key: cord-0989885-y9rqr1h8
authors: Ngo, B. T.; Rendell, M.
title: A SYSTEMATIC ANALYSIS OF THE TIME COURSE TO DEVELOP TREATMENTS FOR COVID-19
date: 2020-06-02
journal: nan
DOI: 10.1101/2020.05.27.20115238
sha: dffb539e07fc50a06f07a07355295a5aed27e8dd
doc_id: 989885
cord_uid: y9rqr1h8

ABSTRACT Background. The spread of COVID-19 from Wuhan in China throughout the world has been alamingly 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 1,592, 599 cases with 95,863 deaths as of May 25, 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 of development of treatments and vaccines focusing on availability in the last half of 2020. Methods. Our search was performed during the week of May 17, 2020. Publications: 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 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 involving potential treatments 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 furtherset 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 19 publications reporting findings on 6 classes of agents. There were 9 publications related to hydroxychloroquine (HCQ), three on lopanovir/ritonavir (LPV/R) (one of which was combined with interferon beta-1),three on remdesivir, two on favipiravir, one on mepaluzamab, and one on tocilizumab. Ten publications reported randomized controlled trials, the rest were retrospective observational. Only one publication touched on outpatient management, the rest on 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. Several treatments for severe disease in hospitalized patients have now been granted emergency authorization. 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 spread of the epidemic in 2020. It will be necessary for public health authorities to make hard decisions with limited data. The choices will be hardest in dealing with potential early release of vaccines. Keywords: Coronavirus, COVID-19, SARS-Cov-2, remdesivir, hydroxychloroquine

The coronavirus SARS-Cov-2 pandemic spread through the world with extraordinary speed from its origin in December 2019 in Wuhan City in the Hubei Province of China. As of May 25, 2020, there were 5,307,298 confirmed cases of COVID-19, and 342,070 deaths worldwide affecting 220 countries and territories (1) . The illness produces mild or no symptoms in about 80% of infected individuals but, in about 20% manifests as a significant pneumonia which can progress to acute respiratory distress requiring mechanical ventilation in 5% of patients (2) . Baud et al calculated a crude mortality ratio of 5.7% using confirmed cases, but that calculation is affected by the high percentage of asymptomatic and mild undiagnosed cases (3) . A calculation based on the outbreak among the passengers and crew of the cruise ship Diamond Princess, essentially a captive population, suggested a case fatality ratio of 2.6% and infection fatality ratio of 1.3% (4) . However, the mean age of the passengers was about 60, and mortality is definitely higher in the elderly and in those with chronic disease.

COVID-19 is a disease of dual pathogenicity with a characteristic sequence of events related to the primary viral attack and then, subsequently, with an overlapping hyperinflammatory reaction (5) . The initial viremia manifests as an influenza like illness with cough, fever, myalgia and fatigue. In patients with severe disease, within seven days of onset of symptoms, bilateral multiple lobular and subsegmental areas of consolidation are typically seen on chest CT (6) . The pneumonia causes dyspnea by 8 days which may progress to acute respiratory distress syndrome (ARDS) by 9 days. Cytokine levels in the patients with ARDS are more elevated than in those patients who do not progress, pointing to a severe immune reaction as the probable cause (7, 8) . There is additionally a coagulopathy which affects the lungs and other organs and can trigger cerebrovascular accidents (9, 10) .

Epidemiologic models have varied on prediction of the continued spread of COVID-19 in the United States. The Insttute for Health Metrics and Evaluation IHME projected that the peak of deaths occurred in midApril with lessening by May 1, predicated however on maintenance of strict social distancing measures (15). Kissler et al performed simulations of the persistence of COVID-19 in the United States (16) . Their model considered known data on the transmissibility of other less threatening betacoronaviruses, crossimmunity with those viruses, seasonal variations, and the impact of social distancing. They predicted that the peak of infections would occur in May with significant reduction by July. However, a significant resurgence of COVID-19 was then expected to follow the end of social distancing with secondary peaks occurring into 2021. The optimal scenario they simulated was for indefinite social distancing measures, which even early on has triggered massive unemployment and economic collapse in the United States. They stated that medications or vaccines for COVID-19 would obviously reduce the need for reliance on intensive social distancing.

Faced with a growing crisis in early January, Chinese health authorities began treating patients empirically with agents with demonstrated in vitro antiviral activity against coronaviruses and those used before during the SARS 2002 and MERS outbreaks in China (17, 18) . The medications used included the antimalarial drugs hydroxychloroquine (HCQ) and chloroquine, the HIV protease inhibitor lopanovirritanovir (LPV/R), the Russian antiviral umifenovir, and traditional Chinese medical approaches. Subsequently, the antimalarial drugs hydroxychloroquine (HCQ) and chloroquine have been widely used to treat COVID-19 patients throughout the world, despite cautions from numerous regulatory bodies. The scientific basis for their use is in vitro evidence of an effect on blocking viral endosomal penetration as well as their known suppressive benefit of undesirable autoimmune effects (19) . Thus far, the clinical evidence supporting the use of antimalarials for COVID-19 is limited (20) .

In view of the projections for resurgence of infections if current social distancing measures are to be relaxed, our goal was to assess the projected timeline for development and release of pharmacologic agents to treat and to prevent COVID-19 over the next 6 months.

Our search was carried on the week of May17, 2020. PUBLICATIONS: We reviewed up to date information from several sources to identify potential treatments for COVID-19: We used the Reagan-Udall Expanded Access Navigator which is a joint effort of the Reagan Udall Foundation and the FDA to track the efforts of companies engaging in research to enable access to investigational treatments for individuals who are unable to find or participate in an existing clinical trial. To address the global pandemic of COVID-19, the Foundation enhanced the Expanded Access Navigator to include a comprehensive COVID-19 Treatment Hub. We then identified all publications on proposed treatments using pubmed.gov to find peer reviewed articles but in addition we reviewed medRxiv to find preprint reports. We further carried out Google searches on each potential treatment to find preliminary reports, typically presented as press releases.

CLINICAL TRIALS: We searched for all investigational trials involving potential treatments using several different sources:

(A) covid-trials.org This is a registry to collate all trials in real time (21) . Data are pulled from the International Clinical Trials Registry Platform, including those from the Chinese Clinical Trial Registry, ClinicalTrials.gov, Clinical Research Information Service -Republic of Korea, EU Clinical Trials Register, ISRCTN, Iranian Registry of Clinical Trials, Japan Primary Registries Network, and German Clinical Trials Register. Both automated and manual searches are done to ensure minimisation of duplicated entries and for appropriateness to the research questions. Identified studies are then manually reviewed by two separate reviewers before being entered into the registry. Concurrently, the registry has developed artificial intelligence (AI)-based methods for data searches to identify potential clinical studies not captured in trial registries.

We cross validated information from covid-trials.org on (B) clinicaltrials.gov This is a registry of clinical trials information maintained by the United States National Library of Medicine for both federally and privately funded trials conducted under investigational new drug applications to test the effectiveness of experimental drugs. Data includes trials in the United States and 210 countries.We further cross referenced the trials on (C) the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP).

We determined which agents were currently available for clinical use, those with published trial results, those which were in ongoing active randomized clinical trial investigation, those which were in observational trials, those in trials projected to begin but not yet recruiting, agents in preclinical phase, and agents in planning phase. We than reviewed each trial to determine if the trials were completed, recruiting for patients, not recruiting or suspended. We only selected those which had completed or were actively recruiting, reasoning that the timeline to implement treatments by the end of the year would require completion within the next 3 months. We excluded studies which were clearly observational for treatment purposes, 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. For each trial selected, we documented the setting of patient contact, either hospital or outpatient, the intended severity of disease in the trial population, the type of control procedure, the date the trial was initially registered, and the proposed date of completion of enrollment. We further reviewed all inclusion and exclusion requirements to verify intended severity of disease. We focused on any inclusion requirements based on duration of symptoms. We categorized the studies as either prevention (PREV) of SARS-Cov-2 infection in healthy subjects or treatment of established COVID-19 disease (TREAT).

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PUBLISHED RESULTS ON COVID 19 TREATMENT. We first searched for all publications reporting on completed investigations of pharmaceutical treatment of COVID-19. We searched on pubmed.gov as well as MedRxiv, the preprint server. As of May 20, we found 19 publications reporting findings on 6 classes of agents (TABLE 1) . There were 9 publications related to hydroxychloroquine, three on lopanovir/ritanovir (LPV/R) three on remdesivir, two on favipiravir, one on meplazumab, and one on tocilizumab. Ten of the publications reported randomized controlled or active comparator trials, the rest were observational.

The largest published randomized controlled trials were with remdesivir, an inhibitor of viral RNA polymerase. Two remdesivir trials were randomized controlled placebo trials. The first multicenter trial at ten hospitals in Hubei, China trial was halted in April due to failure to further enroll since no new cases were occurring (22) . Eligible patients were adults (aged ≥18 years) admitted to the hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrollment of 12 days or less, radiologically confirmed pneumonia, and hypoxia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of LPV/R, interferons, and corticosteroids. The trial enrolled 237 patients when it was suspended due to lack of recruitment. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]).

A report of compassionate use of remdesivir found an overall mortality of 5% in patients not requiring mechanical ventilation but 18% in those who did (23) . The largest trial of remdesivir in 1063 moderate to severely ill patients was a double blind randomized placebo controlled study carried out by the National Institute of Arthritis and Infectious Disease (NIAID). On April 29, Dr. Anthony Fauci, Director of the NIAID, announced that the study had met its endpoint in that a faster time to clinical improvement and discharge was found with remdesivir treatment. On May 22, 2020 the actual trial results were published (24) . The patients who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) for those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days after randomization were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). There was no data documenting the rate of viral clearance. On the basis of this trial, the FDA issued an emergency authorization to use remdesivir for severely ill COVID hospitalized patients.

There were two trials of favipiravir (FVP, which like remdesivir is an inhibitor of viral RNA polymerase. Favipiravir is given as an oral tablet whereas remdesivir only has an intravenous route of administration. Both FVP trials were active control studies carried out in China (TABLE 1) . In a study of 35 patients receiving favipiravir compared to 45 patients receiving LPV/R plus inhaled interferon alpha, a shorter viral clearance time was found for the FVP arm (median (interquartile range, IQR), 4 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 2, 2020. . Published studies on hydroxychloroquine (HCQ) have been less conclusive. In a small study in Marseille, France, COVID-19 patients were included in a single arm protocol to receive 600mg of HCQ daily, with daily viral load testing in nasopharyngeal swabs (27) . Depending on their clinical presentation, azithromycin (AZT) was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported for untreated patients. AZT added to HCQ was significantly more efficient for virus elimination.

The same group has subsequently reported their experience with 1061 patients screened positive for SARS-Cov-2 and then treated with HCQ and AZT (28) . Patients and asymptomatic contacts with positive viral tests were included. There was no control population. After evaluating electrocardiograms to exclude patients at risk of QT prolongation, they used a combination of HCQ and AZT. Viral clearance was measured at days 2,6, and 10 of treatment and further for patients who were deemed poor clinical responders. The patients were young (mean age 43.6). Good clinical outcome with successful viral clearance by ten days was obtained in 91.7% of the patients. Failure to clear the virus by ten days occurred in 47 patients (4.4%). Forty-six patients (4.3%) were classified as poor clinical response due to 10 patients transferred into the ICU and 30 who were hospitalized for ten days or more. There were 10 patients who died (mean age 79) due to respiratory failure giving a case fatality ratio of 0.9%.There were no sudden cardiac deaths.

In a small trial at Renmin Hospital of Wuhan University in a parallel-group randomized trial, 31 patients were assigned to receive 5-days of HCQ (400 mg/d) treatment (29) . The body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group, and 81% (25 of 31) had improvement in pneumonia compared with the control group (54.8%, 17 of 31). All 4 patients who progressed to severe illness were in the control group. However, another small Chinese study showed no difference in viral clearance in HCQ treated subjects (30) .

There have been many retrospective large observational trials which suggest that hospitalized patients on HCQ have worse outcomes (31-34) ( Table 1 ). The largest retrospective observational study was a multinational registry analysis using Surgical Outcomes Collaborative, a data acquisition and warehousing cloud based system which collected electronic data from 671 hospitals in six continents, including patients hospitalized between Dec 20, 2019, and April 14, 2020. The analysis compared 14888 patients who were treated with hydroxychloroquine, chloroquine, or their combination with a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. . 8 macrolide within 48 hours of diagnosis of COVID-19. The control group consisted of 81,144 diagnosed patients who did not receive any of these agents. Using propensity scoring to achieve comparability of baseline characteristics, they found higher mortality in all of the groups receiving antimalarial agents compared to control. They also found a higher incidence of ventricular arrhythmias, a known side effect of HCQ and chloroquine. The difficulty in analyzing retrospective observational data is in the possibility of a selection bias choosing patients who were sicker for treatment. Propensity scoring can help adjust for bias, and there appeared to be comparability of groups after adjustment. However, in one study (31) , even after adjustment, the (Pao2:Fio2 (223) of HCQ patients was lower than that for the propensity scored non-HCQ patients (273).

In a retrospective comparison study at NYU Langone Health for all patients admitted between March 2 and April 5, 2020 (35) , there were a large number of patients treated with HCQ plus AZT. During the one month period, there was a move to add zinc 100 mg daily to the HCQ plus AZT regimen. Zinc supplementation has shown benefit in viral diseases both in inhibiting viral replication and in improvement of systemic immunity (36) . Zinc administered within 24 hours of onset of symptoms has been claimed to reduce the duration of common cold symptoms in healthy people (37). There were 411 patients treated with HCQ+AZT+ zinc at NYU. There were only minor differences in the clinical characteristics of these patients compared to the 521 patients on HCQ and AZT who did not receive zinc. After adjustment for the time period when zinc first came to frequent use, there was a significantly lower mortality (13.1%) among the zinc treated patients compared to those who did not receive zinc (22.8%).

Published results with Lopanovir/ritonavir (LPV/R) have been fairly disappointing. A small Chinese trial of 44 patients found no difference in viral clearance compared to standard of care (38) . In a randomized trial with 99 patients on LPV and 100 receiving standard care, there was no difference in time to clinical improvement, mortality or viral clearance (39) . A potentially more favorable result was obtained in Hong Kong in a study of 86 patients assigned to triple combination therapy with LPV/R plus ribavirin plus interferon beta-1 (40) . Compared to a control group of 41 patients receiving LPV/R alone, the combination group had a significantly shorter median time from start of study treatment to negative SARS-Cov-2 nasopharyngeal swab (7 days [IQR [5] [6] [7] [8] [9] [10] [11] ) than the control group (12 days [8] [9] [10] [11] [12] [13] [14] [15] ;hazard ratio 4·37 [95% CI 1·86-10·24], p=0·0010). The time to complete alleviation of symptoms was 4 days [IQR [3] [4] [5] [6] [7] [8] in the combination group vs 8 days [7] [8] [9] in the control group; HR 3·92 [95% CI 1·66-9·23. The timing of interferon administration was staggered based on time of symptom onset, so there were 34 patients in the combination group who did not receive interferon at all. Those patients did not show clinical or virological superiority to the LPV/R control group. This study was interpreted as supporting further trials focusing on interferon beta-1 as the primary treatment modality.

A very small pilot study of meplazumab, a monoclonal antibody to CD147, in 17 patients showed a marked improvement in viral clearance time from 13 days (6.5-19.5) in a control group of 11 patients to 3 days (1.5-4.5) . This was accompanied by clinical and radiographic improvement (41) .

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The copyright holder for this preprint this version posted June 2, 2020. . https://doi.org/10.1101/2020.05.27.20115238 doi: medRxiv preprint Very hopeful data has emerged for the IL-6 inhibitor tocilizumab in the severe and critically ill phase of the disease. An observational study in China suggested dramatic improvement in 21 patients with abatement of fever, decrease in oxygen requirement and reduction in lung lesions (42) . There was no control group in that study, but it was recently announced that tocilizumab treatment had succeeded in the randomized, controlled CORIMUNO-19 -TOCI trial for severely ill COVID-19 patients in France. On the basis of the French still unpublished findings, the CDC issued an emergency use authorization for tocilizumab.

It is important to note that the published studies to date have dealt with hospitalized patients. Only the Marseille group included outpatients who tested positive for SARS-Cov-2. REVIEW OF CURRENT TRIALS: As of May 25, we identified 781 trials worldwide meeting our review criteria. Approximately half the trials were registered in mainland China, and 103 trials were registered in the United States (TABLE 2) . There were 553 trials in the recruitment process or completed (SUPPLEMENTARY TABLE 1). We found 409 trials meeting the minimum requirement of 100 subjects which were recruiting or completed. The World Health Organization has organized a megatrial appropriately named Solidarity to assess four separate treatment options: Remdesivir; LPV/ R; LPV/R with Interferon beta-1a; and HCQ or chloroquine (43) . The Solidarity Trial provides simplified procedures to randomize patients to one of the four agents or alternatively standard care. Brief identifying details and any other conditions are digitally recorded for the patient, who is then randomly allocated to one of the study options. Critical study information is to be collected only at randomization and when the patient is discharged or dies: which study drugs were given (and for how many days); whether ventilation or intensive care was received (and, if so, when it began), date of discharge, or date and cause of death while still in hospital. Data is transmitted centrally to the trial database. There are over 100 countries now participating. Completion of enrollment of 10,000 patients is estimated in the first quarter of 2021. Very recently, the antimalarial arm of the study has been paused after review of the observational studies previously mentioned pending an interim safety analysis.

OTHER TRIALS WITH THE SOLIDARITY AGENTS: In addition to and independent from the Solidarity trial, we found 46 trials of HCQ, 11 trials of LPV/R and 8 trials of interferons (TABLE 3) . Of these, ten of the HCQ trials focused on prevention of the disease in exposed patients. Only two of these 10 prevention trials proposed completion of enrollment in the second quarter of 2020. There were seven HCQ trials conducted on ambulatory patients with diagnosed mild disease. Only two of these outpatient trials had proposed enrollment completion in the second quarter. There were 21 trials on hospitalized patients. Four of these trials had planned enrollment completion in the second quarter of 2020.

Two prevention trials with LPV/R are currently enrolling, with earliest enrollment completion in the second quarter of 2020 for one and the third quarter for the other. There is one outpatient active comparison trial with HCQ with proposed enrollment end in the second quarter of 2020. There are two . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. (29) Italy (21) >10 Germany (19) Canada (18) Netherlands (14) Brazil (13) Denmark (13) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. . large active comparison trials with earliest enrollment end date in the first quarter of 2021. There is one large interferon prevention trial scheduled to complete enrollment in the second quarter of 2020.

ANTIVIRAL AGENTS: SARs-CoV-2 attacks cells by binding of the spike protein to the host cell ACE2 receptor. A specific serine protease TMPRSS2 then activates membrane fusion allowing viral RNA to enter the cell to be replicated with release of multiple virions. Numerous antiviral agents are now in active trials (TABLE 4 ). In addition to remdesivir and favipiravir, trials are ongoing with umifenovir, a membrane lipid fusion inhibitor with broad antiviral properties (44) and with camostat which is a potent serine protease inhibitor (45) . A very large multicenter prevention trial has begun for hospital workers exposed to COVID-19 in Spain. This involves 4000 subjects who will be randomized to emicitrabine/tenofovir, an HIV agent, or to HCQ or to placebo. The trial has planned to meet its enrollment goal by the beginning of the third quarter of 2020.

tion that leads to the most serious consequences of the disease. Many trials are focusing on several interleukin inhibitors currently approved for treatment for rheumatoid arthritis and other autoimmune conditions to suppress the cytokine storm of COVID-19 (TABLE 5) . Tocilizumab has just received emergency authorization. Selinexor has planned completion of enrollment by the end of the second quarter as well. A trial of sarilumab which will run until 2021 recently completed its first phase and announced success in reducing CRP. These trials are all directed at severely ill COVID-19 inpatients.

There is a large multicenter placebo-controlled trial of colchicine in non-severely ill outpatients scheduled to enroll 6000 patients by end of the third quarter of 2020.

OTHER STUDIES (SUPPLEMENTARY TABLE 2 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. standard of care; PLAC: placebo control, whether treatment (TREAT) or prevention (PREV), the severity of illness, number of subjects, quarter study initiated, quarter study projects completion of enrollment, and duration of symptoms for patient inclusion are listed. Studies projecting completion of enrollment by the end of the second quarter of 2020 are bolded. Outpatient studies with planned completion by the end of the second quarter of 2020 are italicized. PLEMENTARY TABLE 1 ). There was one ongoing study of hyperbaric oxygenation but not due to complete enrollment until the second quarter of 2021. Pirfenidone is an agent approved to treat pulmonary fibrosis, and one study is planning completion of enrollment by the end of the second quarter of 2020.

SUPPLEMENTS: The suggestion that zinc may be a beneficial agent together with HCQ in COVID has generated interest, but there is only one study underway, not including HCQ. A study of HCQ with and without zinc for prevention of COVID infection is soon to begin in Tunisia. TRADITIONAL CHINESE MEDICATIONS: There were 48 such studies. We did not include them in our search for agents which could be made available in the next 6 months for two reasons. First, these medications are not familiar to clinicians in the rest of the world. Second, the success of epidemiologic containment in China has made it unlikely that many projected trials would achieve enrollment.

VACCINES: The World Health Organization has identified 110 programs to develop a SARS-Cov-2 vaccine. Of these, seven have reached initial human trials There are four programs active in China, one in the United Kingdom and two in the United States. The conventional wisdom is that it will take a year to 18 months to implement a vaccination program. Clinical vaccine development is typically a multi-year three-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded and vaccine is given to people who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety. SARS-Cov-2 vaccine developers have approached the regulatory bodies to request acceleration of the process. Optimistic observers have suggested that a vaccine could be available by the beginning of 2021. A bold suggestion has been made to allow emergency authorization of favorable vaccine candidates by the fall. An additional approach has been suggested to attempt to stimulate non-specific immunity prior to availability of a vaccine using oral polio vaccine or BCG vaccination (46) . There are two large prevention trials underway in the Netherlands and Australia using BCG vaccine in health care workers. These trials plan conclusion of enrollment, but not until the fourth quarter of 2020.

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The copyright holder for this preprint this version posted June 2, 2020. (16) . We reproduce their graphic from Science below (FIGURE 1) . Panel B appears to represent the current situation with a relaxation of social distancing, which has begun in midMay. Their projection is for a continuation of new cases and deaths occurring through July, with a possible resurgence in October.

The current pharmaceutical options available in the United States have been limited. In China, it is not the practice to run placebo controlled trials with investigational agents with no alternative choices for the patient. Consequently, their "standard of care" often includes many potentially effective agents, possibly confounding results. Furthermore, their guidance to physicians includes many options which are under active study in certain sites. In contrast to China, in the United States and Europe, there is an emphasis on randomized placebo controlled clinical trials to decide which agents should be widely used for treatment. Those trials are ongoing, but we found that only 40 of 164 trials are proposed to complete enrollment in the second quarter of 2020. It typically may take two months or more to follow patients to completion, verify and analyze data, and our goal was to find treatments to be used during the next six months. In the United States, HCQ, remdesivir, and tocilizumab are currently available on an emergency use basis only for hospitalized severely ill patients. There are other large programs now focusing on immune modulators to prevent ARDS due to cytokine storm in hospital. Most of the agents involved are marketed drugs used to treat autoimmune diseases. Therefore, these treatments have known safety profiles and only require proof of benefit in severe and critically ill COVID-19 patients. Tocilizumab has been successful in a French trial. It is hoped that the availability of remdesivir and success of the immune modulators will improve survival in hospitalized severely ill patients over the next few months.

Studies to date have understandably focused on hospitalized patients to try to prevent death. However, rescue from mortality is not the only goal in fighting COVID-19; it is essential to reduce the spread of the virus. Once patients are hospitalized, they only contribute minimally to the development of new cases, primarily in hospital workers. Community not hospital transmission is the major mode of propagation of SARS-Cov-2. We face a dilemma in having no currently approved prevention or treatment for outpatients with mild to moderate disease, the chief spreaders of SARS-Cov-2. Shortages of testing supplies in the United States have thus far limited the ability to positively diagnose the disease, resulting in the recommendation of home quarantine for the majority of patients with suspicious symptoms. Those shortages are being rapidly remedied. Now, there is a need for therapy which can be used to treat outpatients with positive COVID-19 tests. The Marseille group has treated everyone with a positive test with a combination of HCQ and AZT and provided substantial clinical and virologic data but without a control group. The NYU group treated all hospitalized patients with HCQ and AZT and showed an im-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. .

There is no seasonal forcing; R0 was held constant at 2.2 (see fig. S12 for R0 = 2.6) . The effectiveness of social distancing varied from none to a 60% reduction in R0. Cumulative infection sizes are depicted beside each prevalence plot (F to J) with the herd immunity threshold (horizontal black bar). Of the temporary distancing scenarios, long-term (20-week), moderately effective (20%-40%) social distancing yields the smallest overall peak and total outbreak size.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. . https://doi.org/10.1101/2020.05.27.20115238 doi: medRxiv preprint 13 pressive effect of addition of zinc sulfate, but that was not in mild to moderate disease. They also had no control group for HCQ plus AZT. Remdesivir will be used primarily in severe disease and is administered intravenously, so not a practical outpatient treatment. Favipiravir is an oral tablet, like remdesivir an inhibitor of RNA polymerase, and is in the process of approval in Japan and now in Russia, but not in the United States. Trials with camostat, the serine protease inhibitor, capable of blocking cell entry of SARS-Cov-2 are not due to end till the third or fourth quarter of the year.

The vaccines have been the principal hope held out by public health authorities in the United States. Progress on vaccine development has been extremely rapid. Moderna prepared the sequence of their proposed mRNA-1273 vaccine on January 13 only two days after China shared the genetic sequence of SARS-Cov-2. On February 7, 2020, the first clinical batch of vaccine was completed and shipped on February 24 to the NIH for use in their Phase 1 clinical study. On March 16, 2020, the NIH announced that the first participant in its Phase 1 study was dosed. On May 7, a successful antibody response was documented.. The Company further reported that while a commercially-available vaccine is not likely to be available for at least 12-18 months, it is possible that under emergency use, a vaccine could be available to some people, possibly including healthcare professionals, in the fall of 2020.

In the United Kingdom, the Oxford vaccine ChAdOx1 nCoV-19, an attenuated adenovirus expressing the SARS-Cov-2 spike protein, reduced the viral load in a monkey model. A Phase II study involving 1090 healthy volunteers is underway. The INO-4800 DNA vaccine is in Phase I testing. In China, there are two inactivated SARS-Cov-2 vaccines in Phase I testing. One of the vaccines PiCoVacc has protected monkeys from infection (47) . Cansino is advancing its recombinant adenovirus vector vaccine Ad5-nCoV to Phase II testing. The rapid progress so far does not reduce the challenges of developing a vaccine to be administered to hundreds of millions of people (48) . Although neutralizing antibodies can be produced by the vaccine candidate, the goal is to prove protection from the infection. The demonstration of protection requires Phase III observation and long term follow-up of an exposed vaccinated population. The length of follow-up depends on the degree of active transmission of SARS-Cov-2 during the post vaccination period. No matter how rapidly a vaccine advances to Phase III testing, the duration of follow-up cannot be shortened. In the case of SARS-Cov-2, that follow-up will have to be prolonged due to two factors. First, there is a risk of immune enhancement of infection which occurs when induced antibodies increase entry and internalization of virus into myeloid cells (49) . This major complication struck the newly developed dengue vaccine in 2017 (50, 51) . Second, the sinister autoimmune pathogenicity of SARS-Cov-2 as evidenced by multisystem inflammatory disorder in children raises the risk of delayed long term harm if the virus is not fully and immediately eradicated by the initial vaccine associated immune response. Paradoxically, the large Chinese population is unlikely to serve to test any vaccine due to the success of COVID-19 containment in China For these reasons of needed long term safety observation, the deployment of an effective vaccine could be delayed for more than the 12-18 months currently contemplated. By that time, the primary pandemic may well be over due to infection of most of the world's population and ensuing herd immunity. The vaccine would then serve primarily to prevent a new resurgence. An alternative approach to immunization now is to increase the non-specific immune reaction to the initial infection. This suggestion was . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. . 14 first publicized in an opinion publication by Drs. Chumakov and Gallo in USA Today. They advocated vaccination with oral polio vaccine (46) . Oral polio vaccine is no longer as freely available as their alternative suggestion of BCG vaccine. BCG vaccine has demonstrated heterologous enhancement of immunity (52, 53) . There are very large prevention trials now being conducted in the Netherlands and Australia using BCG vaccination to increase innate immunity to SARS-Cov-2 in health care workers, but those are not due to complete until the fourth quarter of 2020.

COVID-19 has shaken societies throughout the world. The disease has imposed harsh opposing choices. The Chinese have shown that strict epidemiologic control is possible, but their approach has not been fully successful in Western countries where two months of social distancing and quarantine has devastated the economies. Yet, the alternative is continued spread of the virus by person to person contact. Similarly, there has been a contrast in the medical response comparing China to the Western countries. In China, empirical treatments have been offered and officially endorsed by the China National Health Commisson without proof of efficacy (54) . The treatment options they recommend include alpha interferon, LPV/R, chloroquine and umifenovir. They included tociluzimab therapy for patients with cytokine storm prior to the announcement of the CORIMMUNO-TOCI results. They also include many Chinese traditional medications. In comparison, the most recent CDC guidelines developed together with an NIH panel for treatment of COVID-19 now include only remdesivir as well as tocilizumab for severe disease. The U.S. panel recommends against the use of remdesivir for mild to moderate disease outside of a clinical trial. They find no evidence for or against the use of antimalarial drugs and strongly recommend against hydroxychloroquine combined with azithromycin. They strongly recommend against the use of LPV/R and other protease inhibitors. The NIH expert panel has further recommended against the use of interferon. They have no recommended treatments for outpatients.

Ironically, the Western world has much stricter requirements for acceptance of clinical treatments than does the highly regimented Chinese society. That is only one of many incongruities which are affecting the time course of delivering treatments to arrest the spread of SARS-Cov-2. Paradoxically, the success of the Chinese in strict epidemiologic control has jeopardized the completion of the randomized controlled trials begun in China. The remdesivir trials were suspended in China due to failure to accrue new infected patients. Since so many trials were ongoing in China the lack of patients may impair the ability to achieve statistical power to complete the studies. Similarly, the Chinese efforts to develop effective vaccines are affected by the need to demonstrate effectiveness in a population with ongoing exposure to COVID-19 which they no longer have.

On May 25, as this manuscript is being written, there were 100,733 new cases of COVID-19 and 4290 deaths worldwide, and in the United States, there were 24,151 new cases with 1852 deaths (1). Many clinical trials are currently underway. However, the transmission of SARS-Cov-2 has outraced the pace of development of new therapies. There is a need to offer treatment to infected individuals now. HCQ remdesivir, and tocilizumab have received emergency use authorization for severely ill patients. Hopefully, the mortality of COVID-19 will now be significantly reduced, but that alone will not suppress . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted June 2, 2020. . https://doi.org/10.1101/2020.05.27.20115238 doi: medRxiv preprint new infections and propagation of the disease. Hospitalized patients must be rescued, but the goal must be to prevent deterioration requiring hospitalization.

Efforts must now focus on treatments to interfere with the community transmission of the virus. The Marseille study treating patients early at the time of positive diagnosis of SARS-Cov-2 suggests a new emphasis on outpatient management. Favipiravir offers an oral counterpart to remdesivir to block viral propagation prior to hospitalization. The Hong Kong study suggests that interferon beta-1 which can be administered to outpatients has significant benefits in reducing viral replication. The success of oral zinc supplementation in the NYU study offers a simple treatment with minimal potential harm. Of course, none of these available treatments has been proven successful in randomized placebo controlled studies There are strong arguments to avoid emergency use of agents until trials are completed and analyzed, but the agents being tested are not new (55) . Most of them are drugs approved for other conditions with well known safety profiles, like camostat, a Japanese serine protease inhibitor, used for pancreatitis. BCG vaccination is still the norm for children in several countries. The conflict between clinical needs and the demand for rigorous proof of efficacy has resulted in curious events such as the President of the United States announcing that he is taking HCQ and zinc to prevent infection while the CDC and NIH have recommended against such treatment.

The projections suggest continued infections and deaths with a possible serious resurgence as social distancing restrictions are lifted. The Penn-Wharton Budget Model in the United States predicts that removing social distancing restrictions could result in 200,000 more deaths by June 30, but, conversely, save 18,000,000 lost jobs (56). We face these dismal choices if we lack the use of medications to prevent and to treat SARS-Cov-2 infections early before hospitalization. Epidemiologic containment of COVID-19 has not succeeded in the United States and most other countries. With social distancing measures now being relaxed, a large number of new cases and deaths will occur if treatments are not forthcoming in the near future. Several treatments of severe disease in hospitalized patients have now been granted emergency authorization. However, the disease is propagated primarily by infected ambulatory individuals. We have documented that 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.

There is a precedent to resolve the conflict between immediate clinical needs and the requirements for rigorous controlled trials to prove efficacy. We should remember that the greatest success in fighting a pandemic occurred over the past two decades in the battle against the HIV virus which causes AIDS. AIDS was first recognized in 1981 in the gay community (57) . The disease was a death sentence. By 1985, over 20,000 diagnoses and almost 10,000 deaths were recorded. There was widespread fear because there was no treatment, and projections of infection escalated into the millions. The first AIDS remedy was azidothymidine synthesized in 1964 in the hope that it would combat cancer. It was not successful. Twenty years later Dr. Samuel Broder, head of the National Cancer Institute, showed that the drug had activity against the HIV virus in vitro (58) . Burroughs Wellcome launched a rapidly conceived trial with just 300 patients. They stopped the trial in 16 weeks claiming that more patients survived on azidothymidine. The FDA came under enormous pressure from AIDS activists to make the drug available. Azidothymidine was approved by the FDA on March 19, 1987 with only that one trial.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 2, 2020. . https://doi.org/10.1101/2020.05.27.20115238 doi: medRxiv preprint It had taken 20 months for the FDA to give approval to release the drug. To this day, the design and results of that trial remain controversial.

The gay community continued to battle for early release of other medications to combat the AIDS pandemic. On October 11, 1988 , a massive protest occurred at the FDA. It was back then Dr. Anthony Fauci who publicly advanced the idea of a parallel track to make drugs widely available even while studies are progressing: " Clearly, the standard approach to the design of clinical trials-that is, rigid eligibility criteria as well as the strict regulatory aspects that attend clinical trial investigations and drug approval-was not well-suited to a novel, largely fatal disease such as this with no effective treatments, and we had many intense discussions about how to make that approach more flexible and ethically sound. One example, which I and others worked closely with the AIDS activists to develop, was called a parallel track for clinical trials. The parallel track concept, which the United States Food and Drug Administration ultimately came to support, meant that there would be the standard type of highly controlled admission criteria and data collection for the clinical trial of a particular drug. In parallel, however, the drug also could be made available to those who did not meet the trial's strict admission criteria but were still in dire need of any potentially effective intervention, however unproven, for this deadly disease" (59) .

The parallel track advocated by Dr. Fauci was adopted. Today there are 41 drugs or combinations approved by the FDA to treat and to prevent HIV infection. There is still no vaccine. There are now an estimated 1.1 million patients with HIV in the United States. Most have enjoyed near normal life expectancy thanks to the antiviral agents. The CDC has contributed greatly to limit the spread of HIV by advocating safe sex practices, but social distancing is not the norm for HIV. Rather pre-exposure prophylaxis endorsed by the CDC with a daily antiviral combination pill is currently adopted in wide segments of the at risk population (60) .

Dr. Fauci has recently launched an NIAID randomized controlled study of the HCQ plus AZT combination. Interferon beta is one of the randomized controlled Solidarity Trial options. Favipiravir is in trials at Massachusetts General Hospital as well as in Russia and Japan now. A randomized prevention trial with zinc and HCQ is about to begin in Tunisia, and zinc could be added to the NIAID HCQ plus AZT trial. It makes sense to now invoke the parallel track for outpatient use of interferon beta, favipiravir, and zinc while we await the eventual trial completions.

Nowhere is the decision more difficult than in the area of vaccination. The developers of several vaccines have made it clear that they can produce large quantities in a short time. Yet, it remains to be tested whether the immunity generated will be protective and, conversely, given the hyperinflammatory nature of SARS-Cov-2 infection, whether certain vaccines could actually be harmful. Acquiring conclusive answers will take a long experience. COVID-19 fueled by modern air travel, has engulfed the world, overwhelming containment, outspeeding well designed randomized placebo controlled clinical trials. We call on the public health authorities to make the parallel track immediately available. Cross . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted June 2, 2020. . international boundaries and accept data submitted in China and other countries, whether officially published or posted on line, and make promising agents available to treating physicians. If vaccines can be brought forward now, it is reasonable to authorize their use in very large parallel track studies in at risk populations, such as healthcare workers and the elderly. It is now necessary for public health authorities to make hard decisions despite limited current data.

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