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Clinical Trial End Points in Severe COVID-19

      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 has already caused 230,000 deaths. Although most of the patients are asymptomatic or have minimal symptoms, patients with severe COVID-19 often require hospitalization.
      • Guan W.J.
      • Ni Z.Y.
      • Hu Y.
      • et al.
      China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China.
      Mortality in patients admitted to intensive care units or those requiring mechanical ventilation is as high as 25%.
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region.
      There is an urgent need to develop effective therapy for severe COVID-19 that improves mortality. However, clinical trials of agents tested for severe COVID-19 may not necessarily test for mortality outcomes as the primary end point, as was highlighted in the press release of the recent remdesivir trial. Because drugs improving mortality in severe COVID-19 is the most important end point to achieve from both clinical and public policy standpoints, we evaluated the type of primary end points currently being assessed in randomized controlled trials (RCTs) in severe COVID-19.

      Methods

      We searched www.clinicaltrials.gov to identify clinical trials for “severe COVID-19” as of April 30, 2020. We included only phase III and interventional trials. We excluded prophylaxis, prevention, and treatment trials with no mention of “severe COVID-19” in the title. We then extracted information on the primary end point of each eligible study. Two authors (A.D. and A.K.) independently performed the data extraction and analysis.

      Results

      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 19 trials, 16 (84.2%) were randomized studies, and 13 of these 16 trials (81.2%) were placebo-controlled trials. The most common study drugs in the intervention arm were hydroxychloroquine alone (5 of 19 [26.3%]), followed by remdesivir and methylprednisolone (2 of 19 [10.5%]) (Table).
      TableStudy Drugs in Various Intervention Arms in Trials for Severe Coronavirus Disease 2019
      Study drugNo. of trials
      Hydroxychloroquine5
      Methylprednisolone2
      Remdesivir2
      Tocilizumab1
      Hydroxychloroquine + azithromycin1
      Azithromycin alone1
      Yinhu Qingwen Granula1
      IFX-11
      Ravulizumab1
      Dexamethasone1
      Traditional Chinese medicine1
      Pyridostigmine1
      Bevacizumab1
      Intravenous immunoglobulin1
      Tradipitant1
      Convalescent plasma1
      Dalargin1
      Among the 19 trials, we found 12 primary end points. All-cause hospital mortality (4 of 19 [21%]), change in partial pressure of oxygen, arterial/fraction of inspired oxygen ratio (3 of 19 [15.8%]), and composite primary end points that included mortality and time to clinical improvement (2 of 19 [10.5%]) were the most common primary end points studied (Figure).
      Figure thumbnail gr1
      FigureDistribution of primary end points used in trials for severe coronavirus disease 2019. OR = odds ratio; Pao2/Fio2 = partial pressure of oxygen, arterial/fraction of inspired oxygen.

      Discussion

      Our analysis found that only 6 of 19 ongoing phase III RCTs (30%) for severe COVID-19 have mortality as the stand-alone primary end point or part of the composite end point. This finding is surprising given the urgent need for effective drugs that can alter the natural history of severe COVID-19 and reduce mortality. Most of the other primary end points being assessed are unproven surrogate clinical end points or biomarker-based end points. Some surrogate clinical end points such as length of time to clinical improvement (10.5%) and 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 patients with severe COVID-19 who need intensive care unit care and the average time to death is 3 to 6 days,
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.
      ,
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region.
      the number of mortality events needed and follow-up time do not pose an impediment for the analysis of mortality as the primary end point. 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 nonuniformity in the definition of severe COVID-19 among all trials, our findings do raise serious concerns about the use of surrogate measures in current and ongoing clinical trials for severe COVID-19. Any end point other than mortality reduction may not be relevant at the time of a pandemic caused by 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.

      Acknowledgments

      Drs Desai and Kulkarni have equal contribution.

      Supplemental Online Material

      References

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        Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region.
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