Phase III, Randomized, Double-Blind, Placebo Controlled Trial of Efficacy, Safety and Tolerability of Antiviral Drug Umifenovir vs Standard Care of Therapy in Non-Severe Covid-19 Patients

Abstract

SummaryBackground: SARS-Cov2 has caused millions of deaths worldwide and effective antivirals are not yet available. We evaluated the efficacy, tolerability and safety of Umifenovir, a drug used originally against influenza in Russia and China, in non-severe COVID19 adult patients from India. Method : A double-blind placebo controlled Phase III trial spread over 3 hospitals in Lucknow, India viz. King George’s Medical University, ERAs Lucknow Medical College and Ram Manohar Lohia Institute of Medical Sciences was carried out. RT-PCR confirmed COVID19 patients in the age group from 18-75 yrs. were recruited and further stratified into Mild-asymptomatic and Moderate cases. Exclusions included, pregnant or lactating women, severe patients, those suffering from Acute respiratory distress syndrome (ARDS), sepsis shock, requiring invasive ventilator support, ECMO or shock requiring vasopressor support, severe liver disease, severe renal impairment, comorbid conditions like asthma, diabetes with second-third line medicines as defined in the WHO guidance document. Patients were randomized 1:1 on placebo with standard care of therapy or Umifenovir (800 mg BID, maximum 14 days) with standard care of therapy respectively. Computerized randomization was carried out for each group separately through sequentially numbered, opaque, sealed envelopes (SNOSE) in block sizes of six and was administered independently through clinical-site coordinators and to have sufficient number of Mild-asymptomatic and moderate patients. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab negativity by two RT-PCR tests for SARS COV2 antigens taken 24 hrs apart from the date of randomization. For Moderate patients, the average change in the ordinal scale from the baseline scores from randomization on the eight-point ordinal scale as defined by WHO was calculated as the primary endpoint. This trial is registered with the Clinical Trial Registry of India (CTRI) Number: CTRI/2020/09/027535.Findings: A total of 132 patients were recruited in the trial after screening between 3rd October 2020 to 28th April 2021. Of these, 9 patients withdrew consent/ stopped medication on their own. The remaining 123 patients were almost equally distributed into Asymptomatic (35%), Mild (32%) and Moderate (33%) symptoms groups respectively. No Serious adverse events were noted in any of the patients. Only few minor events like headache, stomach ache and nausea were reported and this also was observed almost equally between the Umifenovir and Standard-of-care arms respectively. In the Primary endpoint corresponding to the Mild-asymptomatic patient group (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative on the 5th day (P=0.004), while only 40% patients in the placebo arm were negative. In the moderate group, the WHO scores for the Umifenovir arm corresponded to faster clinical improvement as compared to the Placebo arm (P=0.125 on day 3). In the Mild-asymptomatic group, the clinical improvement assessed by the WHO score on day 5 was statistically significant (P=0.019) in the Umifenovir arm compared to the placebo arm and agrees well with the primary endpoint results. Interpretation: Umifenovir is efficacious for Mild-asymptomatic patients and meets the primary and secondary endpoint criteria of the trial. The drug is safe and well tolerated at a dosage of 800 mg BID, maximum 14 days, in adult patients. It exhibits faster time to cure with median 5 days (95%CI, 5-14) in Umifenovir group and median 7 days (95%CI, 5-14) for the placebo group. In moderate patients, administration of Umifenovir co-relates with faster clinical recovery, albeit with less statistical significance. In future studies, the drug should be evaluated as a prophylactic in high-risk adults, and for efficacy in children and pregnant/lactating women.