Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19

Abstract

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

Keywords: ARDS; COVID-19; ORCHID; SARS-CoV-2; hydroxychloroquine.

Figure 1.

Timeline from study conception to enrollment of the first patient. On February 28, 2020, the first death from coronavirus disease (COVID-19) in the United States was reported. On March 16, 2020, an initial Prevention and Early Treatment of Acute Lung Injury (PETAL) network conference call was held to discuss proposed interventions to treat COVID-19. On March 19, 2020, a brief trial concept and two-page summary was developed for a trial of hydroxychloroquine among hospitalized patients with COVID-19 and presented to the network along with other trial proposals. Following a PETAL Steering Committee vote on March 20, 2020, a trial of hydroxychloroquine was chosen as the first interventional trial for COVID-19 in the PETAL network. On the same day, the National Heart, Lung and Blood Institute reviewed the two-page summary and endorsed protocol development. A first draft of the trial protocol was completed in 72 hours and distributed to the PETAL Steering Committee. The trial protocol was finalized and submitted to the single institutional review board (IRB) on March 25, 2020. The trial was reviewed simultaneously by the single IRB and PETAL Protocol Review Committee, with both providing approval on March 28, 2020. Following an investigational new drug (IND) application submission to the Food and Drug Administration on March 27, 2020, a notification of IND exemption was received on March 30, 2020. The trial was submitted to clinicaltrials.gov on March 31, 2020. The trial was presented to the PETAL Data and Safety Monitoring Board on April 1, 2020, with approval granted on the same day. The first patient was randomized on April 2, 2020, with blinding maintained by encapsulation of hydroxychloroquine and placebo by local pharmacies. DSMB = Data and Safety Monitoring Board; FDA = Food and Drug Administration; NHLBI = National Heart, Lung, and Blood Institute; ORCHID = Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease.