Hydroxychloroquine for pre-exposure prophylaxis of COVID-19 in health care workers: a randomized, multicenter, placebo-controlled trial (HERO-HCQ)
ABSTRACT Objective To determine whether hydroxychloroquine (HCQ) is safe and effective at preventing COVID-19 infections among health care workers (HCW). Design Multicenter, 1:1 randomized, placebo-controlled, double-blind, parallel-group, superiority trial. Setting 34 clinical centers in the United States. Participants 1360 HCW at risk for COVID-19 infection enrolled between April and November 2020. Interventions A loading dose of HCQ 600 mg twice on Day 1 followed by 400 mg daily for 29 days or matching placebo taken orally. Main Outcome Measure Composite of confirmed or suspected COVID-19 clinical infection by Day 30 defined as new onset fever, cough, or dyspnea and either a positive SARS-CoV-2 PCR test (confirmed) or a lack of confirmatory testing due to local restrictions (suspected). Results Enrollment for the study was closed before full accrual due to difficulties recruiting additional participants. The primary composite endpoint occurred in 41 (6.0%) participants receiving HCQ and 53 (7.8%) participants receiving placebo. No statistically significant difference in the proportion of participants experiencing clinical infection (estimated difference of -1.8%, 95% confidence interval -4.6% to 0.9%, p=0.20). We identified no significant safety issues. Conclusion Oral HCQ taken as prescribed appeared to be safe in a group of HCW. No significant clinical benefits were observed. The study was underpowered to rule out a small but potentially important reduction in COVID-19 infections. Trial Registration NCT04334148
Introduction After the emergence of SARS-CoV-2 in late 2019, the virus spread rapidly, resulting in the worst pandemic in nearly a century. Early in the pandemic, health care systems struggled with maintaining adequate supply of personal protective equipment (PPE), and infections in health care workers (HCW) were reported globally.1 Without availability of protective vaccines, there was a need to identify therapies that might prevent infection and could be taken regularly by HCW who were at high risk of frequent exposures, similar to approaches taken with malaria and human immunodeficiency virus pre-exposure prophylaxis. As is common with new diseases, repurposed drugs offered immediate options for therapeutics and usually with a well-known safety profile, allowing for more rapid introduction into clinical trials and thereafter into clinical practice. Chloroquine had been previously reported to have in vitro antiviral activity against SARS-CoV-1 and MERS-CoV, and both chloroquine and hydroxychloroquine (HCQ) showed similar in vitro activity against SARS-CoV-2.2-4 Thus, clinicians turned to HCQ early in the pandemic as a therapy that might have clinical benefit for treating COVID-19, the disease associated with SARS-CoV-2 infection, as investigators began testing the drug’s safety and efficacy in the treatment and prevention of COVID-19. While vaccines are now available for the prevention of SARS-CoV-2 infection, access to sufficient quantities of vaccine remains challenging, particularly in low- and middle-income countries. Vaccine hesitancy further complicates the public health response. Thus, preventative therapy for SARS-CoV-2 infection remains relevant. The Healthcare Worker Exposure Response and Outcomes (HERO) Registry (NCT04342806) was created as a community of HCW from across the United States to learn about issues impacting frontline workers and to offer opportunities to participate in research studies.5 The HERO-HCQ trial was one of the first studies in the United States to test the safety and efficacy of HCQ as pre-exposure prophylaxis in frontline HCW. HERO-HCQ leveraged both the HERO Registry as well as its relationship with PCORnet®, The National Patient-Centered Clinical Research Network as a pragmatic and largely remote clinical trial, using a patient-facing online portal to capture frequent patient-reported outcomes.6 The primary objective of HERO-HCQ was to evaluate the efficacy of HCQ in preventing SARS-CoV-2 clinical infection in HCW when taken daily. Secondary objectives of the study were to assess the efficacy of HCQ in preventing asymptomatic viral shedding of SARS-CoV-2 among HCW and to assess the safety and tolerability of HCQ in this study population.
METHODS Study Design HERO-HCQ was a multicenter, double-blind, randomized, parallel-group study designed to evaluate the superiority of HCQ vs. placebo for COVID-19 pre-exposure prophylaxis in HCWs. The HERO-HCQ trial was reviewed by the Duke University School of Medicine Institutional Review Board and approved by the Western Institutional Review Board (Pro00105274). Participants Eligible participants provided informed consent, were age 18 or older, and were working in a health care setting with potential exposure to patients with COVID-19. A detailed list of eligible health care settings is shown in the protocol [Supplemental Table 1]. The main exclusions were prior diagnosis of COVID-19 infection or contraindications to HCQ. Randomization and Masking Participants were randomized in a 1:1 ratio to receive HCQ or placebo at the level of the individual participant via the study portal. Randomization was stratified by clinical site using a permuted block design with varying block sizes. In the intervention arm, participants received an oral loading dose of study drug at 600 mg twice on the first day, followed by 400 mg daily for 29 days. In the control arm, placebo tablets were administered using the same dosage schedule and number of tablets as the intervention arm. The placebo was similar in appearance to the study drug and packaged and labeled in a masked manner in compliance with regulatory requirements. All study drug doses were oral self-administrations. Study drug was supplied as 200-mg tablets, and each eligible participant was provided a quantity sufficient for 30 days. Procedures Participants were prescreened through the HERO Registry, and eligibility was confirmed by the site by phone or in person.5 Participants were able to electronically consent through the portal, which was done at the time of the site visit or in advance. There were two on-site visits – one at baseline and another at 30 days. Baseline assessments included a nasopharyngeal swab for SARS-CoV-2 and a blood sample to assess baseline SARS-CoV-2 nucleocapsid IgG antibody status. Weekly follow-up was performed remotely via standardized questionnaires utilizing the online portal. These questionnaires included screening for COVID-19 clinical signs/symptoms and self-reporting of COVID-19 testing and diagnosis. Additionally, participants were able to self-report medication changes, hospitalizations, clinical events, and adverse events. A call center provided support for missed visits to re-engage and remind participants to complete the questionnaires. The second on-site visit at approximately 30 days was completed to assess study drug adherence and any subsequent clinical or safety events. A nasopharyngeal swab for SARS-CoV-2 PCR and a blood sample for SARS-CoV-2 nucleocapsid IgG antibody were obtained. Individual participants received study drug for 30 days and were followed for an additional 30 days for clinical events and patient-reported outcomes. An end-of-study virtual visit was conducted approximately 60 days after randomization via the direct-to-participant portal or call center to assess for any subsequent clinical or safety events. Outcomes The primary outcome was a composite of confirmed or suspected clinical infection with COVID-19 through 30 days, which was defined as new onset of fever, cough, or dyspnea and confirmed SARS-CoV-2 PCR positive test result via local testing or suspected COVID-19 disease without confirmation testing due to local restrictions or policies. Participants who developed symptoms of COVID-19 were expected to follow local clinical and/or employee health protocols for testing and management. Secondary outcomes were (1) viral shedding of SARS-CoV-2 at 30 days and (2) safety and tolerability as determined by subject-reported adverse events that met criteria per protocol for serious adverse events and HCQ-associated events of special interest; this latter group comprised fever, arrhythmia (ventricular), psychosis, angioedema, prolonged QT interval, secondary bacterial infection, and suicidal ideation. Exploratory outcomes were (1) SARS-CoV-2 nucleocapsid IgG seroconversion at 30 days; (2) COVID-19 complications including hospitalization, ICU level care, or need for invasive ventilation; (3) days sick or lost work time; (4) self-reported health and well-being obtained from the Patient-Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Anxiety-Short Form7, a Single Item Burnout Measure8-11, and the Patient Health Questionnaire (PHQ-2)12-13; and (5) patient-reported clinical infections among household contacts and other impacts on HCW household. Statistical Analysis The original sample size of approximately 15,000 randomized participants was selected to yield high power for testing the primary outcome of clinical infection with SARS-CoV-2 assuming the usual risk of SARS-CoV-2 infection is 5%. This sample size was expected to provide greater than 80% power to detect a 1% absolute decrease (20% relative decrease) in COVID-19 infection rates between treatment arms. These calculations assumed a two-sided Type I error rate of 0.05 with 1:1 randomization. In October 2020, due to slower than expected enrollment and changing community attitudes about HCQ effectiveness, the study protocol was amended to reduce the total sample size to 2000, which provided 80% power to detect a 50% relative decrease in the risk of COVID-19 infections assuming a placebo group risk of 5%. Statistical comparisons were performed using two-sided significance tests. The primary endpoint was clinical infection with SARS-CoV-2 through the 30-day period. Data collected during the 60-day follow-up were included for the safety analyses. For the primary outcome of clinical infection with SARS-CoV-2, comparisons between treatment arms were presented as differences in proportions with 95% confidence intervals (CIs) using the Miettinen-Nurminen method and a p-value calculated using the Fisher’s exact test. A secondary analysis was based on a logistic regression model with an indicator variable for the treatment group. Supplemental analyses were conducted to (1) examine the differences using other methods for constructing the Cis14 and (2) compute the common odds ratio using the Mantel–Haenszel test stratifying by enrolling site.15 Subgroup analyses were planned for age, sex, race and ethnicity. For each subgroup analysis, a logistic regression model was estimated, with additional terms identifying subgroup membership and intervention by subgroup interaction. The statistical comparisons of serious adverse events and events of special interest were based on chi-square tests and Fisher’s exact test. All analyses were conducted using SAS Version 9.4 software. The DCRI served as the Statistical and Data Coordinating Center. Patient and Public Involvement HCW were engaged in the HERO program and trial through membership in HERO governance, including participation in the steering committee and subcommittees. HCW stakeholders reviewed enrollment materials and the study protocol, and advised on trial conduct throughout the study. An independent data safety monitoring board, which included an HCW representative, met regularly and monitored participant safety and study performance. The protocol as publicly shared and is available on heroesresearch.org.
RESULTS The HERO-HCQ trial start-up timeline was 4 weeks from concept to first participant randomized (Supplemental Figure 1). Between April 2020 and November 2020, a total of 1360 participants were enrolled and randomized from 34 US sites participating in PCORnet (Figure 1). One participant had a positive SARS-CoV-2 PCR test at the time of the baseline visit and was excluded from the primary analysis population. Overall, 92.9% and 92.3% of randomized participants completed their PCR and serology tests, respectively, at their Day 30 visit with no significant difference by treatment group. The Day 60 visit was completed by 89.0% of total participants.
Primary Endpoint
There were a total of 94 primary endpoint events during the 30-day follow-up period. Most of these endpoints were suspected clinical infection (n=85) rather than confirmed clinical infection with COVID-19 (n=9) (Table 2). The most common presenting symptoms were cough (86.2%), fatigue (68.1%), headache (66.0%), and muscle aches/joint pain (51.1%). There were numerically fewer primary endpoint events in the HCQ group, 41 (6.0%), compared with the placebo group, 53 (7.8%); however, this difference of -1.8% (95% CI -4.6% to 0.9%) was not statistically significant (Fisher’s exact p=0.20) (Supplemental Table 2). A secondary analysis based on a logistic regression model yielded similar results (OR 0.75, 95% CI 0.49 to 1.15, p=0.18). Among the participants with confirmed clinical infection, there were numerically fewer in the HCQ group (3 events [0.4%]) compared to the placebo group (6 events [0.9%]), and the difference was not statistically significant (0.45%, 95% CI -1.54% to 0.50%) Supplemental analyses using the Mantel–Haenszel method, which stratified by enrolling site, yielded a similar estimate of the common OR (0.69, 95% CI 0.45 to 1.05). However, there was evidence of heterogeneity at the site level for the primary endpoint (p=0.011).
Strengths and Weaknesses in Context
The original study design was powered to show a 20% relative treatment effect assuming a 5% event rate in the placebo arm. However, due to slowed enrollment early in the study, the study was amended to decrease the sample size and hence the power, increasing the detectable relative treatment effect to 50%. Thus, the study was underpowered to detect a small treatment effect.
SusannaNaggie, AaronMilstone
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