ABSTRACT
Background: To improve the management of SARS-Co2 infection there is an urgent unmet need for an orally administered antiviral drug to prevent disease progression, hospitalization, and clinical complications. Molnupiravir was developed in response to this need. This study assesses its efficacy and safety in Indian patients with mild SARS-CoV2 infection. Methods: This study is a phase III multi-centre open label randomized controlled trial of oral molnupiravir plus standard of care (MOL/SOC) versus SOC alone in Indian adults with mild SARS-CoV2 infection. The molnupiravir formulation used was developed and manufactured by HETERO LABS LTD, Hyderabad, India, under license from MERCK INC, NJ, USA. Eligible patients with RT PCR-confirmed mild SARS CoV2 infection, uncomplicated upper respiratory tract infection, with mild symptoms without any evidence of breathlessness, were randomized 1:1 to either oral MOL 800 mg b.i.d. for 5 days plus SOC or SOC alone. The primary endpoint was rate of hospitalization up to day 14. Secondary endpoints included proportion with a 2-point improvement in WHO 11-Point Clinical Progression Scale and rate of SARS CoV2 RT PCR negativity in naso/oropharyngeal swab at day 5, 10 and 14 and incidence of adverse events. Results: Of 1284 patients screened, 1218 were eligible and randomized, 608 to MOL+SOC, and 610 to SOC. The population consisted mainly of male patients (68%). Both arms were well balanced for age, height and weight. In the MOL/SOC arm 9 patients (1.5%) required hospitalisation vs. 26 (4.3%) in the SOC arm (p<0.01). In the MOL/SOC arm 80.8%, 95.6% and 97.4% had clinical improvement by Day 5, 10 and 14, respectively, compared to 32.1%, 74.3% and 94.1% in the SOC arm (p<0.0001 at day 5 and 10, and <0.01 at day 14). The rate of SARS CoV2 negativity was 77.1%, 91.3% and 93.9% in MOL/SOC vs. 29.3%, 70.2% and 89.0% in SOC at day 5, 10 and 14, respectively (p<0.001). There were no serious adverse events. Mild and self-limiting adverse events occurred in 4.8% of MOL/SOC and 2.6% of SOC participants. The most common adverse events were neurological (headache, somnolence) and gastrointestinal. Conclusion: A lower rate of hospitalisation, earlier clinical improvement, and earlier SARS CoV2 RT PCR negativity document superiority of Molnupiravir to SOC in mild SARS-CoV2 infection in this trial in India. Molnupiravir was well tolerated: adverse events were mild and rare.
ABSTRACT
Background: Tocilizumab is an IgG1 class humanized monoclonal antibody targeting IL-6 receptor (IL-6R). IL-6 is a key cytokine involved in cytokine storm of severe COVID-19. Tocilizumab down-regulates IL-6 preventing fatal and permanent damage to vital organs, significantly preventing COVID-19 related mortality and morbidity. Therefore, this study aimed to compare the efficacy and safety of Tocilizumab (biosimilar) developed by Hetero Biopharma Ltd, India vs reference medicinal product (RMP)-Tocilizumab manufactured by Roche in cytokine storm of severe COVID-19 pneumonia. Methods: This multicenter, randomized, double-blind, active-controlled study enrolled patients aged 18 to 65 years, with laboratory-confirmed, hospitalized, severe COVID-19 disease with elevated inflammatory markers not on mechanical ventilation. Patients were randomized (3:1 ratio) to receive either Test-Tocilizumab (Test) 8 mg/kg or RMP-Tocilizumab 8mg/kg, maximum 800mg, administered once on day 1. The primary endpoint was the cumulative proportion of patients requiring mechanical ventilation by Day 14. Secondary endpoints included 28 day mortality rate, proportion of patients with a 2-point decrease in WHO ordinal scale, time to clinical failure (death or required mechanical ventilation or withdrawn), change in inflammatory markers (CRP, IL-6, Ferritin and D-dimer) and duration of hospital stay in days. Safety endpoints included the incidence of adverse events;the proportion of patients discontinued the study due to adverse events and the incidence of any post-treatment bacterial and/or fungal infection. Results: Out of 211 patients screened, 172 patients were randomized (131 to Test and 41 to RMP) to receive Tocilizumab 8mg/kg. Patients were similar in both groups at baseline in terms of age, gender, weight etc. Fourteen (10.69%) patients in Test and 5 (12.20%) patients in RMP progressed to mechanical ventilation by Day 14 (p=0.7789). Overall, 9 (7.83%) patients died in Test vs 5 (13.16%) in RMP during 28 days follow up (p=0.3382). Clinical improvement was seen 62.60% and 77.10% vs 53.66% and 73.17% in Test vs RMP at day 14 and 28 respectively. The time to clinical failure was 6 vs 5 days and time to clinical improvement was 11 vs 11.5 days. Hospitalization duration was 12.9 versus 13.8 days in the Test and RMP. ARDS, Insomnia and Pain were most commonly reported adverse events. Conclusion: Tocilizumab biosimilar is comparable with RMP-Tocilizumab in preventing mechanical ventilation in severe COVID19 pneumonia patients.