Table 1.
Characteristics of clinical studies evaluating HCQ/CQ for treatment of COVID-19
| Study ID (Study design) | Institution/Country of study conduct | Study Interventions (n)/Regimen | Study control (n)/Regimen | Study population characteristics | Study outcomes |
|---|---|---|---|---|---|
| Barbosa et al. 2020[15] (Quasi-randomised, open label, parallel group trial) | University School of Medicine, Michigan, USA | HCQ (32) HCQ: Loading dose (400 mg orally BD x 1-2 days) followed by 200-400 mg daily dose x 3-4 days |
Standard supportive care (31) | Males: 37 (58.7%); Age: 62.7±15.1 years |
Change in respiratory support level at 5 days: HCQ: 0.63±0.79, Supportive care: 0.16±0.64; P=0.013; Change in Absolute Lymphocyte Count (K/µL): HCQ: -0.16±0.52, Supportive care: -0.61±0.38; p0.413; Change in neutrophil to lymphocyte ratio: HCQ: +9.55±21.5, Supportive care: +1.58±6.26; p0.051; Mortality: HCQ: 4/31 (12.9%); Supportive care: 1/32 (3.13%); p0.196; Torsades de pointes: no reports during study timeframe. |
| Tang et al. 2020[16] (Multi-center, parallel, open-label, randomized, trial) | China | HCQ (75) HCQ: loading dose of 1200 mg daily for 3 days followed by 800 mg daily dose for 2 or 3 weeks (for mild-moderate or severe disease) |
Standard of care (SOC) (75) | Males: 82 (54.7%); Mean age: 46.1±14.7 years (Mild to moderate disease, n=148; severe disease, n=2) |
28-day negative conversion rate of SARS-CoV-2: 85.4% (73.8-93.8%) in HCQ vs 81.3% (71.2-89.6%) in SOC only arm; p0.341 (similar negative conversion rates for the two groups at days 4, 7, 10, 14, and 21). Symptom relief at 28 days (fever, respiratory symptoms, SpO2): 59.9% (45-75.3%) with HCQ vs 66.6% (39.5-90.9%) with SOC alone; Adverse events: 30% in HCQ vs 8.8% in SOC arm; diarrhea most common, 2 serious adverse events in HCQ arm (disease progression, upper respiratory tract infection) |
| Chen J et al. 2020[17] (Randomised controlled trial) | Fudan University, Shanghai, China | HCQ (15) HCQ 400 mg daily for 5 days |
Standard treatment (15) | Males: 21 (70%); Mean age: 50.5±3.8 yrs in HCQ, 46.7±3.6 yrs in control group | Virologic clearance at day 7:13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (p>0.05).; Median time for body temperature normalization: HCQ: 1 (0-2) days, control: 1 (0-3) days; Radiological progression on CT scan: 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group; Adverse events: 4 (26.7%) in HCQ group vs 3 (20%) in control group (transient diarrhea and abnormal liver function): p>0.05 |
| Chen Z et al. 2020[18] (Randomised, double blind, controlled trial) | Renmin Hospital of Wuhan University, Wuhan, China | HCQ (31) HCQ : 400 mg daily for 5 days |
Standard care (31) | Males: 29/62 (46.8%) Age (mean±SD): 44.7 (15.3) years |
Time to clinical recovery (TTCR): Body temperature recovery time [2.2 (0.4) days vs 3.2 (1.3) days] in HCQ vs control group (p0.0008); cough remission time [2 (0.2) vs 3.1 (1.5) days] in HCQ vs control group, (p0.0016). Progression to severe disease: 4 patients in control vs 0 in HCQ. Radiological improvement in pneumonia: 25 (80.6%) vs 17 (54.8%) in HCQ and control groups respectively. Adverse events: HCQ group: 2 patients (mildrash, headache) |
| Huang M et al. 2020 RCT*[19] (Randomised controlled trial) | Sun Yat-sen University, Zhuhai, China | CQ (10) CQ: 500 mg orally BD for 10 days |
Lopinavir/ritonavir (12); 400/100 mg orally BD x 10 days | Males: 13/22 (59%) Age: 44.0 (36.5-57.5) years |
Virologic cure: 10 (100%) in CQ vs 11 (91.67%) in Lop/ritgp. Hospital discharge at Day 14: 10 (100%) vs 6 (50%) in CQ and Lop/ritgp; Clinical recovery at Day 10: 8 (80%) vs 7 (58.33%) in CQ and Lop/rit group; CT scan improvement at day 14:10 (100%) vs 9 (75%) in CQ and Lop/rit group; Adverse events: 5 patients with 9 adverse events in CQ group (diarrhea and vomiting most common), no serious adverse events reported |
| Gautret et al. 2020 OS#[22] (Non-randomised, open label, comparative trial) | IHU-Méditerranée Infection, Marseille, France | HCQ (14), HCQ+AZ (6), HCQ: 600 mg daily for 10 days; AZ: 500 mg on day 1, 250 mg daily for next 4 days | Controls (not receiving HCQ from other centers and those not giving consent) (16) | Males=15 (41.7%); Mean age: 45.1±22.0 years | Virologic clearance at day 6 post inclusion: HCQ: 57.1% (8/14), HCQ + AZ: 100% (6/6), Control: 12.5% (2/16); P<0.001; Mortality: 1/20 (5%). 6 HCQ patients lost to follow up (3 transferred to ICU, 1 died, 1 left the hospital and 1 stopped treatment due to nausea). |
| Cipriani et al. 2020[23] (Observational case-control study) | University of Padua Medical school, Italy | HCQ + AZ (22) HCQ (200 mg, twice daily) and AZ (500 mg, once daily) | Healthy matched controls | Males: 18 (82%); Age [median (IQR)]: 64 (56-70) | QTc interval (ms): 450 (416-476) after therapy vs 426 (403-447) before therapy; p0.02; QTc >480 ms; n (%): 4 (18) after vs 0 before therapy; p0.04 |
| Rosenberg et al. 2020[24] (Retrospective multicenter cohort) | 25 hospitals in New York metropolitan region | HCQ (271), AZ (211), HCQ+AZ (735), | Supportive (221) | Males: 858 (59.7%) Age (median): 63 years |
In-hospital mortality: (unadjusted analyses) HCQ + AZ (n=189, 25.7% [95;% CI, 22.3%-28.9%]), HCQ (n=54, 19.9% (15.2-24.7%), AZ (n=21, 10.0% (5.9-14.0%]), and neither-drug (n=28, 12.7% (8.3-17.1%]) (P<0.001); (adjusted analysis) no significant difference in mortality between groups. Cardiac arrest: more likely in HCQ + AZ group (adjusted OR, 2.13 (1.12-4.05), but not HCQ (1.91, 0.96 to3.81) or AZ (0.64, 0.27 to 1.56]), Abnormal ECG findings: no significant differences in the relative likelihood between different groups. |
| Geleris et al. 2020[25] (Observational study) | New York-Presbyterian Hospital (NYP)- Northern Manhattan. | HCQ (811) (600 mg twice on day 1, then 400 mg daily for a median of 5 days | No HCQ (565) | Males: 778 (56.5%) | Composite end point of intubation or death: HCQ: 262 (32.3%), No HCQ :84 (14.9%); hazard ratio: 2.37 (1.84-3.02); no significant association between HCQ use and intubation or death (hazard ratio, 1.04, 0.82-1.32) |
| Magagnoli et al. 2020[26] (Retrospective cohort study) | US Veterans Health Administration medical centers | HCQ (198), HCQ+AZ (214) | Standard care only (395) | Males: 772 (95.6%); Age [median (IQR): 71 (62-76.8) in HCQ, 68 (59-74) in HCQ+AZ, 70 (59-77) yrs in control group. | Mortality rate (%): HCQ (19.2), HCQ+AZ (22.9), No HCQ (9.4); P<0.001. Rate of ventilation (%): HCQ (19), HCQ+AZ (20.5), No HCQ (19.9); p0.94. Risk of ventilation: HCQ (aHR, 1.19, 95% CI, 0.78-1.82; p0.42); HCQ+AZ (1.09; 0.72-1.66; p0.69), compared with no HCQ group. Risk of death from any cause: HCQ (aHR,1.83; 1.16-2.89; p0.009); HCQ+AZ: (1.31; 0.80-2.15; p0.28) compared with no HCQ group |
| Mahevas et al. 2020[27] (Retrospective cohort study) | 4 tertiary hospitals, France | HCQ (n=84) 600 mg daily |
No HCQ (n=97) | Males: 71.1%; Age [median (IQR)]: 60 (52-68) years (Patients with COVID-19 pneumonia requiring oxygen but not intensive care) | Survival rate without transfer toICU at day 21: 76% in HCQ group and 75% in control group; weighted hazard ratio (95% CI): 0.9 (0.4-2.1). Overall survival at day 21: 89% in HCQ and 91% in control group (1.2, 0.4 to 3.3); Survival without ARDS at day 21: 69% in HCQ vs 74% in control group (1.3, 0.7 to 2.6); Weaning from oxygen at day 21: 82% vs 76% in HCQ vs control group (1.1, 0.9 to 1.3); ECG modifications requiring treatment discontinuations: 8 (10%) in HCQ group |
| Yu et al. 2020[28] (Retrospective cohort) | Wuhan, China | HCQ (48) Low dose - 200 mg BD x 10 days |
Standard treatment (502) | Critically ill patients; Males: 62.5% Age: 68 (59-77) years |
Mortality: 18.8% (9/48) in HCQ group, 47.4% (238/502) in NHCQ group (P<0.001); Duration of hospitalization before death: 15 (10-21) days and 8 (4-14) days for the HCQ and NHCQ groups, respectively (P<0.05). Change in inflammatory cytokine IL-6 levels: Significant reduction from 22.2 (8.3-118.9) pg mL-1 at the beginning of treatment to 5.2 (3.0-23.4) pg mL-1 (P<0.05) at the end of treatment in HCQ group, no change in NHCQ group. |
| Hraiech et al. 2020[29] (Retrospective case-control study) | France | HCQ+AZ (17) | Lopinavir/ritonavir (13), Standard care (15) | Patients with SARS-CoV-2 related moderate to severe ARDS Males: 35 (77.8%); Age: 60±17, 62±13 and 60±16 yrs in HCQ+AZ, Lop/rit and control groups, respectively |
Negative SARS-CoV-PCR at day 6 of treatment: 3 (18%) in HCQ + AZ, 5 (38%) in Lop/rit and 2/10 patients assessed (20%) in control group; p0.39; Negative SARS-CoV-PCR at day 6 from ARDS: 2 (12%) in HCQ + AZ, 5 (38%) in Lop/rit and 2 (13%) in control group; p0.14; Mortality: 2/45 (4.4%), both deaths in HCQ + AZ group |
| Huang M et al. 2020 OS#[30] (multicenter prospective observational study) | China | CQ (197) CQ phosphate 500 mg OD/BD |
Non-CQ (176) | COVID-19 patients (excluding critically ill); Males: 373 (53.1%); Age: 43.8±13.1 in CQ; 45.6±13.5 yrs in non-CQ group | Time from treatment initiation to undetectable viral RNA, median (IQR) days: 3 (3-5) in CQ vs 9 (6-12) in non-CQ group; P<0.0001; Duration of hospitalization, median (IQR) days: 19 (16-23) in CQ vs 20 (15.8-24) in non-CQ group; p0.25; Adverse events: 53 patients (26.9%) in CQ group and 57 (32.4%) in non-CQ group; no serious adverse event |
| Mallat et al. 2020[31] (Retrospective observational study) | Cleveland Clinic Abu Dhabi | HCQ (23) 400 mg BD x 1 day followed by 400 mg daily x 10 days | Non-HCQ (11) | COVID-19 patients with mild to moderate disease; Males: 25 (73.5%); Age: 37 (31-48) yrs | Time to SARS-CoV-2 negativity test: 17 [13-21] vs. 10 [4-13] days in HCQ vs non-HCQ groups; p0.023; Duration of hospitalization: 17 (6-20) vs 9 (6-12.7) days in HCQ vs non-HCQ groups; p0.068 |
| Singh et al. 2020[32]Analysis of Federated electronic medical record network | West Virginia University Health Sciences Center Charleston Division, Charleston, WV | HCQ (910); HCQ + AZ (701) | Control: (Matched cohorts) 910 for HCQ arm; 701 for HCQ + AZ arm | Males: 991 (54.4%) Mean age: 62.17±16.81 and 62.55±17.62 yrs in HCQ and control groups, respectively. |
HCQ vs control Mortality 30 day: 11.43% in HCQ vs 11.98% in control group. Mechanical ventilation: 5.05% in HCQ vs 6.26% in control group. HCQ+AZ versus control. Mortality 30 day: 12.27% in HCQ + AZ vs 10.27% in control group. Mechanical ventilation: 5.71% in HCQ + AZ vs 5.85% in control group. |
| Membrillo et al.[33]Observational cohort study | Central Defense Hospital “Gómez Ulla”, Madrid, Spain | HCQ (123) | No HCQ (43) | Males: 103 (62%) Mean age: 61.6±16.2 and 68.7±18.8 yrs in HCQ and control groups, respectively. |
Mean cumulative survival: Mild group- 14.4 days (95% CI: 13.7-15.2 days) in HCQ, 8.2 days (95% CI: 6.5-9.9 days) in control arm; p0.032 Moderate group- 10.9 days (9.3-12.5) in HCQ, 7.7 days (4.4-10.9) in control arm; p0.205 Severe group- 6 days (3.3-8.5) in HCQ, 4 days (1.7-6.1); p0.297 |
| Shabrawishi et al.[36] Retrospective cohort study | Tertiary hospital in Mecca, Saudi Arabia | HCQ (15), HCQ + AZ (25), HCQ + antivirals (5) | Supportive care (48) | Males: 49 (52.7%) Mean age: 43.9±15.9 yrs |
Virological cure, n (%) : 33 (73.3) in intervention group vs 33 (68.8) in control group, p0.655 |
| RECOVERY Trial RCT (20) | Multicentric, World | HCQ (1561) | Standard of care (3155) | Mean age: HCQ=65.2±15.2 Control=65.4±15.4 |
Mortality rate=rate ratio, 1.09; 95% CI - 0.97 to 1.23; p0.15 Invasive mechanical ventilation or death=risk ratio, 1.14; 95% CI, 1.03-1.27 |
| WHO Solidarity Trial RCT[21] | Multicentric, WHO | HCQ (947) | Standard of care (906) | More number of patients having lesions in both lungs and on supplemental oxygen in HCQ group. | 104 of 947 - HCQ; 84 of 906 - Control Mortality rate=rate ratio, 1.19; 95% CI - 0.89 to 1.59; p0.23 |
*RCT (Randomised controlled trial), #OS (Observational study), ARBs: angiotensin receptor blockers, NEWS: National Early Warning Score