Covid-19 living Data

Pharmacologic treatments for covid-19 patients

Hydroxychloroquine vs Standard Care/Placebo

This comparison will not be updated. Last search date 28 Feb, 2022.

The analysis below do not include the results from 14 unpublished studies reported by Axfors et al 2021 Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis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Of note the study Abd-Elsalam S, Am J Trop Med Hyg, 2020 was retracted on Sep, 2022.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.

Outpatients

Forest plots
(last update: 2022-04-29)

Summary of findings
(last update: 2022-05-18)

Patient or population: COVID-19 patients
Setting: Worldwide
Intervention: Hydroxychloroquine
Comparison: Standard Care/Placebo

Outcome	Relative effect (95% CI)	Absolute effect (95% CI)¹		Certainty of the Evidence (GRADE)
Clinical improvement D28	Outcome not yet measured or reported
Clinical improvement D60	Outcome not yet measured or reported
Hospitalisation or death	RR: 0.76 (0.42 - 1.37)	9 fewer per 1000 (from 23 fewer to 15 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding adequate randomization, deviation from intended intervention, missing data,and selection of the reported results Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
5 trials Schwartz I, 2021; Amaravadi R, 2021; Omrani A, 2020; Skipper CP, 2020; Mitja O, 2020 1330 participants		Hydroxychloroquine 30 per 1,000 (16 - 54)	Standard Care/Placebo 39 per 1,000
WHO progression score (level 7 or above) D28	RR: 0.51 (0.05 - 5.55)	2 fewer per 1000 (from 4 fewer to 19 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level:some concerns regarding adequate randomization and missing data Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
3 trials Skipper CP, 2020; Mitja O, 2020; Schwartz I, 2021 992 participants		Hydroxychloroquine 2 per 1,000 (0 - 24)	Standard Care/Placebo 4 per 1,000
WHO progression score (level 7 or above) D60	Outcome not yet measured or reported
All-cause mortality D28	RR: 1.01 (0.06 - 16.09)	0 fewer per 1000 (from 1 fewer to 24 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding adequate randomization and missing data Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
5 trials Amaravadi R, 2021; Omrami A, 2020; Skipper CP, 2020; Mitja O, 2020; Schwartz I, 2021 1330 participants		Hydroxychloroquine 2 per 1,000 (0 - 25)	Standard Care/Placebo 2 per 1,000
All-cause mortality D60	RR: 0.35 (0.01 - 8.63)	3 fewer per 1000 (from 4 fewer to 31 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
2 trials Reis G, 2021; Amaravadi R, 2021 475 participants		Hydroxychloroquine 1 per 1,000 (0 - 35)	Standard Care/Placebo 4 per 1,000
Viral negative conversion D7	RR: 0.93 (0.79 - 1.09)	27 fewer per 1000 (from 80 fewer to 34 more)		Moderate certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to low number of participants/events
3 trials Reis G, 2021; Omrami A, 2020, Byakika-Kibwika P, 2021 781 participants		Hydroxychloroquine 353 per 1,000 (300 - 414)	Standard Care/Placebo 380 per 1,000
Adverse events	RR: 2.07 (0.96 - 4.43)	204 more per 1000 (from 8 fewer to 653 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level:some concerns regarding adequate randomization, deviations from intended interventions,missing data, outcome measurement and selection of the reported results Inconsistency: Serious Inconsistency downgraded by 1 level: I²=:93.9 Indirectness: Not serious Imprecision: Serious due to low number of participants/events
5 trials Amaravadi R, 2021; Reis G, 2021; Skipper CP, 2020; Mitja O, 2020; Byakika-Kibwika P, 2021 1424 participants		Hydroxychloroquine 394 per 1,000 (183 - 843)	Standard Care/Placebo 190 per 1,000
Serious adverse events	RR: 1.30 (0.74 - 2.29)	7 more per 1000 (from 6 fewer to 28 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level:some concerns regarding deviations from intended intervention, outcome measurement and selection of the reported results Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
7 trials Reis G, 2021; Amaravadi R, 2021; Omrani A, 2020; Skipper CP, 2020; Mitja O, 2020; Byakika-Kibwika P, 2021; Schwartz I, 2021 1876 participants		Hydroxychloroquine 28 per 1,000 (16 - 50)	Standard Care/Placebo 22 per 1,000

¹The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Hospitalized patients

Forest plots
(last update: 2022-04-29)

Funnel plots
(last update: 2022-04-03)

Summary of findings
(last update: 2022-05-02)

Patient or population: COVID-19 patients
Setting: Worldwide
Intervention: Hydroxychloroquine
Comparison: Standard Care/Placebo

Outcome	Relative effect (95% CI)	Absolute effect (95% CI)¹		Certainty of the Evidence (GRADE)
Clinical improvement D28	RR: 0.97 (0.94 - 1.00)	20 fewer per 1000 (from 40 fewer to 0 fewer)		Moderate certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns or high risk regarding adequate randomization, deviation from intended intervention, missing data, outcome measurement, and selection of the reported results. Inconsistency: Not serious Indirectness: Not serious Imprecision: Not serious
8 trials Dubee V, 2020; Cavalcanti AB, 2020; Ulrich RJ, 2020; Lyngbakken MN, 2020; Beltran-Gonzalez J, 2021; Ader F, 2022; Self W, 2020; Horby P, 2020 6449 participants		Hydroxychloroquine 646 per 1,000 (626 - 666)	Standard Care/Placebo 666 per 1,000	1 additional study was identified that assessed this outcome, but no results were reported.
Clinical improvement D60	Outcome not yet measured or reported
WHO progression score (level 7 or above) D28	RR: 0.93 (0.71 - 1.22)	8 fewer per 1000 (from 34 fewer to 25 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Despite some concern or high risk regarding adequate randomization, deviation from intended interventions, missing data and selection of reported results, not downgraded for risk of bias because studies with these concerns contributed only a small proportion of the data Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
9 trials Cavalcanti AB, 2020; Chen CP, 2020; Chen J, 2020; Dubee V, 2020; Lyngbakken MN, 2020; Self W, ORCHID, 2020; Tang W, 2020; Ulrich RJ, 2020; Ader F, 2021 1663 participants		Hydroxychloroquine 108 per 1,000 (82 - 141)	Standard Care/Placebo 116 per 1,000
WHO progression score (level 7 or above) D60	RR: 1.15 (0.76 - 1.76)	43 more per 1000 (from 68 fewer to 216 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns regarding deviation from intended intervention, and missing data Inconsistency: Not serious Indirectness: Not serious Multicentre study conducted across several countries, therefore not downgraded for indirectness Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
1 trials Arabi Y, 2021 429 participants		Hydroxychloroquine 326 per 1,000 (216 - 500)	Standard Care/Placebo 284 per 1,000
All-cause mortality D28	RR: 1.07 (0.98 - 1.17)	13 more per 1000 (from 4 fewer to 31 more)		Moderate certainty Reasons to downgrade Risk of bias: Not serious Despite some concern or high risk regarding adequate randomization, deviation from intended interventions, missing data and selection of reported results, not downgraded for risk of bias because studies with these concerns contributed only a small proportion of the data Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to wide confidence interval consistent with the possibility for benefit and the possibility for harm
16 trials Kamran SM, 2021; Dubee V, 2020; Chen CP, 2020; Cavalcanti AB, 2020; Chen L, 2020; Abd-Elsalam S, 2020; Ulrich RJ, 2020; Lyngbakken MN, 2020; Tang W, 2020; Beltran-Gonzalez J, 2021; Self W, 2020; Pan H, 2020; Horby P, 2020; Hernandez-Cardenas C, 2021; Barratt-Due A, 2021; Chen J, 2020 8525 participants		Hydroxychloroquine 198 per 1,000 (182 - 217)	Standard Care/Placebo 185 per 1,000
All-cause mortality D60	RR: 1.26 (0.66 - 2.42)	18 more per 1000 (from 23 fewer to 97 more)		Low certainty Reasons to downgrade Risk of bias: Not serious Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious Imprecision downgraded by 2 level: due to wide confidence interval consistent with the possibility for benefit and the possibility for harm and few events
2 trials Barratt-Due A, 2021; Ader F, 2022 411 participants		Hydroxychloroquine 86 per 1,000 (45 - 164)	Standard Care/Placebo 68 per 1,000	1 additional study was identified that assessed this outcome, but no results were reported.
Viral negative conversion D7	RR: 1.01 (0.79 - 1.30)	4 more per 1000 (from 86 fewer to 124 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns or high risk regarding adequate randomization, deviation from intended intervention, missing data and selection of reported results. Inconsistency: Serious Inconsistency downgraded by 1 level: I²=70.8% Indirectness: Not serious Imprecision: Serious due to wide confidence interval consistent with the possibility for benefit and the possibility for no effect and low number of participants. This outcome was not downgraded an additional level for imprecision because it was downgraded one level for inconsistency, which is related to and would have contributed to the severity of the imprecision.
7 trials Chen CP, 2020; Chen J, 2020; Dubee V, 2020; Ulrich RJ, 2020, Tang W, 2020; Ader F, 2021, Kamran SM, 2021 1188 participants		Hydroxychloroquine 416 per 1,000 (325 - 535)	Standard Care/Placebo 412 per 1,000
Adverse events	RR: 1.13 (1.00 - 1.28)	42 more per 1000 (from 0 fewer to 90 more)		Low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns or high risk regarding adequate randomization, deviation from intended intervention, missing outcome data, outcome measurement and selection of reported results Inconsistency: Not serious Indirectness: Not serious Imprecision: Serious due to low number of participants/events
12 trials Ader F, 2021; Cavalcanti AB, 2020; Chen L, 2020; Chen Z, 2020; Chen J 2020; Dubee V, 2020; Lyngbakken MN, 2020; Tang W, 2020; Ulrich RJ, 2020; Kamran SM, 2021; Self W, 2020; Beltran-Gonzalez J, 2021 2017 participants		Hydroxychloroquine 364 per 1,000 (322 - 413)	Standard Care/Placebo 322 per 1,000	1 additional study was identified that assessed this outcome, but no results were reported.
Serious adverse events	RR: 1.11 (0.93 - 1.32)	12 more per 1000 (from 8 fewer to 35 more)		Very low certainty Reasons to downgrade Risk of bias: Serious Risk of bias downgraded by 1 level: some concerns or high risk regarding adequate randomization, deviation from intended intervention, outcome measurement and selection of the reported results Inconsistency: Not serious Indirectness: Not serious Imprecision: Very serious due to very wide confidence interval consistent with the possibility for benefit and the possibility for harm
14 trials Ader F, 2021; Cavalcanti AB, 2020; Chen CP, 2020; Chen L, 2020; Chen J, 2020; Chen Z, 2020; Dubee V, 2020; Hernandez-Cardenas C, 2021; Lyngbakken MN, 2020; Mitja O, 2020; Omrani A, Q-PROTECT, 2020; Self W, ORCHID, 2020; Skipper CP, 2020; Tang W, 2020; Kamran SM, 2021; Beltra-Gonzalez J, 2021; Arabi Y, 2021 2398 participants		Hydroxychloroquine 121 per 1,000 (101 - 144)	Standard Care/Placebo 109 per 1,000

¹The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)

CI: Confidence interval; RR: Risk ratio

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Permanent URL for this comparison: https://covid-nma.com/living_data/index.php?comparison=3

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Trial	Funding	Comparisons		Design	Participants	Sample size	Overall risk of bias Highest assessment	Full description
		Treatment 1	Treatment 2
N/A Ahmad B, Clin Med Res, 2021 Full text Commentary	No specific funding	Hydroxychloroquine Chloroquine Hydroxychloroquine	Placebo Placebo Chloroquine	RCT	Patients with confirmed COVID-19 (mild-moderate) admitted to a single center in Pakistan.	N=150	Some concerns Details	Full description
CTRI/2020/04/024479 Gupta S, Med J Armed Forces I, 2021 Full text Commentary	Public/non profit	Hydroxychloroquine	Standard care	RCT	Patients with confirmed COVID-19 (moderate to critical) admitted to a single center in India.	N=110	N/A	Full description
NCT02735707 Arabi Y, Intensive Care Med, 2021 Full text Commentary	Mixed	Lopinavir + Ritonavir Hydroxychloroquine Hydroxychloroquine+Lopinavir+Ritonavir Lopinavir + Ritonavir Lopinavir + Ritonavir Hydroxychloroquine	Standard care Standard care Standard care Hydroxychloroquine Hydroxychloroquine+Lopinavir+Ritonavir Hydroxychloroquine+Lopinavir+Ritonavir	RCT	Patients with suspected or confirmed COVID-19 (critical) admitted to a multiple centers in Australia, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Saudi Arabia, UK, and USA	N=726	Some concerns Details	Full description
NCT04329611 Schwartz I, CMAJ Open, 2021 Full text Commentary	Mixed	Hydroxychloroquine	Placebo	RCT	Outpatients with confirmed COVID-19 (mild, symptomatic) treated in the community by the public health system in Canada	N=148	Some concerns Details	Full description
NCT04860284 HONEST Byakika-Kibwika P, BMC Infect Dis, 2021 Full text Full text Commentary Commentary Commentary	Public/non profit	Hydroxychloroquine	Standard care	RCT	Outpatients with confirmed COVID-19 (asymptomatic and symptomatic, mild) isolated at a single center in Uganda.	N=105	Some concerns Details	Full description
NCT04403100 TOGETHER Reis G, JAMA, 2021 Full text Commentary Commentary	Public/non profit	Lopinavir-Ritonavir Hydroxychloroquine Lopinavir-Ritonavir	Placebo Placebo Hydroxychloroquine	RCT	Outpatients with confirmed COVID-19 (mild) treated at local public health facilities in 10 cities in Brazil	N=685	Some concerns Details	Full description
NCT04491994 Kamran SM, Cureus, 2021 Full text Commentary Commentary	No specific funding	Hydroxychloroquine	Standard care	RCT	Patients with confirmed COVID-19 (mild) admitted to a single center in Pakistan	N=540	High Details	Full description
NCT04321616 NOR-SOLIDARITY Barratt-Due A, Ann Intern Med, 2021 Full text Full text Commentary	Mixed	Hydroxychloroquine	Standard care	RCT	Patients with confirmed COVID-19 (unclear severity) admitted to 23 centers in Norway	N=108	Some concerns Details	Full description
NCT04329923 PATCH Amaravadi R, medRxiv, 2021 Full text Commentary Commentary	Mixed	Hydroxychloroquine	Placebo	RCT	Outpatients with confirmed COVID-19 (symptomatic, mild ) treated by a single center in USA	N=34	Some concerns Details	Full description
NCT04391127 Beltran-Gonzalez J, medRxiv, 2021 Full text Commentary Commentary	Public/non profit	Hydroxychloroquine Ivermectin Hydroxychloroquine	Placebo Placebo Ivermectin	RCT	Patients with suspected or confirmed COVID-19 (moderate/severe) admitted to a single center in Mexico	N=106	Some concerns Details	Full description
NCT04315896 Hernandez-Cardenas C, PloS One, 2021 Full text Full text Commentary Commentary Commentary	Mixed	Hydroxychloroquine	Placebo	RCT	Patients with RT-PCR confirmed COVID-19 (severe-critical) admitted to 3 centers in Mexico	N=214	Some concerns Details	Full description
NCT04315948 DisCoVeRy Ader F, medRxiv, 2022 Full text Full text Commentary Commentary Commentary	Mixed	Lopinavir-Ritonavir Lopinavir-Ritonavir+Interferon beta-1a Hydroxychloroquine Lopinavir-Ritonavir Lopinavir-Ritonavir Lopinavir-Ritonavir+Interferon beta-1a	Standard care Standard care Standard care Lopinavir-Ritonavir+Interferon beta-1a Hydroxychloroquine Hydroxychloroquine	RCT	Patients with confirmed COVID-19 (mild-critical) admitted to 32 centers in France and Luxembourg.	N=603	Some concerns Details	Full description
NCT04349592 Q-PROTECT Omrani A, EClinicalMedicine, 2020 Full text Commentary	Public/non profit	Hydroxychloroquine+azithromycin Hydroxychloroquine Hydroxychloroquine+azithromycin	Placebo Placebo Hydroxychloroquine	RCT	Outpatients with confirmed COVID-19 (mild) treated by 2 centers in Qatar	N=456	Some concerns Details	Full description
NCT04332991 ORCHID Self W, JAMA, 2020 Full text Commentary Commentary	Mixed	Hydroxychloroquine	Placebo	RCT	Patients with COVID-19 confirmed (mild-critical) admitted to 34 centers in the USA	N=479	Some concerns Details	Full description
NCT04325893 Dubee V, Clin Microbiol Infec, 2021 Full text Commentary Commentary	Public/non profit	Hydroxychloroquine	Placebo	RCT	Patients with confirmed COVID-19 (mild-moderate) admitted to 34 centers in France and Monaco.	N=250	Some concerns Details	Full description
NCT04353336 Abd-Elsalam S, Am J Trop Med Hyg, 2020 Full text Commentary	Public/non profit	Hydroxychloroquine	Standard care	RCT	Patients with COVID-19 (mild-severe) admitted to three university hospitals in Egypt.	N=194	Some concerns Details	Full description
ISRCTN83971151; NCT04315948 SOLIDARITY (HCQ) Pan H, N Engl J Med, 2020 Full text Full text Commentary	Mixed	Hydroxychloroquine	Standard care	RCT	Patients with COVID-19 (mild-critical) admitted to 405 centers in 30 countries	N=1863	Low Details	Full description
NCT04369742 TEACH Ulrich RJ, Open Forum Infect Di, 2020 Full text Commentary	Public/non profit	Hydroxychloroquine	Placebo	RCT	Patients with confirmed COVID-19 (mild-severe) admitted to 5 centers in USA	N=128	Some concerns Details	Full description
NCT04316377 NO COVID-19 Lyngbakken MN, Nature, 2020 Full text Commentary	Public/non profit	Hydroxychloroquine	Standard care	RCT	Patients with confirmed COVID-19 (mild-severe) admitted to a single center in Norway	N=53	High Details	Full description
NCT04384380 Chen CP, Plos one, 2020 Full text Full text Commentary	Mixed	Hydroxychloroquine	Standard care	RCT	Patients with confirmed COVID-19 (mild-moderate) admitted to 11 centers in Taiwan	N=33	Some concerns Details	Full description
NCT04322123 Cavalcanti AB, N Engl J Med, 2020 Full text Commentary	Mixed	Hydroxychloroquine+Azithromycin Hydroxychloroquine Hydroxychloroquine	Standard care	RCT	Patients with suspected or confirmed COVID-19 (mild-moderate) admitted to 55 centers in Brazil	N=667	Some concerns Details	Full description
NCT04304053 Mitja O, Clin Infect Dis, 2020 Full text Commentary	Mixed	Hydroxychloroquine	Standard care	RCT	Outpatients with COVID-19 (mild) in an ambulatory setting in Spain	N=353	Some concerns Details	Full description
NCT04308668 Skipper CP, Ann Intern Med, 2020 Full text Commentary	Private	Hydroxychloroquine	Placebo	RCT	Outpatients with suspected or confirmed COVID-19 (symptomatic, mild) with high-risk exposure within 4 days of symptom onset	N=491	Some concerns Details	Full description
NCT04381936 RECOVERY (HCQ) Horby P, N Engl J Med, 2020 Full text Commentary	Mixed	Hydroxychloroquine	Standard care	RCT	Patients with COVID-19 (mild-critical) admitted to 176 centers in the UK	N=4716	Some concerns Details	Full description
ChiCTR2000030054 Chen L, medRxiv, 2020 Full text Commentary	Public/non profit	Hydroxychloroquine Chloroquine Hydroxychloroquine	Standard care Standard care Chloroquine	RCT	Patients with confirmed COVID-19 (moderate) admitted to a single center in China	N=67	High Details	Full description