The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

Effect and safety of combination of interferon alpha-2b and gamma or interferon alpha-2b for negativization of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial. (preprint)

Abstract Objectives: IFN-alpha2b and IFN-gamma combination has demonstrated favorable pharmacodynamics for genes underlying antiviral activity which might be involved in the defense of the organism from a SARS-CoV-2 infection. Considering this we conducted a randomized controlled clinical trial for efficacy and safety evaluation of subcutaneous IFN-alpha2b and IFN-gamma administration in patients positive to SARS-CoV-2. Methods: We enrolled 19-82 years-old inpatients at the Military Central Hospital Luis Diaz Soto, Havana, Cuba. They were hospitalized after confirmed diagnosis for SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction. Patients were randomly assigned in a 1:1 ratio to receive either, subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-alpha2b and 0.5 MIU IFN-gamma (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks, or thrice a week intramuscular injection of 3.0 MIU IFN-alpha2b (Heberon Alpha R, CIGB, Havana, Cuba). Additionally, all patients received lopinavir-ritonavir 200/50 mg every 12 h and chloroquine 250 mg every 12 h (standard of care). The primary endpoints were the time to negativization of viral RNA and the time to progression to severe COVID-19, from the start of treatment. The protocol was approved by the Ethics Committee on Clinical Investigation from the Hospital and the Center for the State Control of Medicines, Equipment and Medical Devices in Cuba. Informed consent was obtained from each participant. Results: A total of 79 patients with laboratory-confirmed SARS-CoV-2 infection, including symptomatic or asymptomatic conditions, fulfilled the inclusion criteria and underwent randomization. Thirty-three subjects were assigned to the HeberFERON group, and 33 to the Heberon Alpha R group. Sixty-three patients were analyzed for viral negativization, of them 78.6% in the HeberFERON group negativized the virus after 4 days of treatment versus 40.6% of patients in the Heberon Alpha R groups (p=0.004). Time to reach the negativization of the SARS-CoV-2 measured by RT-PCR in real time was of 3.0 and 5.0 days for the HeberFERON and Heberon Alpha R groups, respectively. A significant improvement in the reduction of time for negativization was attributable to HeberFERON (p=0.0027, Log-rank test) with a Hazard Ratio of 3.2 and 95% CI of 1.529 to 6.948, as compared to Heberon Alpha R treated group. Worsening of respiratory symptoms was detected in two (6.6%) and one (3.3%) patients in HeberFERON and IFN-alpha2b groups, respectively. None of the subjects transit to severe COVID-19 during the study or the epidemiological follow-up for 21 more days. RT-PCR on day 14 after the start of the treatment was negative to SARS-CoV-2 in 100% and 91% of patients of the combination of IFNs and IFN-alpha2b, respectively. Negativization for HeberFERON treated patients was related to a significant increase in lymphocytes counts and an also significant reduction in CRP as early as 7 days after commencing the therapeutic schedule. All the patients in both cohorts recover by day 14 and were in asymptomatic condition and laboratory parameters return to normal values by day 14 after treatment initiation. Adverse events were identified in 31.5% of patients, 28.5% in the control group, and 34.4% in the HeberFERON group, and the most frequent were headaches (17.4%). Conclusions: In a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly negativized the virus on day 4 of treatment when comparing with IFN-alpha2b. Heberon Alpha R also showed efficacy for the treatment of the viral infection. Both treatments were safe and positively impact on the resolution of the symptoms. None of the patients developed severe COVID-19. Key words: COVID-19, treatment, drug, virus negativization, antiviral, interferon combination, SARS CoV-2.

A SYSTEMATIC ANALYSIS OF THE TIME COURSE TO DEVELOP TREATMENTS FOR COVID-19 (preprint)

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

Phase II randomized controlled trial to evaluate the efficacy and safety of HeberFERON versus Heberon alpha R in symptomatic or asymptomatic patients infected with the SARS-CoV-2 (Study ESPERANZA/HOPE). (preprint)

Background: As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Results from in vitro studies suggest that a combination of IFN type I and Type II may be effective against SARS-CoV. The aim of this study is to investigate the efficacy of treatment with a recombinant IFN alpha 2b and gamma, provided with standard protocol (Kaletra (lopinavir-ritonavir 200/50 mg; 200/100 mg every 12 hour for 30 days; Chloroquine (250 mg) every 12 hours for 10 days) for COVID-19 patients, compared to standard protocol (IFN alpha 2b/Kaletra/Chloroquine) for COVID-19 hospitalized patients, positive diagnosed for SARS-Cov-2. Methods: Hospitalized adult patients with qPCR confirmed SARS-Cov-2 will be enrolled in this open-labeled, single center, prospective, randomized and controlled clinical trial. One hundred and twenty eligible patients with confirmed SARS-CoV-2 positivity by qPCR amplification in oropharyngeal/nasopharyngeal swab samples will be enrolled at “Luis Diaz Soto” Hospital, Havana, Cuba. The primary outcomes are the time to 2019-nCoV RNA negativity in patients and the time until progression to severe COVID-19. Discussion: This will be the first randomized controlled trial of a potential treatment for SARC-Cov-2 using the combinations of IFNs. Trial registration: The study is sponsored by Center for Genetic and Biotechnology and Ministry of Health of Cuba and was duly registered April 2020 at http://registroclinico.sld.cu/en/trials/RPCEC00000307-En. Enrolment for this study began in April 11, 2020, and has enrolled one hundred patients as of May-26-2020.