Covid-19 living Data

Hydroxychloroquine vs Standard Care/Placebo (RCT)

Hospitalized patients

The analysis below do not include the results from 14 unpublished studies reported by Axfors et al 2021 Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials .

Of note the study Abd-Elsalam S, Am J Trop Med Hyg, 2020 was retracted on Sep, 2022. The study is not removed from analysis since retraction happened beyound last search date Feb 28, 2022. FOREST PLOTS -2022-04-29

Studies description

Trial NCT04353336
Publication Abd-Elsalam S, Am J Trop Med Hyg (2020) (published paper)
Dates: 2020-03-23 to 2020-06-30
Funding: Public/non profit (Tanta University)
Conflict of interest: *

Trial NCT04315948
Publication DisCoVeRy - Ader F, medRxiv (2022) (preprint)
Dates: 2020-03-22 to 2020-06-29
Funding: Mixed (Programme Hospitalier de Recherche Clinique, DIM One Health Île-de-France, REACTing, INSERM. GILEAD, SANOFI, MERCK and ABBVIE (drug provision) )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France, Luxembourg Follow-up duration (days): 90
Inclusion criteria	Adult ≥18 years of age at time of enrolment Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay in any specimen < 72 hours prior to randomization Hospitalized patients with illness of any duration, and at least one of the following: ‒ Clinical assessment (evidence of rales/crackles on physical examination) AND SpO2 ≤ 94% on room air, OR ‒ Acute respiratory failure requiring supplemental oxygen, high flow oxygen devices, non-invasive ventilation, and/or mechanical ventilation Women of childbearing potential must agree to use contraception for the duration of the study
Exclusion criteria	Refusal to participate expressed by patient or legally authorized representative if they are present Spontaneous blood alanine transferase (ALT)/AST levels > 5 times the upper limit of normal Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR < 30 mL/min) Pregnancy or breast-feeding Anticipated transfer to another hospital, which is not a study site within 72 hours Patients previously treated with one of the antivirals evaluated in the trial (i.e. remdesivir, interferon ß-1a, lopinavir/ritonavir, hydroxychloroquine) in the past 29 days Contraindication to any study medication including allergy Use of medications that are contraindicated with lopinavir/ritonavir i.e. drugs whose metabolism is highly dependent on the isoform CYP3A with narrow therapeutic range (e.g. amiodarone, colchicine, simvastatine) Use of medications that are contraindicated with hydroxychloroquine: citalopram, escitalopram, hydroxyzine, domperidone, pipéraquine Human immunodeficiency virus infection under highly active antiretroviral therapy (HAART) History of severe depression or attempted suicide or current suicidal ideation Corrected QT interval superior to 500 milliseconds (as calculated with the Fridericia formula)
Interventions
	Treatment Lopinavir-Ritonavir Lpv/R: 400/100 mg orally or by nasogastric tube every 12h for 14 days LPV/r+IFN beta-1a Lpv/R: 400/100 mg orally or by nasogastric tube every 12h for 14 days IFN beta-1a: 44 mcg subcutaneously on days 1, 3 and 6 Hydroxychloroquine 400 mg orally twice on day 1 then 400 mg once daily for 9 days
	Control Standard care
Participants
	Randomized participants : Lopinavir-Ritonavir=150 LPV/r+IFN beta-1a=150 Hydroxychloroquine=151 Standard care=152
	Characteristics of participants N= 603 Mean age : NR 421 males Severity : Mild: n=21 / Moderate: n=354 / Severe: n=62 Critical: n=156
Primary outcome
	In the register Percentage of subjects reporting each severity rating on a 7-point ordinal scale [ Time Frame: Day 15]; a. Not hospitalized, no limitations on activities; b. Not hospitalized, limitation on activities; c. Hospitalized, not requiring supplemental oxygen; d. Hospitalized, requiring supplemental oxygen; e. Hospitalized, on non-invasive ventilation or high flow oxygen devices; f. Hospitalized, on invasive mechanical ventilation or ECMO; g. Death
	In the report Clinical status at day 15 as measured on the 7-point ordinal scale of the WHO Master Protocol (v3.0, March 3, 2020)
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the journal/pre-print article and its supplementary materials, the study registry and published protocol were used in data extraction and risk of bias assessment. DisCoVeRy is an adaptive, add-on trial of the WHO Solidarity trial. The same treatments are evaluated in DisCoVeRy and in Solidarity. Solidarity has three endpoints which are also secondary endpoints of DisCoVeRy: (1) mortality during hospitalization (the primary endpoint of Solidarity), (2) length of hospital stay and (3) time to mechanical ventilation or transfer to intensive care. There were no substantive differences between the protocol, registry and publication/pre-print in study population, procedures, interventions or outcomes. The 3 intervention arms presented here were terminated early. Quote: "The present analysis is based on the protocol v7.0 of April, 5th 2020,(14) with two secondary outcomes added in protocol v9.0 of June, 29th 2020...On May 25th 2020, following a safety warning on hydroxychloroquine use(19), enrollment in the hydroxychloroquine arm was suspended at the request of the French Agency of drug Security (Agence Nationale de Sécurité du Médicament). On June 13th, based on the interim analysis of the Solidarity data, the Solidarity and DisCoVeRy trial DSMBs recommended to definitely stop the hydroxychloroquine arm due to futility. This decision was endorsed by the DisCoVeRy steering committee on June 17th. The Solidarity DSMB advised to stop the lopinavir/ritonavir arm due to futility on June, 23th. Thereafter, the DisCoVeRy DSMB further advised to stop both the lopinavir/ritonavir-containing arms due to additional safety concern on June, 25th. This decision was endorsed by the DisCoVeRy steering committee on June 27th with subsequent interruption on June, 29th." The pre-planned remdesivir arm is continuing and currently enrolling. This was substantially underpowered as <25% of the pre-stated sample size was randomized. On 1st of May, 2021, this study was updated based on the published report. On 26th of April, 2022, this study was updated based on the preprint reporting final results.

Trial *
Publication Ahmad B, Clin Med Res (2021) (published paper)
Dates: 2020-06-01 to 2020-06-15
Funding: No specific funding (The authors have reported no conflicts of interest or financial support for this work.)
Conflict of interest: No

Trial NCT02735707
Publication Arabi Y, Intensive Care Med (2021) (published paper)
Dates: 2020-04-08 to 2020-11-19
Funding: Mixed (The European Union through the Platform for European Preparedness Against emerging Epidemics (PRE‑PARE) consortium and Horizon 2020 research and innovation program (the Rapid European Covid-19 Emergency Research response (RECOVER) consortium; the Australian National Health and Medical Research Council; the Health Research Council of New Zealand; Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant; the U.K. NIHR and the NIHR Imperial Biomedical Research Centre; the Health Research Board of Ireland; the UPMC Learning While Doing Program; the Breast Cancer Research Foundation; the French Ministry of Health; the Minderoo Foundation; Amgen; Eisai; the Global Coalition for Adaptive Research; the Wellcome Trust Innovations Project)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Australia, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Saudi Arabia, UK, USA Follow-up duration (days): 90
Inclusion criteria	≥18 years old admitted with suspected or confrmed COVID-19 receiving respiratory or cardiovascular organ failure support in an intensive care unit (ICU). Organ support included the provision of invasive mechanical ventilation, noninvasive mechanical ventilation, high-fow nasal cannulae with a fow 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
Exclusion criteria	Death was deemed to be imminent during the next 24 h AND one or more of the patient, 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 known hypersensitivity to lopinavir-ritonavir and hydroxychloroquine receiving lopinavir-ritonavir or hydroxychloroquine as a usual medication prior to this hospitalization known human immunodefciency (HIV) infection (an exclusion criterion from receiving lopinavir-ritonavir) severe liver failure (an exclusion criterion from lopinavir-ritonavir) known or suspected pregnancy 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) high clinical risk of sustained ventricular dysrhythmia (an exclusion criterion from hydroxychloroquine)
Interventions
	Treatment Lopinavir-Ritonavir 400 mg + 100 mg orally twice daily for 5-14 days or ICU discharge Hydroxychloroquine Initial dose: two oral 800 mg doses 6 h apart - Maintenance dose: 400 mg orally twice daily for 6 days HCQ+LPV/r 400 mg Lopinavir + 100 mg Ritonavir orally twice daily for 5-14 days or ICU discharge + HCQ two 800 mg oral doses 6 h apart, then 400 mg orally twice daily for 6 days
	Control Standard care
Participants
	Randomized participants : Lopinavir-Ritonavir=268 Hydroxychloroquine=52 HCQ+LPV/r=29 Standard care=377
	Characteristics of participants N= 726 Mean age : NR 488 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=694
Primary outcome
	In the register All-cause mortality [ Time Frame: Day 90 ]; Days alive and not receiving organ support in ICU [ Time Frame: Day 21 ]
	In the report composite ordinal scale of the number of respiratory and cardiovascular organ support-free days (OSFD) and in-hospital mortality with death assigned the worst outcome, up to day 21
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the supplementary appendix with protocol and statistical analysis plan, and study registry were used in data extraction and risk of bias assessment. This was a multi-country adaptive platform trial (REMAP-CAP) with no pre-defined sample size. This paper reported on critically ill patients and four of the trial's intervention arms. The interventions arms reported were added to the registry (15 April 2020) one week after the start of recruitment to the arms (8 April 2020), but the domain-specific protocol amendment was dated before start of recruitment (1 April 2020). There were no substantive differences between the published article and the registry, protocol and statistical analysis plan in population, procedures, interventions and outcomes. Enrollment into the hydroxychloroquine and combination therapy study arms was halted before reaching any pre-specifed internal trigger but based on external evidence, consequently, these arms had much smaller sample sizes compared to the other arms.

Trial NCT04321616
Publication NOR-SOLIDARITY - Barratt-Due A, Ann Intern Med (2021) (published paper)
Dates: 2020-03-28 to 2020-06-08
Funding: Mixed (National Clinical Therapy Research in the Specialist Health Services, Norway; Mylan (drug donation) )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Norway Follow-up duration (days): 90
Inclusion criteria	Adults (≥18 years) laboratory-confirmed SARS-CoV-2 infection admitted to the hospital ward or the intensive care unit with no anticipated transfer to a non-study hospital within 72 hours of inclusion informed consent.
Exclusion criteria	Severe co-morbidity with life expectancy <3 months AST/ALT > 5 times the upper limit of normal QTc-time >470 ms pregnancy breast-feeding acute co-morbidity occurrence in a 7-day period before inclusion known intolerance to study drugs participation in a potentially confounding trial or concomitant medications interfering with the study drugs.
Interventions
	Treatment Hydroxychloroquine Initial dose: 800 mg orally 2 times a day for the first 24 hours- Maintenance dose: 400 mg orally 2 times a day for up to 9 days.
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=54 Standard care=54
	Characteristics of participants N= 108 Mean age : NR 65 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register All cause in-hospital mortality [Time Frame: 3 weeks]
	In the report In-hospital mortality (i.e. death during the original hospitalization; follow-up ceased at discharge), regardless of whether death occurred before or after day 28
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	NOR-Solidarity includes additional data collected beyond the WHO Solidarity core follow-up. HCQ was removed as a treatment arm after advice from the NOR-Solidarity steering committee on June 8th 2020 due to lack of evidence of its effectiveness, confirmed both in internal WHO interim analyses and an external report from the Recovery study. In addition to the peer-reviewed journal and pre-print articles, the study registry and protocol were used in data extraction and risk of bias assessment. A statistical analysis plan was not available. There were no substantive differences between the article and trial registry in population, procedures, interventions. Some secondary outcomes from the registry (e.g. viral clearance as assessed by SARS-CoV-2 PCR) are not reported in the paper, though the supplementary material is not currently accessible. Mortality is in-hospital mortality. On 27th of July, 2021, this study was updated based on published article.

Trial NCT04391127
Publication Beltran-Gonzalez J, medRxiv (2021) (preprint)
Dates: 2020-05-04 to 2020-08-15
Funding: Public/non profit (Aguascalienes State Health Institute)
Conflict of interest: No

Methods
	RCT Blinding: Double blinded, no restrictions
	Location : Single center / Mexico Follow-up duration (days): 30
Inclusion criteria	Age 16 to 90 years hospitalized positive RT-PCR for SARS-CoV-2 by nasal and oropharyngeal swabbing pneumonia, diagnosed by X-ray or high-resolution chest CT scan, with a pattern suggesting involvement due to coronavirus recently established hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heart disease.
Exclusion criteria	Required high oxygen volumes (face mask > 10 L/ min) had predictors of a poor response to high-flow oxygen nasal prong therapy required mechanical ventilation
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice a day for the first day. Maintenance dose: 200 mg orally twice a day for another 4 days. Ivermectin 12 mg for one day in patients weighing < 80 kg and 18 mg for one day in those >80 kg.
	Control Placebo Two calcium citrate tablets orally twice a day for one day. Subsequently one tablet twice a day for 4 more days.
Participants
	Randomized participants : Hydroxychloroquine=33 Ivermectin=36 Placebo=37
	Characteristics of participants N= 106 Mean age : NR 66 males Severity : Mild: n=0 / Moderate: n=16 / Severe: n=90 Critical: n=0
Primary outcome
	In the register Mean days of hospital stay [ Time Frame: Three months ]; Rate of Respiratory deterioration, requirement of invasive mechanical ventilation or dead [ Time Frame: Three months ]; Mean of oxygenation index delta [ Time Frame: Three months ]
	In the report Hospitalization duration until discharge due to clinical improvement, the total duration of hospitalization, and the safety outcomes were duration of hospitalization until respiratory deterioration (previously defined) or death
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. Inclusion criteria in registry and the pre-print article differ slightly in that the pre-print article also included hypoxemic respiratory failure or acute clinical deterioration of pre-existing lung or heart disease. Some pre-stated primary (i.e., mean of oxygenation index delta) and secondary (i.e., mean time to negative PCR) outcomes were not reported. There were no substantive differences between the pre-print article and the trial registry in interventions. Patients considered at high risk of development of QT interval prolongation due to hydroxychloroquine were only randomized to the ivermectin or placebo arms. The trial was terminated due to a reduction in eligible participants. As a result, the target sample size was not achieved. This trial was updated on July 28th, 2021 with data gained from contact with authors.

Trial NCT04322123
Publication Cavalcanti AB, N Engl J Med (2020) (published paper)
Dates: 3/29/2020 to 5/17/2020
Funding: Mixed (Hospitals and research institutes participating in Coalition Covid-19 Brazil; EMS Pharma )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil Follow-up duration (days): 15
Inclusion criteria	1. Patients who were 18 years of age or older and were hospitalized with suspected or confirmed COVID-19. 2. Fewer than 14 days since symptom onset.
Exclusion criteria	1. Need for oxygen supplementation >4 L/min via nasal cannula or ?40% via Venturi mask 2. Need for oxygen supplementation via high-flow nasal cannula 3. Need for non-invasive ventilation 4. Need for invasive mechanical ventilation 5. Previous use of chloroquine, hydroxychloroquine, azithromycin, or any other macrolide for more than 24 hours before enrollment 6. History of severe ventricular cardiac arrhythmia or electrocardiogram with corrected QT interval (QTc) ?480 ms 7. History of liver cirrhosis 8. Chronic renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2) 9. Known retinopathy or macular degeneration 10. History of pancreatitis 11. Less than 18 years of age 12. Known allergy to chloroquine or hydroxychloroquine 13. Known allergy to azithromycin 14. Pregnancy or breastfeeding.
Interventions
	Treatment HCQ+AZM Hydroxychloroquine: 400 mg orally or via nasogastric tube twice a day for 7 days Azithromycin: 500 mg IV or orally once a day for 7 days Hydroxychloroquine 400 mg orally or via nasogastric tube twice a day for 7 days
	Control Standard care
Participants
	Randomized participants : HCQ+AZM=217 Hydroxychloroquine=221 Standard care=229
	Characteristics of participants N= 667 Mean age : NR 388 males Severity : Mild: n=387 / Moderate: n=278 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Evaluation of the clinical status of patients on the 15th day after randomization defined by the Ordinal Scale of 7 points.
	In the report Clinical status at 15 days, evaluated with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition)
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published report and supplementary file, the study registry, protocol and SAP were used in data extraction and risk of bias assessment. The study achieved the target sample size reported in the registry. There is no change from the trial registration in the intervention and control treatments. All outcomes from the registry are reported in the paper. Quote: "We had originally planned for the trial to include 630 patients, using the intention-to-treat analysis population, with a six-level ordinal outcome as the primary outcome, as described in the Supplementary Appendix. However, before the first interim analysis was conducted, we changed the primary-outcome assessment to the seven-level ordinal scale and the main analysis population from the intention-to-treat population to a modified intention-to-treat population that included only patients with a diagnosis of Covid-19 that had been confirmed by reverse-transcriptase- polymerase-chain-reaction (RT-PCR) testing (using the test available at each site)." Comment: Furthermore, safety analysis on a safety population of 4 arms was performed - hydrxychloroquine plus azithromycin (n=239), hydroxychloroquine only (n=199), azithromycin only (n=50)and neither hydroxychloroquine nor azithromycin (n=177). Data could not be accurately extracted from this safety population, therefore adverse events data from ITT population were used.

Trial NCT04384380
Publication Chen CP, Plos one (2020) (published paper)
Dates: 01/04/2020 to 31/05/2020
Funding: Mixed (Hospital and Social Welfare Organizations Administration Commission, Ministry of Health and Welfare, Taiwan biotec donation of investigational products)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Taiwan Follow-up duration (days): 14
Inclusion criteria	Enrolled patients were aged 20-79 y and confirmed positive for SARS-CoV-2 infection by real-time reverse transcription polymerase chain reaction (rRT-PCR). They provided signed informed consent. Patients with mild and moderate illness.
Exclusion criteria	Participants presenting with severe illness were excluded from this study. The following patients were excluded from the trial: (a) documented history of hypersensitivity to quinine derivatives (b) retinal disease (c) hearing loss (d) severe neurological or mental illness (e) pancreatitis (f) lung disease (g) liver disease (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3x the normal upper limit) (h) kidney disease (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2 according to MDRD or CKD-EPI) (i) hematological disease (j) 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 Fridericias correction at screening (k) known HIV infection (l) active hepatitis B or C without concurrent treatment (positive for hepatitis B [HBsAg and HBeAg] or hepatitis C ribonucleic acid [RNA] titer > 800,000 IU/mL) (m) G6PD (n) psychiatric disorders and alcohol/substance dependence/abuse that may jeopardize patient safety and (o) pregnant or breast-feeding women.
Interventions
	Treatment Hydroxychloroquine 200 mg orally twice daily on day 1 or 200 mg twice daily for 6 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=21 Standard care=12
	Characteristics of participants N= 33 Mean age : NR 19 males Severity : Mild: n=29 / Moderate: n=4 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Time to negatively RT-PCR [ Time Frame: 14 days ]
	In the report Time to negative rRT-PCR assessments from randomization up to 14 days
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published article, pre-print article, the study registry, protocol and data from direct contact to authors were used in data extraction and risk of bias assessment. The study achieved the target sample size reported in the registry. There is no change from the trial registration in the intervention and control treatments. No pre-specified statistical analysis plan is available. There is no change from the trial registration in the primary outcome. Some secondary outcomes in the report are not present in the registry. One secondary outcome stated in the paper, 'the proportion of discharge by day 14', was not reported. This study was updated on August 12th with data from contact with authors. This study was updated on December 9th with data from the published manuscript.

Trial NCT04261517
Publication Chen J, Journal of Zhejiang (2020) (published paper)
Dates: 06feb2020 to 25feb2020
Funding: Public/non profit (Shanghai Public Health Clinical Center)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / China Follow-up duration (days): 14
Inclusion criteria	Age >/=18 years, COVID-19 was diagnosed according to the "diagnosis and treatment plan" and informed consent was signed
Exclusion criteria	Patients who are allergic to chloroquine and hydroxychloroquine Pregnant women Patients with serious diseases such as heart, lung, kidney, brain, blood and other organs with insufficiency Retinal disease, hearing loss or hearing loss Patients Patients with severe neurological or psychiatric disorders Researchers who believe that they cannot complete the study as required or are not suitable to participate in the research
Interventions
	Treatment Hydroxychloroquine 400 mg orally once daily for 5 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=15 Standard care=15
	Characteristics of participants N= 30 Mean age : NR 21 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register 1. The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 3 [ Time Frame: 3 days after randomization ] 2. The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 5 [Time Frame: 5 days after randomization ] 3. The virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 7 [ Time Frame: 7 days after randomization ] 4. The mortality rate of subjects at weeks 2 [ Time Frame: 14 days after randomization ]
	In the report Virological clearance of a throat swab, sputum, or lower respiratory tract secretion on day 7 or death of the patient within 2 weeks
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published article, the study registry was used in data extraction and risk of bias assessment. The extraction was based on the translation of the article to English by using an online translation tool. There is no change from the trial registration in the intervention and control treatments. The outcomes indicated in registry reflect the outcomes reported in the paper. On July 9th, 2020 we received additional information from authors on this study.On July 9th, 2020 we received additional information from authors on this study.

Trial ChiCTR2000030054
Publication Chen L, medRxiv (2020) (preprint)
Dates: 18feb2020 to 30mar2020
Funding: Public/non profit (Medical and Health Key project of Xiamen, a project of the Xiamen Science and Technology Bureau)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / China Follow-up duration (days): 28
Inclusion criteria	1. Aged 18-75 years old 2. RT-PCR positive for 2019-nCoV or Confirmed lung involvement with chest imaging 3. The clinical symptoms are slight, and there is no obvious manifestation of pneumonia (mild disease) or clinical symptoms such as fever and respiratory tract in imaging. The manifestation of pneumonia (common type) can be seen in imaging 4. <=7 days since onset of the disease 5. Willingness of study participant to accept randomization to any assigned treatment arm 6. Must agree not to enroll in another study of an investigational agent prior to completion of Day 28 of study.
Exclusion criteria	1. Investigator makes a decision that trial participation is not in patients' best interest, or any condition that does not allow the protocol to be followed safely 2. As judged by investigator historic or current diseases that may have impact on the subjects participation of the study or the study outcome. These diseases include but not limited to cadiac diease and arrhythmia and QT prolongation), neurological disease psychiatric disease,active bleeding, serious malnutrition and endocrine disease currently complicated with serious respiratory disease or that seriously affect immune system, such as flu, COPD, asthma, HIV infection, blood system disease, or splenectomy, organ transplantation etc. 3. Severe liver disease (AST>3 ULN) 4. Patients with known severe renal impairment (estimated glomerular filtration rate <=60 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis 5. QT elongation 6. Allergic to chloroquine or hydroxychloroquine 7. Pregnant or breastfeeding, or positive pregnancy test in a predose examination 8. Will be transferred to another hospital within 72 hours 9. Receipt of any experimental treatment for 2019-nCoV (off-label, compassionate use, or trial related) within the 14 days prior to the time of the screening evaluation.
Interventions
	Treatment Hydroxychloroquine 200 mg orally twice a day for 10 days Chloroquine 1000 mg orally four times a day for the first day, then 500 mg four times a day for additional 9 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=28 Chloroquine=25 Standard care=14
	Characteristics of participants N= 67 Mean age : NR 22 males Severity : Mild: n=0 / Moderate: n=48 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Clinical recovery time
	In the report The primary outcome measurement for this study was time to clinical recovery (TTCR), defined as the number of days from randomization to clinical recovery.
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to all available versions of the published/pre-print article, the study registry was used in data extraction and risk of bias assessment. The study did not achieve the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The initial inclusion criteria included mild patients who were then removed after randomization. Table 1 reported characteristics for moderate patients only. 5 additional patients excluded before outcome analysis because they were asymptomatic. No pre-specified statistical analysis plan. Statistical measures (OR, RR, HR) were not reported; PO reported as median days (IQR). Data analysis is pending required information on outcomes

Trial ChiCTR2000029559
Publication Chen Z, medRxiv (2020) (preprint)
Dates: 04feb2020 to 28feb2020
Funding: Public/non profit (Epidemiological Study of COVID-19 Pneumonia to Science and Technology Department of Hubei Province)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / China Follow-up duration (days): 6
Inclusion criteria	1. Age >/= 18 years 2. Laboratory (RT-PCR) positive of SARS-CoV-2 3. Chest CT with pneumonia 4. SaO2/SPO2 ratio > 93% or PaO2/FIO2 ratio > 300 mmHg under the condition in the hospital room (mild illness) 5. Willing to receive a random assignment to any designated treatment group and not participating in another study at the same time.
Exclusion criteria	1. Severe/Critical illness patients or participating in the trial does not meet the patient's maximum benefit or does not meet any criteria for safe follow-up in the protocol after a doctor’s evaluation 2. Retinopathy and other retinal diseases 3. Conduction block and other arrhythmias 4. Severe liver disease (e.g., Child-Pugh score >/= C or AST> twice the upper limit) 5. Pregnant or breastfeeding 6. Severe renal failure [estimated glomerular filtration rate (eGFR) 7. Possibility of being transferred to another hospital within 72 h 8. Received any trial treatment for COVID-19 within 30 days before this research
Interventions
	Treatment Hydroxychloroquine 200 mg orally twice a day for 5 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=31 Standard care=31
	Characteristics of participants N= 62 Mean age : NR 29 males Severity : Mild: n=0 / Moderate: n=62 / Severe: n=0 Critical: n=0
Primary outcome
	In the register The time when the nucleic acid of the novel coronavirus turns negative and T cell recovery time
	In the report NR
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published/pre-print article, the study registry was used in data extraction and risk of bias assessment. The study was initially registered as a 3-arm RCT, with a placebo-control arm and two arms receiving hydrochloroquine. It did not achieve the target sample size specified in the trial registry. Neither of the outcomes specified in the registry as primary is reported in the paper. Some outcomes (time to recovery, pulmonary recovery base on chest CT scan improvement, adverse events) are reported in the paper, but was not pre-specified in the trial registry/protocol.

Trial NCT04325893
Publication Dubee V, Clin Microbiol Infec (2021) (published paper)
Dates: 2020-04-01 to 2020-05-26
Funding: Public/non profit (French Ministry of Health, Pays de la Loire region, Angers Loire Metropole conurbation)
Conflict of interest: Yes

Methods
	RCT Blinding:
	Location : Multicenter / France, Monaco Follow-up duration (days): 28
Inclusion criteria	1) Men and non-pregnant women aged ≥ 18 years old 2) Diagnosis of COVID-19 confirmed by positive RT-PCR SARS-CoV-2 within 2 days were assessed for eligibility or by thorax CT-scan showing typical features of COVID-19. At least one 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 between 60 and 74 years and presence of at least one of the following comorbidities: obesity (body mass index ≥30 kg/m²), arterial hypertension requiring treatment, or diabetes mellitus requiring treatment.
Exclusion criteria	1) Patients requiring more than 3 L/min of oxygen to reach an SpO2 of 94% 2) Those with a clinical condition necessitating admission to intensive care unit 3) A negative SARS-CoV-2 RT-PCR 4) A short-term life-threatening comorbidity (life expectancy <3 months) 5) 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) 6) Conditions associated with an increased risk of adverse event
Interventions
	Treatment Hydroxychloroquine 200 mg orally twice daily for 8 days.
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=125 Placebo=125
	Characteristics of participants N= 250 Mean age : NR 121 males Severity : Mild: n=96 / Moderate: n=151 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Number of death from any cause, or the need for intubation and mechanical ventilation during the 14 days following inclusion and start of treatment. [ Time Frame: Day 14 ]
	In the report Composite of death and the need for invasive mechanical ventilation within 14 days following randomization
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print article, the trial registry, protocol, statistical analysis plan and supplementary materials were used in data extraction and assessment of risk of bias. The trial did not reach its proposed sample size as it was terminated due to a low inclusion rate in the context of the slowdown of the pandemic in France, shortly after being suspended due to reports of hydroxychloroquine toxicity in other trials. There were no substantive differences between the pre-print article and the trial registry, protocol, statistical analysis plan and supplementary materials in study procedures, treatments or outcomes. On 13th of April ,2021, this study was updated based on the published report.

Trial CTRI/2020/04/024479
Publication Gupta S, Med J Armed Forces I (2021) (published paper)
Dates: 2020-05-30 to 2020-09-30
Funding: Public/non profit (Command Hospital Airforce)
Conflict of interest: No

Trial NCT04315896
Publication Hernandez-Cardenas C, PloS One (2021) (published paper)
Dates: 2020-04-08 to 2020-07-12
Funding: Mixed (Participating hospitals; CONACYT (National Council of Science and Technology of Mexico); SANOFI)
Conflict of interest: *

Methods
	RCT Blinding: quadruple blinding
	Location : Multicenter / Mexico Follow-up duration (days): 30
Inclusion criteria	Adults over 18 years of age, with <14 days from symptoms onset Confirmed diagnosis of COVID-19 by RT-PCR (in a pharyngeal/nasopharyngeal swab sample or in a tracheal aspirate/bronchial lavage) that required hospitalization as decided by the attending physicians Hypoxemia (SaO2 <90% ambient air or PaO2/FIO2 <250 in Mexico City) Opacities in the chest roentgenogram or the tomography Hospitalization was usually due to the requirement of respiratory support, either supplementary oxygen or mechanical ventilation.
Exclusion criteria	Known previous COVID-19 infection Previously treated with HCQ or chloroquine during the last month Pregnant woman Planned transfer to another hospital unit Participating in another COVID-19 trial Contraindication to start or continue HCQ including known hypersensitivity to HCQ or chloroquine, a corrected QT interval (QTc) >0.50 s, severe liver or kidney disease, a history of pre-existing maculopathy, >11 score points (of a maximum of 21 score points) on a scale assessing the risk of QTc prolongation in hospitalized patients, including age, gender, myocardial infarction or heart failure, sepsis, the use of drugs known to prolong the QTc or diuretics, and hypokalemia.
Interventions
	Treatment Hydroxychloroquine 200 mg twice a day for 10 days, orally or by nasogastric tube
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=106 Placebo=108
	Characteristics of participants N= 214 Mean age : NR 161 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=52 Critical: n=162
Primary outcome
	In the register All-cause hospital mortality [ Time Frame: From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 120 days ]
	In the report 30-day mortality rate after randomization
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print article and the trial registry were used in data extraction and assessment of risk of bias. The statistical analysis plan was not available. There were no substantive differences between the registry and the pre-print/published article in population, procedures or interventions. Outcomes were pre-specified at 120 days vs 30 days in the published report. The study was stopped early due to reduced recruitment following the worldwide suspension of several large trials testing HCQ. Quote: "In mid-July, 2020, the rhythm of recruitment was reduced drastically, due to several reasons including patient refusal, that of their relatives, or that of their treating physicians, coinciding with the worldwide suspension of several large trials testing HCQ in which no benefits of the drug were found. Thus, it became unfeasible to complete the proposed sample size." The study was updated on the November 24th, 2021 with data from the published report.

Trial NCT04381936
Publication RECOVERY (HCQ) - Horby P, N Engl J Med (2020) (published paper)
Dates: 25mar2020 to 05jun2020
Funding: Mixed (University of Oxford from UK Research and Innovation/National Institute for Health Research (NIHR); NIHR Oxford Biomedical Research Centre; Wellcome; Bill and Melinda Gates Foundation; Department for International Development; Health Data Research UK)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK Follow-up duration (days): 28
Inclusion criteria	Hospitalized patients were eligible for the study if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Initially, recruitment was limited to patients aged at least 18 years but from 9 May 2020, the age limit was removed.
Exclusion criteria	Patients with known prolonged electrocardiograph QTc interval were ineligible for the hydroxychloroquine arm. Co-administration with medications that prolong the QT interval was not an absolute contraindication but attending clinicians were advised to check the QT interval by performing an electrocardiogram.
Interventions
	Treatment Hydroxychloroquine 200 mg tablet orally: 4 tablets at baseline and at 6 hours, then 2 tablets starting at 12 hours after initial dose and then every 12 hours for the next 9 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=1561 Standard care=3155
	Characteristics of participants N= 4716 Mean age : NR 2934 males Severity : Mild: n=1112 / Moderate: n=* / Severe: n=* Critical: n=793
Primary outcome
	In the register All-cause mortality [ Time Frame: Within 28 days after randomisation ]
	In the report 28-day mortality
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print preliminary report and supplementary appendix, the study registry, protocol, and statistical analysis plan were also used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments nor primary and secondary outcomes. On 4 June, in response to a request from the MHRA, the independent Data Monitoring Committee conducted a review of the data and recommended the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial. The Chief Investigators and Trial Steering Committee concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalized with COVID-19. The decision to stop enrolment of participants to the hydroxychloroquine arm was made on June 5 and investigators were advised that any patients currently taking hydroxychloroquine as part of the study should discontinue the treatment.

Trial NCT04491994
Publication Kamran SM, Cureus (2021) (published paper)
Dates: 2020-04-10 to 2020-05-17
Funding: No specific funding (No financial support was received from any organization for the submitted work. )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Pakistan Follow-up duration (days): 14
Inclusion criteria	Mild COVID-19 RT-PCR-confirmed infection hospital-admitted patients 18-80 years of age.
Exclusion criteria	Moderate, severe, or critical COVID-19 day-zero C-reactive protein (CRP) >6 mg/dl or absolute lymphocyte count (ALC) <1000 evidence of infiltrates on X-ray chest co-morbidity with life expectancy of less than six months contraindications to HCQ therapy.
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice a day for day 1 - Maintenance dose: 200 mg twice a day for the next five days.
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=360 Standard care=180
	Characteristics of participants N= 540 Mean age : NR 467 males Severity : Mild: n=500 / Moderate: n=0 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Number of Participants With Progression [ Time Frame: 5 days ] After start of treatment, development of fever > 101 F for > 72 hours, shortness of breath by minimal exertion (10-Step walk test), derangement of basic lab parameters (ALC < 1000 or raised CRP) or appearance of infiltrates on CXR during course of treatment was labeled as progression irrespective of PCR status.
	In the report Disease progression within five days of start of treatment. Progression of disease was defined by the development of fever >101 F for >72 hours, shortness of breath with minimal exertion, derangement of basic laboratory parameters (ALC < 1000 or raised CRP), or appearance of infiltrates on X-ray chest
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published article, the retrospective trial registry with results was used in data extraction and assessment of risk of bias. Neither full study protocol nor statistical analysis plan was available. There were no differences between the trial registry and brief protocol and the published article in population, procedures, interventions or outcomes. The study achieved its target sample size. Despite satisfactory randomisation procedure, the study was assessed as being at a high risk of bias due to apparent selection of control participants based on preference and/or contraindications to the study drug (patients who did not give consent for treatment with HCQ or had a known allergy to HCQ or chloroquine or had any other known contraindication to treatment with the study drug served were allocated as controls) and because of some concerns in three of four other domains.

Trial NCT04316377
Publication NO COVID-19 - Lyngbakken MN, Nature (2020) (published paper)
Dates: 2020-03-25 to 2020-05-25
Funding: Public/non profit (University Hospital, Akershus;European Virus Archive Global (EVA-GLOBAL) project [publication])
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Norway Follow-up duration (days): 30
Inclusion criteria	All reverse transcriptase polymerase chain reaction (RT-qPCR) SARS-CoV-2 positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission (National Early Warning Score 2 [NEWS2] of 6 or less). For patients who tested positive for SARS‐CoV-2 before admission, SARS-CoV-2 status was verified with the external laboratory.
Exclusion criteria	(1) the need of admission to intensive care unit on hospital admission, (2) history of psoriasis, (3) reduced hearing/tinnitus, (4) visual impairment, (5) known adverse reaction to hydroxychloroquine sulphate, (6) pregnancy, or (7) prolonged corrected QT interval (>450 ms)
Interventions
	Treatment Hydroxychloroquine 400 mg orally twice daily for 7 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=27 Standard care=26
	Characteristics of participants N= 53 Mean age : NR 35 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Rate of decline in SARS-CoV-2 viral load, Time Frame: Baseline (at randomization) and at 96 hours
	In the report Rate of decline in SARS-CoV-2 viral load in the oropharynx from baseline through the first 96 hours after randomization
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	High
General comment	In addition to the published and pre-print articles, the supplementary materials, study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. Additionally, an open source repository of the trial used for data extraction. The trial was terminated early by the study sponsor (University Hospital, Akershus) after the first planned interim analysis due to rapidly decreasing incidence of COVID-19 in Norway. Some planned outcomes in the protocol and registry were not reported in the paper. There was no change from the trial registration in the intervention and control treatments. Time point at termination of the study (30 days expected) are not reported. This study (complete result section and Risk of Bias assessment) was updated on 04/11/2020.

Trial ISRCTN83971151; NCT04315948
Publication SOLIDARITY (HCQ) - Pan H, N Engl J Med (2020) (published paper)
Dates: 2020-03-22 to 2020-10-04
Funding: Mixed (World Health Organization; Mylan (drug donation))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Multinational (30) Follow-up duration (days): 28
Inclusion criteria	Age ≥18 years, hospitalized with a diagnosis of COVID-19, not known to have received any study drug, without anticipated transfer elsewhere within 72 hours, and, in the physician’s view, with no contra-indication to any study drug.
Exclusion criteria	The only exclusions were patients without clear consent to follow-up
Interventions
	Treatment Hydroxychloroquine 200 mg tablets orally: four tablets at hour 0, four tablets at hour 6, and, starting at hour 12, two tablets twice daily for 10 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=954 Standard care=909
	Characteristics of participants N= 1863 Mean age : NR 1109 males Severity : Mild: n=686 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register All-cause mortality, subdivided by the severity of disease at the time of randomization, measured using patient records throughout the study
	In the report In-hospital mortality
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	In addition to all available versions of the published manuscript, the pre-print article, the study registry and protocol were used in data extraction and risk of bias assessment. This was a report of interim results of an adaptive trial evaluating 4 drugs: Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon-β1a. No target sample size was pre-specified. Quote: "The protocol stated “The larger the number entered the more accurate the results will be, but numbers entered will depend on how the epidemic develops… it may be possible to enter several thousand hospitalised patients with relatively mild disease and a few thousand with severe disease, but realistic, appropriate sample sizes could not be estimated at the start of the trial.” The Executive Group, blind to any findings, decided the timing of release of interim results." Quote: "The hydroxychloroquine, lopinavir, and interferon regimens were discontinued for futility on, respectively, June 19, July 4, and October 16, 2020." There was no change from the trial registration in the intervention and control treatments, nor in the primary and secondary outcomes. Discrepancy between exclusion criteria in the protocol and in the paper. Lack of clarity on why/how Hydrochloroquine was administered to ventilated patients(for lopinavir, it is stated: Other formulations were not provided, so ventilated patients received no study Lopinavir while unable to swallow). This study was updated on December 9th using data from the published manuscript.

Trial NCT04332991
Publication ORCHID - Self W, JAMA (2020) (published paper)
Dates: 2020-04-02 to 2020-06-19
Funding: Mixed (National Heart, Lung, and Blood Institute (NHLBI), NCATS, Harvard Catalyst, Sandoz.)
Conflict of interest: Yes

Methods
	RCT Blinding: Participants, outcome assessor and health care pro
	Location : Multicenter / USA Follow-up duration (days): 28
Inclusion criteria	Age ≥18 year Currently hospitalized or in an emergency department with anticipated hospitalization Symptoms of acute respiratory infection, defined as one or more of the following: cough, fever (> 37.5° C / 99.5° F), shortness of breath (operationalized as any of the following: subjective shortness of breath reported by patient or surrogate tachypnea with respiratory rate ≥22 /minute hypoxemia, defined as SpO2 <92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy), sore throat Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior to randomization.
Exclusion criteria	Prisoner Pregnancy Breast feeding Symptoms of acute respiratory infection for >10 days before randomization >48 hours between meeting inclusion criteria and randomization Seizure disorder Porphyria cutanea tarda Diagnosis of Long QT syndrome QTc >500 ms on electrocardiogram within 72 hours prior to enrollment Known allergy to hydroxychloroquine, chloroquine, or amodiaquine Receipt in the 12 hours prior to enrollment, or planned administration during the 5-day study period that treating clinicians feel cannot be substituted for another medication, of any of the following: amiodarone cimetidine dofetilide phenobarbital phenytoin sotalol Receipt of >1 dose of hydroxychloroquine or chloroquine in the 10 days prior to enrollment Inability to receive enteral medications Refusal or inability to be contacted on Day 15 for clinical outcome assessment if discharged prior to day 15 Previous enrollment in this trial The treating clinical team does not believe equipoise exists regarding the use of hydroxychloroquine for the treatment of this patient.
Interventions
	Treatment Hydroxychloroquine 400 mg orally twice daily for first 2 doses, then 200 mg twice daily for subsequent 8 doses for a total of 10 doses over 5 days
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=242 Placebo=237
	Characteristics of participants N= 479 Mean age : NR 267 males Severity : Mild: n=168 / Moderate: n=224 / Severe: n=55 Critical: n=32
Primary outcome
	In the register COVID Ordinal Outcomes Scale on Day 15 [ Time Frame: assessed on study day 15 ] We will determine the COVID Ordinal Scale for all patients on study day 15
	In the report Clinical status 14 days after randomization assessed with a 7-category ordinal scale (the COVID Outcomes Scale) recommended by the World Health Organization.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registry, published design and rationale article, study protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. There were no differences between trial registry, study protocol and published article in terms of population, procedures, treatments or outcomes. The trial was stopped at the fourth interim analysis due to probable futility, announcements of no benefit from the RECOVERY trial in the UK, and advisories from national regulatory agencies.

Trial ChiCTR2000029868
Publication Tang W, BMJ (2020) (published paper)
Dates: 11feb2020 to 29feb2020
Funding: Mixed (Emergent Projects of National Science and Technology; National Natural Science Foundation of China; National Key Research and Development Program of China; Shanghai Municipal Key Clinical Specialty; National Innovative Research Team of High-level Loc)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / China Follow-up duration (days): 33
Inclusion criteria	1) age >18 years 2) with ongoing SARS–CoV–2 infection confirmed in upper or lower respiratory tract specimens with real–time reverse–transcriptase–polymerase–chain–reaction (RT–PCR) 3) willingness to participate 4) consent not to be enrolled by other clinical trials during the study period.
Exclusion criteria	1) age <18 years 2) with severe conditions including malignancies, heart/liver/kidney disease or poorly controlled metabolic diseases 3) not suitable to be administrated through the gastrointestinal tract 4) pregnant or lactation 5) allergy to HCQ 6) unable to cooperate with investigators due to cognitive impairments or poor mental status 7) with severe liver disease (e.g. Child Pugh grade C, alanine aminotransferase >5 fold of times upper limit) 8) with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis. In the original protocol, patients with severe COVID–19 were excluded. Considering the anti–inflammatory property of HCQ might favor disease regression, we decided to include patients with severe COVID–19. (change approved by the Ethics Committee on February 17, 2020).
Interventions
	Treatment Hydroxychloroquine Initial dose: 1200 mg orally daily for 3 days- Maintenance dose: 800 mg orally daily for the remaining days. Treatment duration: 2 weeks (mild to moderate); 3 weeks (severe)
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=75 Standard care=75
	Characteristics of participants N= 150 Mean age : NR 82 males Severity : Mild: n=22 / Moderate: n=126 / Severe: n=2 Critical: n=0
Primary outcome
	In the register Viral nucleic acid test
	In the report Negative conversion of SARS–CoV–2 by 28 days and whether patients with severe COVID–19 had a clinical improvement by 28 days
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to all available versions of the published/pre-print article, the study registry, protocol, and statistical analysis plan were used in data extraction and risk of bias assessment. The study was terminated early by the IDMC after interim review of safety and efficacy data. The study did not achieve the target sample size specified in the trial registry. The primary outcome included clinical improvement, however the authors do not report this. They provide an explanation for this change: "since the trial was stopped early and only 2 patients with severe disease were enrolled, results on clinical improvement are not presented". There is no change from the trial registration in the intervention and control treatments. Some outcomes (e.g., all cause mortality) are reported in the paper, but were not pre-specified in the trial registry. They are, however, pre-specified in the protocol. On July 15th 2020, we received additional information from authors on this study.

Trial NCT04369742
Publication TEACH - Ulrich RJ, Open Forum Infect Di (2020) (published paper)
Dates: 2020-04-17 to 2020-05-12
Funding: Public/non profit (NYU Grossman School of Medicine; National Center for Advancing Translational Sciences, National Institutes of Health)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / USA Follow-up duration (days): 30
Inclusion criteria	Hospitalized patients with positive SARS-CoV-2 RT-PCR...In addition to a positive RT-PCR within 72 hours of enrollment, at least one COVID-19 symptom (e.g., fever, cough, dyspnea, nausea, diarrhea, myalgia, anosmia, dysgeusia) and the subject’s (or legally authorized representative’s) written informed consent
Exclusion criteria	Admitted to the ICU, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use at enrollment, had received any doses of hydroxychloroquine or chloroquine within 30 days, were unable to take oral medications, were allergic to HCQ or CQ, had a baseline corrected QT interval >500 milliseconds, were on concomitant therapy with antiarrhythmic medications (flecainide, amiodarone, digoxin, procainamide, propafenone, thioridazine, or pimozide), had a history of cardiac arrest, retinal disease, or glucose-6-phosophate dehydrogenase deficiency
Interventions
	Treatment Hydroxychloroquine 400 mg (2 tablets) twice daily (day 1) and 200 mg (1 tablet) twice daily (days 2-5)
	Control Placebo Calcium citrate: 400 mg (2 tablets) twice daily (day 1) and 200 mg (1 tablet) twice daily (days 2-5)
Participants
	Randomized participants : Hydroxychloroquine=67 Placebo=61
	Characteristics of participants N= 128 Mean age : NR 76 males Severity : Mild: n=45 / Moderate: n=62 / Severe: n=21 Critical: n=0
Primary outcome
	In the register Cumulative incidence of SAEs through day 30; Cumulative incidence of grade 3 or 4 AEs through day 30; Incidence of discontinuation of therapy (for any reason); Severe disease progression composite outcome
	In the report Proportion of subjects meeting a severe COVID-19 progression composite endpoint (death, ICU admission, mechanical ventilation, ECMO, and/or vasopressor use) at day 14; Cumulative incidence of SAE, grade 3 or 4 AE, and/or discontinuation of therapy at day 30.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the accepted manuscript, the study registry was used in data extraction and risk of bias assessment. The protocol and data analysis plan were not available. The report stated the existence of the protocol in the supplementary materials but this could be found. The report stated that the protocol was amended to allow for co-enrollment in other COVID-19 therapeutic trials and for the enrollment of children and pregnant women. The study was registered retrospectively. The authors states that the study team initiated registration prospectively, but a separate office submitted the registration later due to administrative delays during COVID-19. The study was terminated early by the investigators due to a decrease in COVID-19 admissions and consequently did not achieve the target sample size. There was no change from the trial registration in the intervention and control treatments. The primary outcomes indicated in registry reflected the primary outcomes reported in the paper.

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Egypt Follow-up duration (days): 28
Inclusion criteria	1) All patients admitted with SARS-CoV-2 infection 2) Enrolled both genders
Exclusion criteria	1) Patient who had allergy or contraindication to HCQ 2) Pregnant and lactating females 3) Patients with cardiac problem (chronic heart failure or prolonged QT interval on electrocardiogram [ECG])
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice daily on day 1, maintenance dose: 200 mg orally twice daily for 15 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=97 Standard care=97
	Characteristics of participants N= 194 Mean age : NR 114 males Severity : Mild: n=* / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register Number of patients with cure or death [Time Frame: 1 month]
	In the report Recovery within 28 days, need for mechanical ventilation, or death.
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry was used in data extraction and assessment of risk of bias. Neither the study protocol nor the statistical analysis plan was available. The study was retrospectively registered. There is no change from the trial registration in the intervention and control treatments. It is not clear how many patients received which aspects of standard care. Several outcomes are reported in the manuscript that are not included in the registry.

Methods
	RCT Blinding: single blinding
	Location : Single center / Pakistan Follow-up duration (days): 12
Inclusion criteria	Adults admitted into the hospital COVID confirmed by PCR mild to moderate symptoms as per Chinese guidelines for COVID-19
Exclusion criteria	Severe or critical COVID-19 pregnant women ischemic heart disease or cardiac arrhythmias retinopathy patients who refused to participate in the study
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice a day on day 1 - Maintenance dose: 200 mg orally twice a day on days 2-5 Chloroquine 250 mg orally twice a day for 7 days
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=50 Chloroquine=50 Placebo=50
	Characteristics of participants N= 150 Mean age : NR 0 males Severity : Mild: n=* / Moderate: n=* / Severe: n=0 Critical: n=0
Primary outcome
	In the register NR
	In the report Development of cytokine release syndrome (CRS)
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	Only the published article was used in data extraction and assessment of risk of bias. No registry, protocol or statistical analysis plan was available. The article reported no NMA-specific outcomes eligible for extraction.

Methods
	RCT Blinding: Unblinded
	Location : Single center / India Follow-up duration (days): *
Inclusion criteria	COVID-19–positive based on real time reverse transcription polymerase chain reaction (rRT PCR) symptomatic for the disease for ≤4 days 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	Younger than 14 years asymptomatic mild illness allergic to chloroquine unwilling to give informed consent prolonged QTc interval on ECG
Interventions
	Treatment Hydroxychloroquine Initial dose: 400 mg orally twice a day on day 1 - Maintenance dose: 400 mg orally once a day on days 2-5.
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=55 Standard care=55
	Characteristics of participants N= 110 Mean age : NR 80 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=*
Primary outcome
	In the register number of days of hospitalization (discharge)
	In the report number of days of hospitalization till discharge or death
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	*
General comment	This study is pending contact with authors. In addition to the published paper, the registry was available (dated April 4 2020). Neither protocol nor statistical analysis plan was available. The primary outcome in the article reflected that in the registry. The trial (n = 110) exceeded its target sample size (n = 32). No follow-up time was reported. No outcomes eligible for COVID NMA were reported.