.

Day 7 COVID scale score
OR= 1.16 (0.68 to 1.96)

Day 14 COVID scale score
OR= 1.07 (0.63 to 1.83)

Day 28 COVID scale score
OR= 1.17 (0.68 to 2.00)

Ventilator-free days at 28 days
OR= 0.85 (0.50 to 1.46)

Hospital-free days at 28 days
OR= 0.91 (0.54 to 1.54)

Days to a 1-point decrease in WHO COVID scale
OR= 1.02 (0.61 to 1.71)

Median (IQR)

ICU-free days at 28 daysI: 18 (8 to 22)
C: 19 (8.5 to 22)

Ventilator-free days at 28 days
I: 18 (10.75 to 18)
C: 18 (12-18)

Days to a 1-point decrease in WHO COVID scale
I: 7 (3 to 13)
C:6 (2.5 to 10)

Subgroup analysis (Median; Mean; Mode; 95% CI)

Duration symptoms <10 days (N=52)
Median= 1.058
Mean= 1.105
Mode= 0.968
95% CI= 0.591 to 1.893

Duration symptoms >10 days (N=33)
Median= 0.924
Mean= 0.973
Mode= 0.833
95% CI= 0.492 to 1.734

Not in ICU at enrolment (N=48)
Median= 0.947
Mean= 0.992
Mode= 0.864
95% CI= 0.523 to 1.716

In ICU at enrolment (N=37)
Median= 1.132
Mean= 1.187
Mode= 1.029
95% CI= 0.617 to 2.074

Definitions:
-

Remarks:
-

Authors conclusion:
In summary, we find no suggestion of a large clinical benefit or harm associated with hydroxychloroquine as opposed to azithromycin among hospitalized patients with COVID-19, although AKI may be more common with hydroxychloroquine. Azithromycin may merit further investigation in focused trials, but should not be implemented in clinical care without additional evidence.

Cavalcanti, 2020

Type of study:

RCT

Setting:

Multicenter, 55 hospitals in Brazil

Country:

Brazil

Source of funding:

The trial was funded by the hospitals and research institutes participating in Coalition Covid-19

Brazil. EMS Pharma provided additional funding and logistic

support for the trial and also donated and supplied the trial drugs.

Inclusion criteria:

Consecutive patients who were

18 years of age or older and who had been hospitalized

with suspected or confirmed Covid-19 with 14 or fewer days since symptom onset.

Exclusion criteria:

Among the reasons for exclusion from the trial were the use of supplemental oxygen at a rate of more than 4 liters per minute as administered by

a nasal cannula or at a level of at least 40% as administered by a Venturi mask; the use of supplemental oxygen administered by a high-flow

nasal cannula or invasive or noninvasive ventilation; previous use of chloroquine, hydroxychloroquine,

azithromycin, or any other macrolide for more than 24 hours before enrollment (and

since the onset of symptoms); and a history of severe ventricular tachycardia or electrocardiographic findings with a corrected QT interval

(QTc) of at least 480 msec.

N total at baseline:

N = 665

Total / with positive RT-PCR

I (HCQ): 221 / 159

I (HCQ+AZI): 217 /172

Control: 227 / 173

Important characteristics:

Age, mean (SD):

I (HCQ): 51.3±14.5

I (HCQ+AZI): 49.6±14.2

C: 49.9±15.1

P=not reported

Sex, n/N (%) male:

I (HCQ): 142/221 (64$)

I (HCQ+AZI): 123/217 (57%)

C: 123/227 (54%)

P=not reported

Groups comparable at baseline?

Not reported, but likely because of randomisation

Hydroxychloroquine alone (HCQ)

Standard care plus hydroxychloroquine at a dose of 400 mg twice daily for 7 days. The use of macrolides was not allowed in the

hydroxychloroquine-alone group.

Hydroxychloroquine + azithromycin (HCQ+AZI)

Standard care plus hydroxychloroquine

at a dose of 400 mg twice daily plus

azithromycin at a dose of 500 mg once a day for 7 days.

Standard care

The current standard care for Covid-19 was at

the discretion of the treating physicians. The use of glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents was allowed. The administration

of hydroxychloroquine or chloroquine and macrolides were not allowed in the control group.

 15 days

Clinical status at 15

days

Seven-level ordinal scale. Effect estimate (95% CI)

HCQ+AZI vs control: 0.99 (0.57 to 1.73)

HCQ vs control: 1.21 (0.69 to 2.11)

HCQ+AZI vs HCQ: 0.82 (0.47 to 1.43)

Clinical status at 7 days

Six-level ordinal scale. Effect estimate (95% CI)

HCQ+AZI vs control: 0.81 (0.54 to 1.22)

HCQ vs control: 0.92 (0.61 to 1.38)

HCQ+AZI vs HCQ: 0.89 (0.58 to 1.34)

Use of high-flow nasal cannula or noninvasive ventilation (n (%)

HCQ+AZI: 16 (9.3)

HCQ: 17 (10.7)

Control: 16 (9.2)

Use of mechanical ventilation (n (%)

HCQ+AZI: 19 (11.0)

HCQ: 12 (7.5)

Control: 12 (6.9)

Duration of hospital stay (n (%)

HCQ+AZI: 10.3±8.4

HCQ: 9.6±6.5

Control: 9.5±7.2

Not significantly different.

In-hospital death (n (%)

HCQ+AZI: 5 (2.9)

HCQ: 7 (4.4)

Control: 6 (3.5)

Not significantly different.

Thromboembolic complications (n (%)

HCQ+AZI: 2 (1.2)

HCQ: 3 (1.9)

Control: 2 (1.2)

Not significantly different.

Acute kidney injury (n (%)

HCQ+AZI: 6 (3.5)

HCQ: 4 (2.5)

Control: 5 (2.9)

Not significantly different.

Number of days alive and

free from respiratory support up to 15 days (mean (sd))

HCQ+AZI: 11.1±4.9

HCQ: 11.2±4.9

Control: 11.1±4.9

Not significantly different.

Safety outcomes

More adverse events were

reported in patients who received hydroxychloroquine

plus azithromycin (39.3%) or hydroxychloroquine alone (33.7%) than in those who

received azithromycin alone (18.0%) or none of the trial drugs (22.6%). Serious adverse events occurred in nine patients. Prolongation

of the QTc interval was more common in patients receiving hydroxychloroquine plus

azithromycin or hydroxychloroquine alone than

in patients in the control group; however, fewer

patients in the control group had serial electrocardiographic

studies performed during follow-up than did patients in the other two groups. Elevation in liver-enzyme levels was more common in patients receiving hydroxychloroquine

plus azithromycin than in the control group.

Remarks:

- Seven-level ordinal scale of primary outcome: score of 1 indicated not hospitalized with no limitations on activities; 2, not hospitalized but with limitations on activities; 3, hospitalized

and not receiving supplemental oxygen; 4,

hospitalized and receiving supplemental oxygen; 5, hospitalized and receiving oxygen supplementation

administered by a high-flow nasal cannula or noninvasive ventilation; 6, hospitalized and

receiving mechanical ventilation; and 7, death.

- 24% tested negative on RT-PCR or test results were unavailable

- analyses were performed among those with positive RT-PCR

- despite intense efforts to maintain adherence to the assigned treatments, a lack of medications that were perceived as beneficial by clinicians and patients led to some protocol deviations.

- the use of hydroxychloroquine plus

azithromycin was widespread among patients hospitalized with Covid-19 in participating hospitals.

The enrollment of patients with no previous use of these medications was challenging, so we decided to enroll patients provided that their previous use since the onset of symptoms

was limited to 24 hours.

Authors conclusion:

- In this trial involving hospitalized patients

with mild-to-moderate Covid-19, we did not find a significant difference in a 15-day ordinal clinical-status outcome among groups that received standard care, hydroxychloroquine alone,or hydroxychloroquine plus azithromycin. Patients

who received hydroxychloroquine, either with azithromycin or alone, had more frequent events of QTc interval prolongation and elevation of liver-enzyme levels than patients who did not receive either agent.

Describe method of randomisation

Bias due to inadequate concealment of allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?

(unlikely/likely/unclear)

Bias due to loss to follow-up?

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?

(unlikely/likely/unclear)

Barratt-Due, 2021

Computerized.

Eligible patients were allocated in an equal ratio using computer randomization procedures. There were 2 separate allocation lists. The first was the global list, in which the allocation sequence was prepared by an independent statistician appointed by the international trial steering group. A secondary national list was additionally prepared as a backup if allocation according to the global list was not available. The randomization procedure ensured that a patient could be allocated only to an available treatment. The randomization lists were not stratified or blocked; thus, the randomization can be regarded as simple.

Unlikely

The first was the global list, in which the allocation sequence was prepared by an independent statistician appointed by the international trial steering group. A secondary national list was additionally prepared as a backup if allocation according to the global list was not available.

Likely

Open label

Likely

Open label

Unclear

Despite being a randomized controlled trial with blinded analyses of all relevant data, it did not include a placebo group.

Unlikely

All outcomes were reported in main article of appendix

ClinicalTrials.gov: NCT04321616

Likely

15 to 24% of participants in study groups were lost to follow-up.

Missing data on outcomes due to discharge or participant withdrawal were imputed with best outcome.

Unlikely

Each pairwise intention-to-treat analysis was between the remdesivir or HCQ group and its respective SoC. Some participants receiving SoC act as controls for both active treatment groups, whereas some act in one or the other, giving a partial overlap of the 2 control groups.

Arabi, 2021

Online randomization system

Using a concealed online randomization system, patients were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or control (no antiviral agents against COVID-19). Based on local equipoise and drug availability, investigators at each participating site selected a priori two or more interventions, one of which had to be control, to which patients could be randomized. Te REMAP-CAP platform uses response-adaptive randomization; however, the allocation in the COVID-19 Antiviral Terapy Domain did not deviate from the starting equal ratio before enrollment was halted. Although the interventions were given as open-label drugs, neither the clinical staf nor the ITSC were provided any information about aggregate patient outcomes.

Unlikely

Using a concealed online randomization system, patients were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or control (no antiviral agents against COVID-19).

Likely

Unblinded cohort: Restricted to patients randomized to an intervention in domains that have been unblinded including the COVID-19 Antiviral Therapy Domain and domains that have ceased recruitment

Unlikely

Although the interventions were given as open-label drugs, neither the clinical staff nor the ITSC were provided any information about aggregate patient outcomes.

Unlikely

Although the interventions were given as open-label drugs, neither the clinical staff nor the ITSC were provided any information about aggregate patient outcomes.

Unlikely

All predefined outcome measures were reported.

NCT02735707

Unlikely

 Lost to follow-up differences between the groups were small.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial.

Schwartz, 2021

Computerized

Randomization was conducted using a custom-developed online tool to allow for dynamic randomization and allocation concealment. We used a minimal sufficient balance randomization tool to ensure balance on age, sex, risk status, days since symptom onset and provincial health zone. Participants were randomly assigned in a stochastically governed (not blocked) 2:1 ratio.

Unlikely

Masking to allocation sequence was complete because randomization assignment was determined dynamically at randomization.

Unlikely

All participants were blinded.

Unlikely

The research team was blinded, except for the research pharmacist and randomization website programmer.

Unlikely

The research team was blinded, except for the research pharmacist and randomization website programmer.

Unlikely

All outcome measures described in the methods are reported in the results.

Unclear

Based on the information presented in the flow chart (Fig. 2), no participants were lost to follow-up in the ITT population. However, the table of results (Tab. 2) shows that for most of the outcomes data was missing for ≥ 1 participants, for which the reasons are not specified per treatment arm in the case of time to COVID-19 recovery.

Likely

For most of the outcomes data was missing for ≥ 1 participants. As a result, not all randomized participants were included in the ITT analyses, which is in contrary to information presented in the flow chart (Fig. 2).

Ader, 2021

Computerized randomisation

Participants were randomly assigned to treatment arms in a 1:1:1:1 ratio, through computer227 generated blocks of various sizes and stratification by administrative region and severity of disease at enrolment

Unlikely

Randomization was implemented in the electronic Case

Report Form to ensure appropriate allocation concealment

Likely

Open-label study

Likely

Open-label study

Likely

Open-label study

Unlikely

Outcomes mentioned in the Methods section were reported in the Results section.

Unlikely

Loss to follow-up was limited :

L/r: 1/145 (0.7%)

L/r + IFN: 1/145 (0.7%)

HCQ: 2/145 (1.4%)

C: 0/148 (0%)

Unlikely

The intention-to-treat population included all randomized participants for whom a valid consent form was obtained.

Réa-Neto, 2021

Web-bases in blocks of variable size (2, 4 and 6)

Patients were randomized (1:1) within 48 h of admission to take Clq or HClq for 5 days plus standard treatment or control (standard treatment only).

Randomization was performed in blocks of variable size (2, 4 and 6) in a centralized web-based automated system and stratified by site and whether the patient was on IMV.

Unlikely

The allocated group was disclosed to the investigator only after all information regarding patient enrollment had been recorded in the web system.

Likely

open-label trial

Likely

open-label trial

Likely

open-label trial

Likely

Trial registered (NCT04333589);

Retrospectively

Registered protocol.

“Although the outcomes presented in the latest version were updated late on ClinicalTrials.org, on October 23, 2020, these outcomes were already present in the trial protocol approved by the Brazilian National Commission for Ethics in Research on April 8, 2020 (approval number: 3960331) and amending the protocol, approved by the same National Commission on May 25, 2020 (approval number: 4044848)”

Unclear

Loss to follow-up:

I: 0/53 (0%)

C: 1/52 (1.9%)

The reason is not reported.

Likely

33 patients from ITT population (n=138) received the intervention (Clq/HClq) until the test result was returned.

Reis, 2021

Randomization schedule

We randomized patients to the hydroxychloroquine, lopinavir-ritonavir, and placebo groups at 1:1:1.Randomization was stratified by site, age (aged 50 years or older vs less than 50 years), and time of

onset of flulike symptoms (at least 5 days vs less than 5 days). Patients, investigators, health care practitioners, and sponsors were masked to the study drug assignment.

Unlikely

The randomization schedule was prepared by a masked statistician and provided to site-level pharmacists.

Unlikely

Patients, investigators, health care practitioners, and sponsors were masked to the study drug assignment.

Unlikely

Patients, investigators, health care practitioners, and sponsors were masked to the study drug assignment.

Unlikely

Patients, investigators, health care practitioners, and sponsors were masked to the study drug assignment.

Unlikely

Outcomes mentioned in the Methods section were similar as the outcomes reported in the Results section.

Likely

At the end of the trial, 79 participants (11.5%) did not complete all phases of the study. The lopinavir-ritonavir intervention group had 44 participants

(18%) who did not complete the study, which was more than either of the other 2 groups.

In addition, the independent DSMB, based on interim analysis results, made the decision to stop enrollment to the hydroxychloroquine and lopinavir-ritonavir groups because of a low number of emerging events.

Unlikely

The Cox proportional hazards model was used for the analysis of time-to-event

outcomes of COVID-19–associated and all-cause hospitalizations for both intention-to-treat (ITT) and

per-protocol (PP) analyses.

Gupta, 2021

Randomization was carried out by simple alternate allocation of patients in a1:1 fashion by the first author to either the control or HCQ arm.

Likely

The allocation was not concealed either from the patient or the physicians and other medical staff.

Likely

“This open-label randomized control trial with unblinded assessment…”

“The chief limitation of our trial is that there was no blinding at randomization or at assessment…”

Likely

“This open-label randomized control trial with unblinded assessment…”

“The chief limitation of our trial is that there was no blinding at randomization or at assessment…”

Likely

“This open-label randomized control trial with unblinded assessment…”

“The chief limitation of our trial is that there was no blinding at randomization or at assessment…”

Unlikely

All predefined outcome measures were reported.

Unlikely

No loss to follow-up reported.

Unlikely

Participants included in the analysis are exactly those who were randomized into the trial.

Dubée, 2021

Computerized

“Patients were randomized immediately after their inclusion into the study using an online

application on the study website”

Unclear

Unclear at what point in time allocation concealment was available.

Unlikely

“The allocation arm was concealed for the patient and for all medical and paramedical staff.”

Unlikely

“The allocation arm was concealed for the patient and for all medical and paramedical staff.”

Unlikely

“The allocation arm was concealed for the patient and for all medical and paramedical staff.”

Likely

No trial register available or link to study protocol; Prematurely stopped after the inclusion of 19% of the planned number of patients; possible bias for over- of underestimating results and missing data

Unlikely

Both intention-to-treat and per-procotol analyses conducted; only small percentage of lost to follo-up; no bias expected

Unlikely

Both intention-to-treat and per-procotol analyses conducted; only small percentage of lost to follo-up; no bias expected

Brown, 2020

Permuted blocks with concealed allocation

Unlikely

Eligible patients were randomly assigned (permuted blocks with concealed allocation) in a 1:1 ratio to hydroxychloroquine or azithromycin. Randomization was stratified by study site.

Likely

Remdesivir was differentially prescribed to patients in the hydroxychloroquine arm. The differential use of remdesivir among hydroxychloroquine patients, which has expected efficacy in this patient population, likely biases our estimates in favor of hydroxychloroquine.

Unclear

Unlikely

The statistical analysis plan was finalized by investigators/statisticians blinded to trial data

Unlikely

Unlikely

Unlikely

Analyses were performed according to the intention to treat principle.

Cavalcanti, 2020

Electronic case-report form system

Randomization was performed in blocks

of six and was stratified according to the use or

nonuse of supplemental oxygen at the time of

randomization. Randomization was performed centrally by means of an electronic case-report form system (RedCap) as described in the Supplementary

Appendix

Unclear

Note: allocation concealment was not described

Likely

Note: patients were not blinded

Likely

Note: care providers were not blinded

Likely

Note: All the trial outcomes were assessed by the site investigators, who were aware of the trial-group assignments (except for patients who had been discharged before day 15 and who were assessed for the primary outcome by means of a blinded telephone interview).

Unlikely

Note: outcomes well defined

Unclear

Note: loss to follow-up was not described

Unclear

Note only patients with confirmed diagnosis were analysed.