ABSTRACT
ABSTRACT Background. The spread of COVID-19 from Wuhan in China throughout the world has been alarmingly rapid. Epidemiologic techniques succeeded in containing the disease in China, but efforts were not as successful in the rest of the world, particularly the United States where there have been 2,079,592 confirmed cases with 115,484 deaths as of June 15, 2020. Projections are for continued new infections and deaths if no effective treatments can be activated over the next six months. We performed a systematic review to determine the potential time course for development of treatments and vaccines focusing on availability in the last half of 2020. Methods. Publications: Our search was performed during the week of June 15, 2020 We reviewed up to date information from several sources to identify potential treatments for COVID-19: We used the Reagan-Udall Expanded Access Navigator COVID-19 Treatment Hub to track the efforts of companies to develop treatments. We then used the results to search for publications identified treatments on pubmed.gov and on medRxiv, the preprint server. We further used a targeted Google search to find announcements of trial results. Clinical Trials: We searched for all investigational trials begun in the first quarter of 2020, with cut off on April 1, using several different sources: (A) covid-trials.org, then validated results on (B) clinicaltrials.gov and the (C) World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP). We focused on trials which were completed or currently recruiting for patients, reasoning that the timeline to arrive at treatments by the end of the year would require completion within the next 6 months. We excluded studies which were clearly observational, with no randomization, control or comparison group. We further set a cutoff of 100 for numbers of subjects since smaller trial size could lack statistical power to establish superiority of the intervention over the control condition. Results. Published Data: We found 44 publications reporting findings on 11 classes of agents. There were 12 publications related to hydroxychloroquine (HCQ),11 on tocilizumab, 4 publications related to remdesivir, four on lopanovir/ritonavir (LPV/R), four on interferons, three on favipiravir, two on convalescent plasma, one on meplazumab, one on corticosteroids, one on famotidine, and one on ivermectin. Of these, only 16 were randomized or active control studies; the rest were retrospective observational. Only two publications dealt with outpatient care, the rest all in hospitalized patients. Clinical Trials: We found 409 trials meeting our minimum requirement of 100 subjects which were recruiting or completed. The WHO has launched the Solidarity megatrial performed in over 100 countries actively comparing HCQ, lopanovir/ritonavir (LPV/R) alone and in combination with interferon beta-1, and remdesivir. That trial is scheduled to complete enrollment in the first quarter of 2021. In addition, we found 46 trials of HCQ, 11 trials of LPV/R and 8 trials of interferons. There were 18 ongoing trials of antiviral agents, 24 immune modulator trials, 9 vaccine trials, and 62 trials of other agents. We excluded a large number of trials of Chinese traditional medications, reasoning that there was insufficient clinical experience with these agents outside China to offer these treatments to the rest of the world. Forty four trials were hoping to complete enrollment by the end of the second quarter of 2020. Of these, only 9 were conducted on outpatients. A few vaccine trials are hoping to complete Phase 3 enrollment by the end of the third quarter, but a prolonged follow-up of patients will likely be required. Conclusion. Remdesivir and tocilizumab have now been granted emergency authorization in many countries for treatment of hospitalized patients. However, the disease is propagated primarily by infected ambulatory individuals. There are only a few randomized controlled studies in outpatients which can be expected to yield results in time to impact on the continuing epidemic in 2020. It will be necessary for public health authorities to make hard decisions with limited data to prevent the continued spread of the disease. The choices will be hardest in dealing with potential early release of vaccines. Keywords: Coronavirus, COVID-19, SARS-Cov-2, remdesivir, hydroxychloroquine, favipiravir *email: Binh.ngo@med.usc.edu