Study and Publication Date | |||||
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Study Characteristic | Borba et al, 202011 | Boulware et al, 20206 | Cavalcanti et al, 20207 | Chen CP et al, 202010 | Chen J et al, 20204 |
Study design | Double-blind, randomized controlled | Double-blind, randomized controlled | Multicenter, open-label, randomized controlled | Multicenter, open-label, randomized controlled | Randomized controlled |
Country/countries of origin | Brazil | United States and Canada | Brazil | Taiwan | China |
Patient population | Hospitalized patients ≥18 years, clinical suspicion of COVID-19 with ≥1 of respiratory rate >24/min, heart rate >125/min, O2 saturation <90% on room air, shock | Asymptomatic individuals ≥18 years, household or occupational exposure to a person with confirmed COVID-19 at <6 feet for >10 minutes | Hospitalized patients ≥18 years, suspected or confirmed COVID-19 within 14 days of symptom onset | Patients 20-79 years, mild or moderate illness by CXR | Patients ≥18 years, confirmed moderate COVID-19 disease |
Method of COVID-19 testing | RT-PCR (patients were enrolled before results returned) | None for study subjects Contacts initially only required to have presumptive COVID-19; switched to RT-PCR confirmation during enrollment | RT-PCR | RT-PCR | Not specified |
Intervention | High-dose CQ + standard of care (n=81) | HCQ (n=414) | HCQ + standard of care (n=59) HCQ + azithromycin + standard of care (n=172) | HCQ + standard of care (n=21) | HCQ + standard of care (n=15) |
Treatment medication dose | CQ 600 mg twice daily for 10 days Ceftriaxone 1 g twice daily for 7 days Azithromycin 500 mg daily for 5 days | 800 mg once, then 600 mg 6-8 hours later, then 600 mg daily for 4 days | HCQ 400 mg twice daily for 7 days Azithromycin 500 mg daily for 7 days + standard of care | HCQ 400 mg twice daily on day 1, then 200 mg twice daily for 6 days + standard of care | HCQ 400 mg daily for 5 days + standard of care |
Control | Low-dose CQ + standard of care (n=40) | Placebo (n=407) | Standard of care (n=173) | Standard of care (n=12) | Standard of care (n=15) |
Control medication dose | CQ 450 mg twice daily on day 1, then 450 mg daily for 4 days Ceftriaxone 1 g twice daily for 7 days Azithromycin 500 mg daily for 5 days | N/A | Not specified; at discretion of treating physicians Glucocorticoids, immunomodulators, antibiotics, and antivirals permitted | Ceftriaxone 2 g daily for 7 days ± azithromycin 500 mg on day 1, then 250 mg for 4 days OR levofloxacin 750 mg daily for 5 days OR levofloxacin 500 mg daily OR moxifloxacin 400 mg daily for 7-14 days | Not specified; included interferon-α, umifenovir, lopinavir, ritonavir, antibiotics |
Primary endpoints | Mortality by day 28 | Symptomatic illness with positive molecular assay or COVID-19–related symptoms | Clinical status at 15 days | Time to negative RT-PCR from randomization until 14 days | Proportion of negative SARS-CoV-2 pharyngeal swabs on day 7 |
Secondary endpoints | Mortality by day 13 Participant clinical status and laboratory examinations ECG on days 13 and 28 Duration of supplemental oxygen and/or mechanical ventilation Time from treatment initiation to death | Hospitalization or death from COVID-19 Discontinuation of intervention for any cause Symptoms at days 5 and 14 | Clinical status at 7 days Intubation within 15 days HFNC or noninvasive ventilation use within 15 days Duration of hospital stay In-hospital mortality Thromboembolism AKI Days alive and free of respiratory support up to 15 days | Proportion of negative viral RT-PCR on day 14 Resolution of clinical symptoms Proportion discharged by day 14 Mortality rate | Mortality Time to negative seroconversion Time to body temperature normalization Radiologic evidence of improvement Safety profile |
Results | Study stopped after interim analysis showed increased incidence of QTc interval prolongation and lethality in high-dose CQ group Because of small sample size, unable to show any benefit regarding treatment efficacy | No significant difference in development of new COVID-19 No mortality | No significant difference in clinical status at day 15 No significant difference in any secondary outcome | No significant difference in time to negative RT-PCR No significant difference in proportion of negative RT-PCR on day 14 No mortality in either group | No significant difference in proportion of negative testing at 7 days No significant difference in time to negative seroconversion, time to body temperature normalization, or radiologic improvement No mortality |
Study limitations | Small sample size Single center No placebo group No exclusion criteria based on baseline QTc No chest CT scans to evaluate disease severity More patients with heart disease assigned to high-dose vs low-dose group High-dose group more susceptible to cardiac complications with or without medication use | Single center Most subjects were health care workers Most subjects unable to access COVID-19 testing to confirm infection Online recruitment led to generally younger and healthier research population (selection bias) and increased difficulty of follow-up Exposure poorly defined No outcomes based on imaging or viral load Moderate adherence | Large range of odds ratios Unblinded Protocol deviations related to lack of medication Included patients who had received HCQ and/or azithromycin before study enrollment Included patients up to 14 days after beginning of symptoms Unspecified control group treatment No outcomes based on imaging or viral load Fewer patients in control group had serial ECGs during follow-up | Only included patients with mild/moderate illness Small sample size Younger patient population (mean 32.9 years) than other studies Three patients concomitantly administered azithromycin No outcomes based on imaging | Single center Only included patients with moderate disease No diagnosis confirmation method specified Small sample size Heterogeneous control group treatment, including antivirals and unspecified antibiotics No QTc monitoring |
Medication-related adverse events | QTc prolongation (>500 ms with CQ) Myopathy and rhabdomyolysis with CQ Myocarditis related to SARS-CoV-2 may progress to arrhythmias with prolonged QTc | Increased incidence of adverse events in HCQ group; most commonly GI upset, neurologic symptoms (headache, vertigo, irritability) No cardiac arrhythmias or other serious complications | Increased incidence of adverse events in HCQ group Increased risk of QTc prolongation in HCQ group Increased risk of aminotransferase elevation in HCQ + azithromycin vs control groups | HCQ-associated GI upset, headache, dizziness No QTc prolongation reported | No difference in adverse events between groups Mild diarrhea, muscle weakness, and ALT elevations reported in HCQ group |
Study and Publication Date | |||||
Study Characteristic | Chen L et al, 20208 | Chen Z et al, 20205 | Mitjà et al, 202012 | Skipper et al, 202013 | Tang et al, 20209 |
Study design | Open-label, randomized, controlled | Double-blind, randomized controlled | Multicenter, open-label, randomized controlled | Multicenter, double-blind, randomized controlled | Multicenter, open-label, randomized controlled |
Country/countries of origin | China | China | Spain | United States and Canada | China |
Patient population | Patients 18-75 years, mild or moderate illness | Patients ≥18 years positive for SARS-CoV-2 by RT-PCR, mild illness (SaO2/SpO2 >93% or PaO2/FiO2 >300), chest CT evidence of pneumonia | Nonhospitalized patients ≥18 years, mild symptoms of COVID-19 | Nonhospitalized patients ≥18 years, <4 days of COVID-compatible symptoms | Patients ≥18 years positive for SARS-CoV-2 by RT-PCR |
Method of COVID-19 testing | RT-PCR or chest CT | RT-PCR | RT-PCR | PCR-confirmed COVID-19 or exposure to individual with PCR-confirmed COVID-19 within 14 days | RT-PCR |
Intervention | HCQ + standard of care (n=18) CQ + standard of care (n=18) | HCQ + standard of care (n=31) | HCQ + standard of care (n=136) | HCQ + standard of care (n=212) | HCQ + standard of care (n=75) |
Treatment medication dose | HCQ 200 mg twice daily for 10 days CQ 1,000 mg on day 1, then 500 mg daily for 9 days + standard of care | HCQ 400 mg daily for 5 days | HCQ 800 mg on day 1, then 400 mg daily for 6 days | HCQ 800 mg once, then 600 mg 6-8 hours later, then 600 mg once daily for 4 days | HCQ 1,200 mg daily for 3 days followed by 800 mg daily for 2 weeks for mild-moderate disease, 3 weeks for severe disease |
Control | Standard of care (n=12) | Standard of care (n=31) | Standard of care (n=157) | Placebo (n=211) | Standard of care (n=75) |
Control medication dose | Not specified | Not specified; included antivirals, antibiotics, immunoglobulins, corticosteroids | Not specified | N/A | Not specified; according to Chinese national guidelines |
Primary endpoints | Time to clinical recovery | Time to clinical recovery | Reduction of viral RNA load on days 3 and 7 | Clinical outcome at day 14 | Proportion of negative SARS-CoV-2 by 28 days |
Secondary endpoints | Time to negative RT-PCR Length of hospital stay Changes on chest CT Duration of supplemental oxygen Frequency of adverse events Clinical status All-cause mortality Vital signs Inflammatory marker testing | Radiologic evidence of improvement Safety profile | Clinical progression Time from randomization to resolution of symptoms Safety profile | Symptom severity at days 5 and 14 Incidence of hospitalization or death Incidence of study medicine withdrawal | Clinical improvement Inflammatory marker levels Radiologic evidence of improvement Mortality Adverse events |
Results | Shorter time to clinical recovery in CQ group and trend toward shorter recovery in HCQ group Shorter time to negative RT-PCR in both CQ and HCQ groups Trend toward decreased hospitalization length and improved CT chest changes in both CQ and HCQ groups No mortality in any group No significant difference in inflammatory markers | Significantly quicker time to clinical recovery in HCQ group Increased improvement in chest CT (80.6% vs 54.8%) in HCQ group | No significant difference in viral RNA load at days 3 or 7 No significant difference in hospitalization or time to symptom resolution No mortality | No significant difference in symptom resolution, hospitalization, or death between treatment groups | No significant difference in proportion of negative conversion or speed to negative conversion No difference in clinical course No difference in inflammatory markers No mortality |
Study limitations | Single center Unblinded Only included patients with mild/moderate illness Small sample size HCQ dosing based on rheumatoid arthritis treatment Unspecified control group treatment | Single center Only included patients with mild illness Small sample size Heterogeneous control group treatment Relatively short observation period No outcomes based on viral load No QTc monitoring | Unblinded Only included patients with mild illness Standard of care treatment not specified No initial plan to evaluate clinical assessments on day 7, so fewer results than on day 3 High (>80%) enrollment of health care workers No outcomes based on imaging No QTc monitoring | Majority of subjects were health care workers Underrepresentation of Black/African American subjects Lack of laboratory-confirmed SARS-CoV-2 infection in all participants Enrollment of patients based on epidemiologic links to known cases No outcomes based on imaging or viral load Moderate adherence No QTc monitoring | Unblinded High proportion (98%) of patients with mild/moderate disease Relatively long lead-in time from symptom onset to treatment (16 days) Premature termination of enrollment for lack of participants |
Medication-related adverse events | Increased incidence of mild adverse events in HCQ and CQ groups, most commonly diarrhea, nausea, ALT/AST elevation One grade 2 ALT/AST elevation in HCQ group No cardiac adverse events reported | Two patients in HCQ group with mild adverse events (rash and headache) No severe adverse events reported | Increased incidence of adverse events in HCQ group (GI upset, drowsiness, headache, taste change) No HCQ-related serious adverse events | Increased incidence of adverse events in HCQ group (GI upset) No serious adverse events attributable to HCQ | Increased incidence of adverse events in HCQ patients (GI upset, blurry vision, increased thirst) Two serious adverse events in HCQ group (disease progression, upper respiratory tract infection) No cardiac arrhythmias reported |
AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; COVID-19, coronavirus disease 2019; CQ, chloroquine; CT, computed tomography; CXR, chest x-ray; ECG, electrocardiogram; FiO2, fraction of inspired oxygen; GI, gastrointestinal; HCQ, hydroxychloroquine; HFNC, high-flow nasal cannula; N/A, not applicable; O2, oxygen; PaO2, partial pressure of arterial oxygen; PCR, polymerase chain reaction; RNA, ribonucleic acid; RT-PCR, reverse transcription polymerase chain reaction; SaO2, oxygen saturation on arterial blood gas; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SpO2, oxygen saturation by pulse oximetry.