Hydroxychloroquine Use in Patients With COVID-19: A Brief Perspective on Current Clinical Trials

Alaa A. Abd-Elsayed; David Hao; Robert Chu; Ivan Urits; Omar Viswanath; Vwaire Orhurhu

doi:10.31486/toj.20.0124

Article Figures & Data

Tables

View popup

Table.

Characteristics of Clinical Trials Investigating Hydroxychloroquine Use in Patients With Coronavirus Disease

	Study and Publication Date
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; FiO_2, fraction of inspired oxygen; GI, gastrointestinal; HCQ, hydroxychloroquine; HFNC, high-flow nasal cannula; N/A, not applicable; O₂, oxygen; PaO_2, partial pressure of arterial oxygen; PCR, polymerase chain reaction; RNA, ribonucleic acid; RT-PCR, reverse transcription polymerase chain reaction; SaO_2, oxygen saturation on arterial blood gas; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SpO_2, oxygen saturation by pulse oximetry.