key: cord-299150-1noy0z88
authors: Desai, Aakash; Kulkarni, Amit; Rajkumar, S Vincent; Gyawali, Bishal
title: Clinical Trial Endpoints in Severe COVID-19
date: 2020-06-06
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.025
sha: 
doc_id: 299150
cord_uid: 1noy0z88

nan

Since the first outbreak in Wuhan, China in late December 2019, the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has already tolled 230,000 deaths. Although most of the patients are asymptomatic or have minimal symptoms, patients with severe COVID19 often require hospitalization [1] .

Mortality in patients admitted to intensive care units (ICU) or those requiring mechanical ventilation is as high as 25% [2, 3] .

There is an urgent need to develop effective therapy for severe COVID19 that improves mortality. However, clinical trials of agents tested for severe COVID19 may not necessarily test for mortality outcomes as the primary endpoint, as was highlighted in the press release of the recent remdesivir trial. Since drugs improving mortality in severe COVID-19 is the most important endpoint to achieve both from clinical and public policy standpoint, we evaluated the type of primary endpoints currently being assessed in randomized controlled trials (RCTs) in severe COVID19.

We searched www.clinicaltrials.gov to identify clinical trials for "Severe COVID19" as of April 30th, 2020. We included only Phase III and interventional trials. We excluded prophylaxis, prevention, and treatment trials with no mention of "Severe COVID" in the title.

We then extracted information on the primary endpoint of each eligible study. Two authors (A.D and A.K) independently performed the data extraction and analysis.

Of the 50 trials identified initially, 19 trials (with 17 study drugs) satisfied our inclusion and exclusion criteria and were included in the final analysis. Of these, 16/19 (84.2%) trials were randomized studies and 13/16 (81.2%) of these were placebo-controlled trials. The most common study drugs in the intervention arm were hydroxychloroquine alone (5/19, (26.3%)), followed by remdesivir and methylprednisolone (2/19, (10.5%)) ( Table 1) .

Among the 19 trials, we found 12 different primary endpoints. All cause hospital mortality 4/19 (21%), change in PaO2 to FiO2 ratio 3/19 (15.8%), and composite primary endpoints that included mortality and time to clinical improvement 2/19 (10.5%) were the most common primary endpoints studied. (Figure 1 ).

Our analysis found that only 6/19 (30%) ongoing phase III RCT in severe COVID19 have mortality as the standalone primary endpoint or a part of composite endpoint. This finding is surprising given the urgent need for effective drugs that can alter the natural history of severe COVID19 and reduce mortality. Most of the other primary endpoints being assessed are unproven surrogate clinical endpoints or biomarker-based endpoints. Some surrogate clinical endpoints like length of time to clinical improvement (10.5%), hospital stay (5.3%) may offer meaningful information from a cost of care or resource perspective but these studies are not powered to detect mortality benefit.

Given that mortality is as high as 25% in severe COVID19 who need ICU care and average time to death is 3-6 days [2, 3] , the number of mortality events needed and follow-up time do not pose an impediment for analysis of mortality as the primary endpoint. Furthermore, as the pandemic subsides, we may lose valuable time to enroll patients into well-designed RCTs to obtain definitive answers for treatment efficacy.

Although our search results may not be comprehensive given the non-uniformity in the definition of severe COVID19 among all trials, our findings do raise serious concerns about the use of surrogate measures, in current and ongoing clinical trials for severe COVID19. Any endpoint other than mortality reduction may not be relevant at the time of a pandemic with a virus that has high mortality rates. We must prioritize discovery of a drug that truly reduces mortality rather than squandering resources in finding a drug that may make us complacent but not improve any meaningful outcomes. 

Clinical Characteristics of Coronavirus Disease 2019 in China

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Baseline Characteristics and Outcomes of 1591 Patients Infected with SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy