Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19: a summary of the protocol and analysis plan for a decentralized randomized controlled trial

Abstract

Background Coronavirus disease 2019 (COVID-19) has a heterogeneous outcome in individuals from remaining asymptomatic to death. In a majority of cases, mild symptoms are present that do not require hospitalization and can be successfully treated in the outpatient setting, though symptoms may persist for a long duration. We hypothesize that drugs suitable for decentralized study in outpatients will have efficacy among infected outpatients Methods The TREAT NOW platform is designed to accommodate testing multiple agents with the ability to incorporate new agents in the future. TREAT NOW is an adaptive, blinded, multi-center, placebo-controlled superiority randomized clinical trial which started with two active therapies (hydroxychloroquine and lopinavir/ritonavir) and placebo, with the hydroxychloroquine arm dropped shortly after enrollment began due to external evidence. Each arm has a target enrollment of 300 participants who will be randomly assigned in an equal allocation to receive either an active therapy or placebo twice daily for 14 days with daily electronic surveys collected over days 1 through 16 and on day 29 to evaluate symptoms and a modified COVID-19 ordinal outcome scale. Participants are enrolled remotely by telephone and consented with a digital interface, study drug is overnight mailed to study participants, and data collection occurs electronically without in-person interactions. Discussion If effective treatments for COVID-19 can be identified for individuals in the outpatient setting before they advance to severe disease, it will prevent progression to more severe disease, reduce the need for hospitalization, and shorten the duration of symptoms. The novel decentralized, “no touch” approach used by the TREAT NOW platform has distinction advantages over traditional in-person trials to reach broader populations and perform study procedures in a pragmatic yet rigorous manner. Trial registration ClinicalTrials.gov NCT04372628. Registered on April 30, 2020. First posted on May 4, 2020.

The Digital Therapeutics Real-World Evidence Framework: An Approach for Guiding Evidence-Based Digital Therapeutics Design, Development, Testing, and Monitoring

“…For detailed guidance on comparator selection, see NIH expert panel recommendations [ 45 ]. For DTx testing, options include but are not limited to between-person RCTs [ 106 , 107 ], including remote RCTs [ 108 , 109 ], cluster RCTs [ 110 , 111 ], stepped wedge trial [ 104 , 105 ], and, when sufficient RWD is available, the use of simulated clinical trials [ 14 - 17 ] could be considered.…”

Decentralized clinical trials in the trial innovation network: Value, strategies, and lessons learned

“…Confirmation of eligibility to participate in a research study can be approached with a wide array of remote tools and methods, including online survey responses, phone interviews, video calls, electronic source (eSource) data entered directly into electronic case report forms (eCRFs), physiologic data (e.g., blood pressure, heart rate), pupillometer devices, magnetic resonance imaging (MRIs), EHR data, lab results, and digital biomarkers. An example of remote initial evaluation is the Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT Now) study [ 21 ]. Researchers conducted a Google Ads campaign, in which individuals diagnosed with COVID-19 could click on an ad for a survey to determine study eligibility.…”

“…The remote application of a treatment or procedure, administration of a drug, or use of a medical device are examples of decentralized interventions. These can be delivered to participants via direct-to-patient shipping, such as medications being delivered to participants in the TREAT Now [ 21 ] study; the “Clinical-trial-in-a-box” sent to participants in the Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms (Niclosamide) trial [ 27 ]; home visits by study staff; teleconferencing; and platforms such as MyCap [ 32 ], REDCap, or patient portals. In the REACT-AF [ 14 ] study, an Apple Watch is provided to the participant pre-loaded with a cloud-based mobile application, Eureka, which notifies the participant of an AF event and subsequently instructs them when to start and when to stop taking their medication.…”

“…1 displays the flow of a clinical trial, from design through retention, listed as steps that can potentially be executed remotely. The column on the left displays 11 trials [14,16,[19][20][21][22][23][24][25][26][27] supported and/or conducted by TIC/RIC investigators that employ one or more decentralized elements, some of which will be discussed in the text. Notably, none of the trials listed are fully decentralized; instead, they employ different combinations of decentralized elements in a fit-for-purpose approach.…”

The Digital Therapeutics Real World Evidence Framework: An approach for guiding evidence-based DTx design, development, testing, and monitoring

“…For detailed guidance on comparator selection, see NIH expert panel recommendations 44 . For DTx testing, options include but are not limited to: between-person randomized controlled trials (RCTs) 75,76 including remote RCTs 77,78 , cluster RCTs 79,80 , or stepped wedge trial. 73,74 If SMART benchmarks are not met or there was not a clinically significant difference observed between the DTx and comparator, then returning to Phase I or Phase II activities is appropriate.…”