Table 1.
Summary of findings in included trials.
| Study authors | Study design | No of patients | Treatment regimen | Patient characteristics |
Outcomesb |
Adverse eventsc (n/N) | Treatment discontinuationb (n/N) | Summary of findings | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age (years) (mean ± SD) | Male (%) | Common comorbid conditions | Baseline disease severity | Viral clearance (n/N) | Lung clearance (n/N) | Patients discharged (n/N) | Death or transfer to ICU or hospitalization (n/N) | Confirmed or probable COVID-19 (n/N) | Development of new symptoms (n/N) | |||||||
| Boulware et al. (2020) | Double-blind placebo-controlled RCT | 414 | Orally administered HCQ 800 mg once, followed by 600 mg in 6–8 h, then 600 mg daily for an additional 4 days | 41 (33–51)a | 47.3 | Hypertension Asthma Diabetes |
NR | NR | NR | NR | None | 49/414 (11.8%) | 57/414 (13.8%) | Any adverse event = 140/349 (40.1%); nausea = 80/349 (32.9%); diarrhoea = 81/349 (23.2%); neurologic reaction = 19/349 (5.4%); visual changes = 3/349 (0.9%) | 17/414 (4.1%) | Inconclusive: no statistically significant benefit |
| 407 | Placebo | 40 (32–50)a | 49.4 | Hypertension Asthma Diabetes |
NR | NR | NR | NR | None | 58/407 (14.3%) | 59/407 (14.5%) | Any adverse event = 59/351 (16.8%); nausea = 27/351 (7.7%); diarrhoea = 15/351 (4.3%); neurologic reaction = 13/351 (3.7%); visual changes = none | 8/407 (2.0%) | |||
| Gautret et al. (2020) | Open-label non-randomized controlled trial | 20 | Orally administered HCQ 200 mg, three times per day for 10 days | 51.2 ± 18.7 | 45.0 | NR | NR | 14/20 (70.0%; 6 dropped out) at day 6 | NR | NR | ICU admission = 3/20 (15.0%); death = 1/20 (5.0%) | NR | NR | Nausea reported in one patient where the patient ceased HCQ treatment and was excluded from the analysis | One patient discontinued treatment because of nausea and was excluded from the analysis | Suggestive of benefits: increased negative conversion rate with HCQ but with a low degree of certainty because of critical risk of bias |
| 16 | Control | 37.3 ± 24.0 | 37.5 | NR | NR | 2/16 (12.5%) at day 6 | NR | NR | NR | NR | NR | NR | NR | |||
| Chen et al. (2020a) | Open-label RCT | 15 | Orally administered HCQ 400 mg daily for 5 days plus conventional treatments | 48 | NR | Hypertension Diabetes COPD |
NR | 13/15 (86.7%) at day 7 | 5/15 (33.3%) on day 3 | NR | None | NR | NR | Any adverse event = 4/15 (26.7%); diarrhoea = 2/15 (13.3%); abnormal liver function = 1/15 (6.6%) | NR | Inconclusive: no statistically significant benefit |
| 15 | Control | 48 | NR | Hypertension Diabetes COPD |
NR | 14/15 (93.3%) at day 7 | 7/15 (46.7%) on day 3 | NR | None | NR | NR | Any adverse event = 3/15 (20.0%); abnormal liver function and anaemia = 1/15 (6.6%) | NR | |||
| Tang et al. (2020) | Open-label RCT | 75 | Orally administered HCQ loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg/day for remaining days (total treatment duration 2 weeks or 3 weeks for patients mild/moderate or severe disease, respectively) | 48.0 ± 14.1 | 56.0 | Diabetes Hypertension | Mild = 15/75 (20.0%); moderate = 59/75 (78.7%); severe = 1/75 (1.3%) | Frequency was not reported; probability of viral clearance estimated by Kaplan–Meier method = 85.4% | NR | NR | NR | NR | NR | Any adverse event = 21/70 (30.0%); serious adverse event = 2/70 (2.9%); diarrhoea = 7/70 (10.0%) | 1/75 (1.3%) due to blurred vision | Inconclusive: no statistically significant benefit |
| 75 | SOC as per Chinese guidelines | 44.1 ± 15.0 | 53.3 | Diabetes Hypertension | Mild = 7/75 (9.3%); moderate = 67/75 (89.3%); severe = 1/75 (1.3%) | Frequency was not reported; probability of viral clearance estimated by Kaplan–Meier method = 81.3% | NR | NR | NR | NR | NR | Any adverse event = 7/80 (8.8%); serious adverse event = none; diarrhoea = none | None | |||
| Chen et al. (2020b) | Open-label RCT | 31 | Orally administered HCQ 200 mg twice daily | 44.1 ± 16.1 | 45.2 | NR | NR | NR | 25/31 (80.6%) at day 6 | NR | NR | NR | NR | Mild adverse event = 2/31 (6.5%); serious adverse event = none | None | Suggestive of benefits: more rapid lung clearance but with a moderate degree of certainty because of some concerns regarding the risk of bias |
| 31 | Control | 45.2 ± 14.7 | 48.3 | NR | NR | NR | 17/31 (54.8%) at day 6 | NR | NR | NR | NR | None | None | |||
| Esper et al. (2020) | Open-label non-randomized controlled trial via telemedicne | 412 | Orally administered HCQ 800 mg on the first day and 400 mg for another 6 days and AZT 500 mg once daily for 5 days | 63.6 ± 14.9 | 36.4 | Diabetes | NR | NR | NR | NR | Hospitalization = 8/412 (1.9%); death = 2/412 (0.49%) but non COVID-19 related | NR | NR | Serious adverse event = none; dizziness = 8/412 (1.9%); diarrhoea = 68/412 (16.5%); nausea = 31/412 (7.5%) vomiting = 5/412 (1.2%) visual disturbance = 1/412 (0.2%); allergy = 4/412 (1.0%) | NR | Suggestive of benefits: reduced need for hospitalization in suspected COVID-19 patients but with a low degree of certainty because of serious risk of bias |
| 224 | Control (refused HCQ + AZT) | 61.0 ± 16 | 38.4 | Diabetes | NR | NR | NR | NR | Hospitalization = 12/224 (5.4%) | NR | NR | NR | NR | |||
| Huang et al. (2020b) | Open-label parallel RCT | 10 | Orally administered CQ 500 mg orally twice daily for 10 days | 41.5 (33.8–50.0)a | 30.0 | NR | Severe disease = 3/10 (30.0%) | At day 10 = 9/10 (90%); at day 14 = 10/10 (100%) | At day 10 = 2/10 (20%); at day 14 = 10/10 (100%) | At day 14 = 10/10 (100%) | None | NR | NR | Any adverse event = 9/10 (90.0%); serious adverse event = none; vomiting = 5/10 (50.0%); diarrhoea = 5/10 (50.0%); nausea = 4/10 (40.0%) | None | Inconclusive: no statistically significant benefit |
| 12 | Orally administered lopinavir/ritonavir 400 mg/100 mg for 10 days | 53.0 (41.8–63.5)a | 50.0 | NR | Severe disease = 5/12 (41.7%) | At day 10 = 9/12 (75.0%); at day 14 = 11/12 (91.7%) | At day 10 = 2/12 (8.3%); at day 14 = 9/12 (75.0%) | At day 14 = 6/12 (50%) | None | NR | NR | Any adverse event = 10/12 (83.3%); serious adverse event = none; vomiting = 1/12 (8.3%); diarrhoea = 8/12 (66.7%); nausea = 5/12 (41.7%) | NR | |||
| Borba et al. (2020) | Double-blind parallel RCT | 41 | Orally administered CQ (4 × 150 mg tablets, twice daily for 10 days; total dose 12 g) | 54.7 ± 13.7 | 75.0 | Hypertension kidney disease | NR | NR | NR | NR | Death = 16/41 (39.0%) | NR | NR | Ventricular tachycardia = 2/37 (5.4%); prolonged QT interval = 7/37 (18.9%) | NR | Suggested: safety concerns with high dose of CQ |
| 40 | Orally administered CQ (3 × 150 mg tablets and 1 placebo tablet twice daily on day 0, 3 × 150 mg tablets plus 1 placebo tablet once a day followed by 4 placebo tablets from day 1 to day 4, then 4 placebo tablets twice daily from day 5 to day 9; total dose 2.7 g) | 47.4 ± 13.3 | 74.5 | Hypertension | NR | NR | NR | NR | Death = 6/40 (15.0%) | NR | NR | Severe rhabdomyolysis = 1/36 (2.8%); ventricular tachycardia = 0/36 (5.4%); prolonged QT interval = 4/36 (11.1%) | NR | |||
| Cavalcanti et al. (2020) | Open label RCT | 217 | Orally administered HCQ 400 mg twice daily plus AZT 500 mg once daily for 7 days | 49.6 ± 14.2 | 56.7 | Heart failure HypertensionCOPDAsthmaObesityDiabetes AIDSChronic kidney d isease Current or former smoking Cancer |
Mild-to-moderate disease | NR | NR | At day 15 = 184/217 (84.8%) | At day 15 death = 3/217 (1.4%) | NR | NR | Any adverse event = 94/239 (39.3%); serious adverse event = 5/239 (2.1%); prolonged QT interval = 17/116 (14.7%); arrhythmia = 3/239 (1.3%); nausea = 6/239 (2.5%); abnormal liver function = 26/239 (10.9%) | NR | Suggested: no clinical improvement after treatment with HCQ alone or in combination with AZT |
| 221 | Orally administered HCQ 400 mg twice daily for 7 days | 51.3 ± 14.5 | 64.3 | Heart failure HypertensionCOPDAsthmaObesityDiabetes AIDSC hronic kidney disease Current or former smoking Cancer |
Mild-to-moderate disease | NR | NR | At day 15 = 185/221(83.7%) | At day 15 death = 7/221 (3.2%) | NR | NR | Any adverse event = 67/199 (33.7%); serious adverse event = 2/199 (1.0%); prolonged QT interval = 13/89 (14.6%); arrhythmia = 3/199 (1.5%); nausea = 9/199 (4.5%); abnormal liver function = 17/199 (8.5%) | NR | |||
| 227 | SOC | 49.9 ± 15.1 | 54.2 | Heart failure HypertensionCOPDAsthmaObesityDiabetes AIDSC hronic kidney disease Current or former smoking Cancer |
Mild-to-moderate disease | NR | NR | At day 15 = 195/227(85.9%) | At day 15 death = 6/227 (2.6%) | NR | NR | Any adverse event = 49/227 (21.6%); serious adverse event = 2/227 (0.9%); prolonged QT interval = 1/64 (1.6%); arrhythmia = 1/227 (0.4%); nausea = 2/227 (0.9%); abnormal liver function = 8/227 (3.5%) | NR | |||
| Mitjà et al., 2020a | Open-label RCT | 136 | Orally administered HCQ 800 mg once on day 1, followed by 400 mg daily for 6 days | 41.6 ± 12.4 | 27.9 | Cardiovascular disease Respiratory disease Metabolic disease Nervous system disease |
NR | NR | NR | 128/136 (94.1%) | Hospitalization = 8/136 (5.9%); death = none | NR | NR | Any adverse event = 121/169 (72.0%); gastrointestinal disorders = 148/169 (88.1%); infections and infestations = 9/169 (5.4%); general disorders = 30/169 (17.9%); nervous system disorder = 63/169 (37.5%); ear and labyrinth disorders = 5/169 (3.0%) | NR | Inconclusive: no statistically significant benefit |
| 157 | Control | 41.7 ± 12.6 | 34.4 | Cardiovascular disease Respiratory disease Metabolic disease Nervous system disease |
NR | NR | NR | 143/155 (92.3%) | Hospitalization = 11/155 (7.1%); death = none | NR | NR | Any adverse event = 16/184 (8.7%); gastrointestinal disorders = 7/184 (3.8%); infections and infestations = 12/184 (6.6%); general disorders = 1/184 (0.5%); nervous system disorder = 3/184 (1.6%); ear and labyrinth disorders = 0/184 (0%) | NR | |||
| Skipper et al. (2020) | Double-blind placebo-controlled RCT | 212 | Orally administered HCQ 800 mg once, followed by 600 mg in 6–8 h, then 600 mg daily for 4 days (5 days in total) | 41 (33–49)a | 42.0 | Hypertension Diabetes Asthma |
Mean symptom severity score = 4.2 | NR | NR | NR | Hospitalization = 4/212 (1.8%); death = 1/212 (0.4%) | 73/212 (34.4%) | NR | Any adverse event = 92/212 (43.4%); serious adverse event = none; upset stomach/nausea = 66/212 (31.1%); rash = 6/212 (2.8%); changes in vision = 4/212 (1.9%) | NR | Inconclusive: no statistically significant benefit |
| 211 | Control | 39 (31–50)a | 45.4 | Hypertension Diabetes Asthma |
Mean symptom severity score = 4.1 | NR | NR | NR | Hospitalization = 10/211 (4.7%); death = 1/211 (0.5%) | 72/211 (34.1%) | NR | Any adverse event = 46/211 (21.8%); serious adverse event = none; upset stomach/nausea = 26/211 (12.3%); rash = 2/211 (1.0%); changes in vision = 5/211 (2.4%) | NR | |||
| Chen et al. (2020c) | Open-label RCT | 21 | Orally administered HCQ 400 mg twice on day 1, followed by 200 mg twice daily for an additional 6 days | 33.0 ± 12.0 | 52.4 | NR | Mild = 19/21 (90.5%); moderate = 2/21 (9.5%) | At day 14 = 17/21 (81.0%) | NR | NR | NR | NR | NR | Serious adverse event = none | NR | Inconclusive: no statistically significant benefit |
| 12 | SOC | 32.8 ± 8.3 | 66.7 | NR | Mild = 10/12 (83.3%); moderate = 2/12 (16.7%) | At day 14 = 9/12 (75.0%) | NR | NR | NR | NR | NR | Serious adverse event = none | NR | |||
| Horby et al. (2020) | Open-label RCT | 1561 | Orally administered HCQ 800 mg at 0 and 6 h followed by 400 mg at 12 h after the initial dose and then every 12 h for the next 9 days or until discharge | 65.2 ± 15.2 | 61.6 | Diabetes Heart disease Lung disease Tuberculosis HIV positive Severe liver disease Severe kidney impairment |
NR | NR | NR | At day 28 = 941/1561 (60.3%) | Death at day 28 = 418/1561 (26.8%) | NR | NR | Serious adverse event = 1/698 (0.14%); torsades de pointes = 1/698 (0.14%) | NR | Inconclusive: no statistically significant benefit |
| 3155 | SOC | 65.4 ± 15.4 | 62.6 | Diabetes Heart disease Lung disease Tuberculosis HIV positive Severe liver disease Severe kidney impairment |
NR | NR | NR | At day 28 = 1,982/3155 (62.8%) | Death at day 28 = 788/3155 (25.0%) | NR | NR | NR | NR | |||
| Abd-Elsalam et al. (2020) | Open-label RCT | 97 | Orally administered HCQ 400 mg twice daily on day 1, followed by 200 mg twice daily | 40.4 ± 18.7 | 57.7 | Liver diseases Renal impairment |
NR | NR | NR | NR | ICU admission= 11/97 (11.3%); death = 6/97 (6.1%) | NR | NR | NR | NR | Inconclusive: no statistically significant benefit |
| 97 | Control | 41.09 ± 20.07 | 59.8 | Liver diseases Renal impairment |
NR | NR | NR | NR | ICU admission = 13/97 (13.4%); death = 5/97 (5.1%) | NR | NR | NR | NR | |||
| Furtado et al. (2020) | Open-label RCT | 214 | Orally administered HCQ 400 mg twice daily plus AZT 500 mg once daily for 10 days | 59.4 (49.3–70.0)a | 65.4 | Hypertension DiabetesHeart failurePrevious strokeP revious myocardial infarction COPDActive cancerC hronic kidney failure |
NR | NR | NR | NR | Death at day 29 = 90/214 (42.1%) | NR | NR | Serious adverse events = 102/241 (42.3%); corrected QT interval prolongation = 47/241 (19.5%); gastrointestinal intolerance = 61/241 (25.3%); ventricular arrhythmias = 8/241 (3.3%); acute kidney failure = 147/241 (61.0%); death due to acute kidney failure = 2/241 (0.8%) | NR | Inconclusive: no statistically significant benefit with addition of AZT |
| 183 | Orally administered HCQ 400 mg twice daily for 10 days | 60.2 (52.0–70.1)a | 66.7 | Hypertension DiabetesHeart failurePrevious strokeP revious myocardial infarction COPDActive cancerC hronic kidney failure |
NR | NR | NR | NR | Death at day 29 = 73/183 (39.9%) | NR | NR | Serious adverse events = 75/198 (37.9%); corrected QT interval prolongation = 42/198 (21.2%); gastrointestinal intolerance = 48/198 (24.2%); ventricular arrhythmias = 5/198 (2.5%); acute kidney failure = 103/198 (52.0%); death due to acute kidney failure = 3/198 (1.5%) | NR | |||
| Mitjà et al., 2020b) | Open-label RCT | 1116 | Orally administered HCQ 800 mg once, followed by 400 mg daily for 6 days | 48.6 ± 18.7 | 27.1 | Cardiovascular disease Respiratory disease Metabolic disease Nervous system disease |
NR | NR | NR | NR | NR | 64/1116 (5.7%) | NR | Any adverse event = 671/1,197 (51.6%); palpitations = 5/1,197 (0.4%); gastrointestinal disorder = 510/1,197 (42.6%); nervous system disorder = 260/1,197 (21.7%); general disorder = 103/1,197 (8.6%) | NR | Inconclusive: no statistically significant benefit |
| 1198 | Control | 48.7 ± 19.3 | 26.9 | Cardiovascular disease Respiratory disease Metabolic disease Nervous system disease |
NR | NR | NR | NR | NR | 74/1198 (6.2%) | NR | Any adverse event = 77/1,300 (5.9%); palpitations = 1/1,300 (0.1%); gastrointestinal disorder = 33/1,300 (2.5%); nervous system disorder = 32/1300 (2.5%); general disorder = 10/1300 (0.8%) | NR | |||
AIDS, acquired immunodeficiency syndrome: AZT, azithromycin; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; HIV, human immunodeficiency virus; ICU, intensive care unit; NR, not reported; RCT, randomized controlled trial; SD, standard deviation; SOC: standard of care.
a
Reported as the median (interquartile range).
b
Intention-to-treat population.
c
Safety population.