A safer option to hydroxychloroquine in the chemoprophylaxis of COVID-19 in high-risk health- care workers: A randomized controlled, non-inferiority trial
Authors: Chopra Arvind , Rao Prasanna Kumar , Reddy R. Govind , Gundeti Manohar , Choudhary Kuldeep , Lakadwalla Muzaffal , Saluja Manjit , Tamoli Sanjay , Tillu Girish , Sarmukaddam Sanjeev , Gode Dilip , Raut Ashwinikumar , Chandrasekhararao Bhogavalli , Khanduri Shruti , Srikanth N. , Patwardhan Bhushan 
Published: September 2021

Objectives: Comparative study of Ashwagandha (Withania somnifera; WS) and hydroxychloroquine (HCQ) for chemoprophylaxis against COVID-19 in actively engaged high-risk health-care workers. Design: Randomized, multicentric, open label, active control, two arm parallel efficacy study of 16 weeks. Sample size was based on pre-set 15% non-inferiority margin to HCQ for prophylaxis against COVID-19 with 80% power and alpha &lt; 0.05. Participants: 400 health-care workers from three sites who were asymptomatic and tested negative for a quantitative Reverse Transcription Polymerase Chain Reaction test (RT-PCR) for COVID-19 and SARS-CoV-2 antibodies (IgG) were randomized in a 1:1 ratio. Participants observed physical protection measures as per the national policy. All incident confirmed COVID-19 were withdrawn.Interventions: Two tablets of 250 mg standardized aqueous extract of WS, twice daily after meal or HCQ 800 mg loading followed by 400 mg weekly for 16 weeks as per the national guidelines. Main outcome measures: The primary efficacy measure was “failure of prophylaxis” as confirmed by RT-PCR at any time during the study. Both intention-to-treat (ITT) and per-protocol (PP) efficacy analyses were performed.Results: 95 participants in the Ashwagandha (WS) arm and 101 participants in the HCQ arm completed the study. Both groups were well matched at the baseline. 91 participants from the Ashwagandha arm and 84 from the HCQ arm were withdrawn because they received the COVID-19 vaccination. Four participants (2%; 95% CI 2.8 to 3.9%) in the Ashwagandha and 5 (2.5%; 95% CI 5.4 to 8%) in the HCQ arm developed confirmed COVID-19. This was within the prefixed non-inferiority margin and the 95% CI of the absolute risk reduction (ARR) was -2.9 to 3.8% intention to treat (ITT) and -5.9 to 7.5% per protocol (PP). The 95% CI of ARR for the total COVID-19 cases was -2.8 to 11.9% ITT and -5.7 to 20.3% PP. Several health measures, particularly anxiety and stress, improved significantly in the Ashwagandha arm. Seven out of 117 in the Ashwagandha and 59 out of 178 in the HCQ groups were reported to be possible drug-related adverse events (AE); there were significantly less gut-related AE in the Ashwagandha group. AE were mostly mild and did not cause withdrawal. All incident COVID-19 cases recovered without complications. Conclusions: Ashwagandha was non-inferior to HCQ in the chemoprophylaxis against COVID-19 in high risk health-care workers. It was significantly safer, well tolerated and improved quality of life measures. Ashwagandha as COVID-19 prophylaxis seems appropriate in high-risk populations. Trial registration: The Clinical Trials Registry India Number CTRI/2020/08/027163 dated August 14, 2020.