Covid-19 living Data

Hydroxychloroquine vs Standard Care/Placebo (RCT)

Mild outpatients

The analysis below do not include the results from 14 unpublished studies reported by Axfors et al 2021 Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis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Of note the study Abd-Elsalam S, Am J Trop Med Hyg, 2020 was retracted on Sep, 2022.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 NCT04329923
Publication PATCH - Amaravadi R, medRxiv (2021) (preprint)
Dates: 2020-04-15 to 2020-07-14
Funding: Mixed (Leonard & Madlyn Abramson and Mark & Cecilia Vonderheide (philanthropic donations to the University of Pennsylvania) , iRhythm Technologies, Inc. (Cardiac arrhythmia monitoring provided as an in-kind gift))
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Single center / USA Follow-up duration (days): 19
Inclusion criteria	1) Age ≥40 years, 2) PCR-positive for the SARS-CoV-2 virus, 3) fever, or cough, or shortness of breath at the time of testing, 4) ≤4 days had elapsed since the first COVID-19 symptom and testing, 5) not taking azithromycin at the time of enrollment, 6) symptomatic at the time of enrollment, 7) did not require hospitalization, 8) lived within 30 miles of Hospital of the University of Pennsylvania, 9) had access to a working computer, or smartphone and have internet access, 10) willing to fill out a daily electronic symptom score, 11) available for a daily phone call, 12) willing to take their own temperature twice a day, 13) willing to report the observed symptoms and development of COVID-19 in co-habitants.
Exclusion criteria	1) known history of allergy or sensitivity to HCQ, 2) history of glucose-6-phosphate dehydrogenase deficiency, 3) history of retinal disease, 4) history of significant cardiac disease, 5) current use of tricyclic antidepressants, and other medications known to prolong the QT interval, 6) history of psoriasis, 7) history of significant lung disease, 8) participation in any other pharmacologic research study for COVID-19, 9) pregnancy or intention to become pregnant within the study period.
Interventions
	Treatment Hydroxychloroquine 400 mg (two 200 mg tablets) orally twice daily up to 14 days
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=17 Placebo=17
	Characteristics of participants N= 34 Mean age : NR 13 males Severity : Mild: n= 34/ Asymptomatic: n=0
Primary outcome
	In the register Time to Release From Quarantine Time [ Time Frame: until quarantine release or hospitalization ]
	In the report Median time to RFQ [Release From Quarantine]
Documents avalaible	Protocol Yes. In English Statistical plan Yes 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 pre-print article, the trial registry, study protocol, statistical analysis plan and supplementary material were used in data extraction and assessment of risk of bias. There were no substantive differences between the pre-print article and the trial registry, study protocol and statistical analysis plan. The trial was sub-study 1 of the PATCH trial, which consisted of 3 sub-studies: Cohort 1: a double-blind placebo controlled trial of high dose HCQ as a treatment for home bound COVID-19 positive patients; Cohort 2: a randomized study testing different doses of HCQ in hospitalized patients; Cohort 3: a double blind placebo controlled trial of low dose HCQ as a preventative medicine in health care workers. This sub-study was terminated at the first interim analysis due to the large numbers of patients screened with few enrolled and growing literature about the lack of efficacy of HCQ for COVID-19. As a result, the target sample size specified in the registry was not achieved, some efficacy outcomes were not reported.

Trial NCT04860284
Publication HONEST - Byakika-Kibwika P, BMC Infect Dis (2021) (published paper)
Dates: 2020-09-18 to 2021-02-28
Funding: Public/non profit (Government of Uganda through the Makerere University Research and Innovation Fund)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Uganda Follow-up duration (days): 10
Inclusion criteria	Aged 18 years and above diagnosed with COVID-19 using RT-PCR in the last 3 days.
Exclusion criteria	Known allergies to HCQ or chloroquine on medications that have clinically significant interactions with HCQ a positive rapid test for malaria diagnosed with severe/critically ill COVID-19 (WHO Ordinal Scale of ≥ 5) QTc prolongation of > 450ms for males and > 470ms for females pregnant or breastfeeding on chronic HCQ use. Participants found to have hypo- or hyperkalemia at baseline were withdrawn from the study.
Interventions
	Treatment Hydroxychloroquine Initial dose: 400mg orally twice a day for the first day - Maintenance dose: 200mg orally twice daily for the next 4 days.
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=55 Standard care=50
	Characteristics of participants N= 105 Mean age : NR 77 males Severity : Mild: n= / Asymptomatic: n=
Primary outcome
	In the register SARS COV-2 viral clearance [ Time Frame: From randomization to day 6 ]
	In the report Median time from randomization to SARS COV-2 viral clearance by day 6
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 published and pre-print articles, the retrospective registry was used in data extraction and assessment of risk of bias. Neither study protocol nor statistical analysis plan was available. The primary outcome in the article and registry were similar. The secondary outcomes in the article (the proportion of PCR negative conversion by day 6 and day 10, and proportion of participants with 25% reduction of SARS COV-2 viral load from baseline at day 6, change in SARS COV-2 viral load over time, time to symptom clearance by day 10, safety outcomes like incident elevated ALT, incident elevated QTc interval, incident color vision loss/deficiency and adverse events) differed somewhat from the registry (clinical and laboratory adverse events day 6, time to symptom clearance day 10, pharmacokinetic-pharmacodynamic model demonstrating drug concentration day 8, sero-reversion to negative antibody test day 90). The trial was stopped because of the national roll-out of HCQ as standard of care by the Uganda Ministry of Health. As a result the study (n = 105) did not achieve its target sample size (n = 284). This study was updated on April 27th, 2022 with data from the peer-reviewed report.

Trial NCT04304053
Publication Mitja O, Clin Infect Dis (2020) (published paper)
Dates: 17mar2020 to 26may2020
Funding: Mixed (Crowdfunding campaign JoEmCorono; Laboratorios Rubio, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, Generalitat de Catalunya)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Spain Follow-up duration (days): 28
Inclusion criteria	Adult patients aged 18 years or more were eligible if they had mild symptoms of Covid-19 (i.e., fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like-illness) for less than five days before enrollment, were non-hospitalized, and had a positive PCR test for SARS-CoV-2 in the baseline nasopharyngeal swab.
Exclusion criteria	Patients were excluded if they had 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. Females who were pregnant (verbally declared or positive pregnancy test) or breastfeeding were also excluded.
Interventions
	Treatment Hydroxychloroquine Initial dose: 800 mg orally on day 1; Maintenance dose: 400 mg once daily for 6 days
	Control Standard care
Participants
	Randomized participants : Hydroxychloroquine=169 Standard care=184
	Characteristics of participants N= 353 Mean age : NR 92 males Severity : Mild: n= 293/ Asymptomatic: n=0
Primary outcome
	In the register NR
	In the report The reduction of viral RNA load in nasopharyngeal swabs at days 3, and 7 after treatment start
Documents avalaible	Protocol NR 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, the study registry was used in data extraction. Quote: "This trial was a secondary study of the Barcelona Postexposure Prophylaxis Study against SARS-CoV-2 (BCN PEP CoV-2 Study) registered in ClinicalTrials.gov, NCT04304053" No protocol or pre-specified statistical analysis plan are available. There was a change in the protocol for the intervention. Quote: "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." Safety analysis was performed. Quote: "Twenty SAE were reported, 12 in the control arm and 8 in the intervention arm, none of them related to HCQ (Table S3)."

Trial NCT04349592
Publication Q-PROTECT - Omrani A, EClinicalMedicine (2020) (published paper)
Dates: 2020-04-13 to 2020-08-01
Funding: Public/non profit (Hamad Medical Corporation (government health service of the State of Qatar))
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Multicenter / Qatar Follow-up duration (days): 21
Inclusion criteria	Positive Covid test (PCR) used during routine care (i.e. not as part of Q-PROTECT) Patient is in HMC facility for Covid-positive quarantine patients of low acuity (i.e. not requiring hospitalization or antiviral therapy by current Ministry of Public Health guidelines) most cases are anticipated to be healthy young expatriates who cannot be home-quarantined Age at least 18
Exclusion criteria	Treating physician judges patient not appropriate for study participation for any reason Known retinal disease or macular degeneration Psoriasis On tamoxifen for breast cancer Age <18 Breastfeeding or pregnancy (patient-reported pregnancy status is sufficient) Hypersensitivity to chloroquine or HC or AZ History of or known QT prolongation EKG required before study entry and on each visit during the subject’s first seven days on protocol, during the time period HC is being taken Baseline QTc >480 if QRS width normal QTc >510 if QRS >120 Known G6PD deficiency, porphyria, or retinopathy Known hepatic or renal impairment/disease (or abnormality on liver/renal testing at study day 1) Low magnesium or low potassium (by testing on day 1) Current (pre-study) therapy with antimalarial or dapsone Current (pre-study) therapy with antiviral agents (e.g. oseltamivir) Tisdale38 score exceeding 6 as tallied below (based on ACC recommendations)
Interventions
	Treatment HCQ+AZM Hydroxychloroquine: 200 mg orally 3 times a day for 7 days. Azithromycin: 500 mg orally on day 1 followed by 250 mg orally once a day for the next 4 days. Hydroxychloroquine 200 mg orally 3 times a day for 7 days
	Control Placebo
Participants
	Randomized participants : HCQ+AZM=152 Hydroxychloroquine=152 Placebo=152
	Characteristics of participants N= 456 Mean age : NR 449 males Severity : Mild: n= 456/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of virologically cured (PCR-negative status) as assessed on day six [ Time Frame: Day 6 ]
	In the report Virologic cure (PCR-negative status) as assessed on day six.
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 the published article, the trial registry and study protocol were used for data extraction and assessment of risk of bias. No statistical analysis plan was available. There were no substantive differences between the published article, the current trial registration and the study protocol in terms of procedures, population or treatments. The trial registry was changed near to end of recruitment to include outcomes not included in the original entry and the study protocol is not dated, but the data extracted are not affected. The study achieved its pre-stated sample size. Although open to both sexes and conducted in Qatar, the study population was overwhelmingly male and no Qataris were included, reflecting the country’s workforce.

Trial NCT04403100
Publication TOGETHER - Reis G, JAMA (2021) (published paper)
Dates: 2020-06-02 to 2020-10-09
Funding: Public/non profit (Bill and Melinda Gates Foundation)
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Multicenter / Brazil Follow-up duration (days): 90
Inclusion criteria	18 years or older reported less than 8 days since onset of flu-like 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 life-threatening cardiac arrhythmias long QT syndrome known allergy to study drugs
Interventions
	Treatment Hydroxychloroquine Initial dose: 800 mg orally once-off - Maintenance dose: 400 mg orally once per day for 9 days Lopinavir-Ritonavir LPV/r: Initial dose 800/200 mg orally twice on day 1 - Maintenance dose: 400/100 mg orally every 12 hours for 9 days
	Control Placebo
Participants
	Randomized participants : Placebo=227 Hydroxychloroquine=214 Lopinavir-Ritonavir =244
	Characteristics of participants N= 685 Mean age : NR 308 males Severity : Mild: n= 685/ Asymptomatic: n=0
Primary outcome
	In the register Proportion of participants who were hospitalized for progression of COVID-19 disease [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]; Proportion of participants who died due to COVID-19 progression and/ or complications [ Time Frame: Measuring during 28-day period since randomization (Intention to treat analysis) ]
	In the report COVID-associated hospitalization and death
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 published article, the study registry and protocol were used in data extraction and risk of bias assessment. Enrollment into the hydroxychloroquine and lopinavir-ritonavir groups was discontinued in this platform study based on a decision from the independent Safety Monitoring Board following interim analysis results showing that it would be clinically irrelevant to recommend either treatment. The longest follow up in the report was 90 days, and in the registry 28 days. A number of outcomes in the registry were not reported (need for mechanical ventilation, shock and need for vasoactive amines, death due to pulmonary or cardiovascular complications). The definition used in the time to symptom resolution outcome in the paper (resolution of combined symptoms using the WURSS scale) was not pre-specified in the registry [Time to clinical improvement - Proportion of participants with clinical improvement, defined as normalization of temperature, Respiratory rate, SaO2, and cough relief (> 50% compared to baseline measured on a visual analog scale) in the last 72 hours] or in the protocol [Time until clinical improvement (up to 28 days), defined normalization of temperature, respiratory rate, SaO2, and cough relief (> 50 in relation to baseline measured on a visual analog scale) in the last 72 hours; Reduction in the perception of dyspnea (upper respiratory tract respiratory symptoms scale - WURSS-11) on days 0, 3, 7, 14 and 28 days)].

Trial NCT04329611
Publication Schwartz I, CMAJ Open (2021) (published paper)
Dates: 2020-04-15 to 2020-05-22
Funding: Mixed (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.)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Canada Follow-up duration (days): 30
Inclusion criteria	Adults with 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 with at least 1 risk factor for severe disease.
Exclusion criteria	Hospitalized pregnant or breastfeeding unable to swallow pills or unable to comply with the medical regimen used hydroxychloroquine, chloroquine, lumefantrine, mefloquine or quinine within the previous 30 days at higher risk for arrhythmia secondary to hydroxychloroquine, including those concurrently using a drug that prolonged the corrected QT interval (QTc) and those with a modified Tisdale Risk Score of 7 or greater.
Interventions
	Treatment Hydroxychloroquine Initial dose: 200 mg orally 4 times a day for one day - Maintenance dose: 200 mg 2 times a day for 4 days.
	Control Placebo
Participants
	Randomized participants : Hydroxychloroquine=111 Placebo=37
	Characteristics of participants N= 148 Mean age : NR 82 males Severity : Mild: n= 148/ Asymptomatic: n=*
Primary outcome
	In the register Composite of hospitalization, invasive mechanical ventilation or death within 30 days [ Time Frame: Within 30 days of randomization ]
	In the report Development of severe disease defined as the composite of hospitalization, invasive mechanical ventilation, or death within 30 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 the published article, the trial registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. There were some changes to secondary outcome measures during the conduct of the trial, but prior to its termination. Some secondary outcomes reported in the article (ICU admission, SAEs, emesis) were not included in the registry but were in the retrospective protocol. Recruitment to the trial was stopped due to a since-retracted publication raised safety concerns for hydroxychloroquine and was not restarted due to decreasing cases in the community and slow recruitment. Thus the study (n = 148) did not achieve its target sample size (n = 1446).

Trial NCT04308668
Publication Skipper CP, Ann Intern Med (2020) (published paper)
Dates: 22-mars-20 to 05-juin-20
Funding: Private (Private donors)
Conflict of interest: Yes

Methods
	RCT Blinding: Participants and outcome assessor
	Location : Multicenter / USA, Canada Follow-up duration (days): 14
Inclusion criteria	Registry and Protocol: Provision of informed consent Exposure to a COVID19 case within 4 days as either a household contact or occupational exposure, OR Symptomatic COVID19 case with confirmed diagnosis within 4 days of symptom onset OR symptomatic high risk exposure with known COVID19 contact and within 4 days of symptom onset Report: We enrolled nonhospitalized adults who were required to have 4 or fewer days of symptoms and either 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. High-risk exposure was defined as an immediate household contact or a close occupational exposure to someone with COVID-19 (for example, health care worker or first responder). Health care workers who had COVID-19???compatible symptoms and high-risk exposure but whose contact had PCR results pending were enrolled after symptom review by an infectious diseases physician. All of these participants met the COVID-19 case definition of the U.S. Council of State and Territorial Epidemiologists (Supplement) (10). Participants in a third group had a high-risk exposure and were asymptomatic at the time of consent for a companion postexposure prophylaxis trial, which had the same inclusion and exclusion criteria (11) however, these participants became symptomatic before starting their study medicine on day 1 and were analyzed as part of this trial.
Exclusion criteria	Supplemental Methods 2: Symptoms >4 days (per inclusion criteria) Age <18 years old Current hospitalization Hydroxychloroquine allergy Retinal eye disease Known glucose-6 phosphate dehydrogenase deficiency Known chronic kidney disease (stage 4 or 5 or receiving dialysis) Known porphyria Weight less than 40 kg Receiving chemotherapy Current use of hydroxychloroquine, chloroquine Current use of cardiac arrhythmia medicines of: flecainide amiodarone digoxin procainamide or sotalol. In Canada, additional exclusions mandated by regulatory authorities were: pregnancy, breastfeeding severe diarrhea or vomiting known cirrhosis with encephalopathy or ascites known prolonged cardiac QT interval, ventricular arrhythmia, or history of sudden cardiac death or QT-prolonging medicines (as below) (3) On April 20, 2020, additional U.S. exclusions were added for weight less than 50kg, structural or ischemic heart disease, personal or family history of cardiac QT prolongation, and QT-prolonging medications (as below). Concomitant QT prolonging medications included current use of: QT prolonging medicines of: Antimicrobials: azithromycin clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, ketoconazole, itraconazole, or mefloquine Antidepressants: amitriptyline, citalopram, desipramine, escitalopram, imipramine, doxepin, fluoxetine, wellbutrin, or venlafaxine Antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone Methadone Sumatriptan, zolmitriptan The prohibition of azithromycin and other QT prolonging medicines was at the express direction of the U.S. FDA as potentially unsafe in an outpatient clinical trial.
Interventions
	Treatment Hydroxychloroquine 800 mg orally once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days
	Control Placebo folic acid 400 mcg / lactose
Participants
	Randomized participants : Hydroxychloroquine=244 Placebo=247
	Characteristics of participants N= 491 Mean age : NR 185 males Severity : Mild: n= 423/ Asymptomatic: n=0
Primary outcome
	In the register Incidence of COVID19 Disease among those who are asymptomatic at baseline [ Time Frame: 14 days ] Number of participants at 14 days post enrollment with active COVID19 disease. Overall change in disease severity over 14 days among those who are symptomatic at baseline [ Time Frame: 14 days ] Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
	In the report Ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death
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. 100 participants that were randomized in a prevention trial (https://www.nejm.org/doi/full/10.1056/NEJMoa2016638?query=TOC) but became symptomatic by D1 were included in this trial. There is no change from the trial registration in the intervention and control treatments. All outcomes specified in the protocol/registry are reported in the paper. The primary outcome was modified while still blinded due to the pooled event rate of the initial primary outcome (ordinal outcome by day 14 of not hospitalized, hospitalized, or intensive care unit stay or death) being substantially lower than the initial 10% expectation (original sample size calculations as described in Statistical Analysis section). The target sample size was thus modified and reduced following the change in outcome and the decision to stop recruitment was made by the DSMB."