Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi
Bharti Wadhwa, Vikas Malhotra, Sukhyanti Kerai, Farah Husain, Nalini Bala Pandey, Kirti N Saxena, Vinay Singh, Tom M Quinn, Feng Li, Erin Gaughan, Manu Shankar-Hari, Bethany Mills, Jean Antonelli, Annya Bruce, Keith Finlayson, Anne Moore, Kevin Dhaliwal, Christopher Edwards
doi:10.1101/2022.07.01.22277163
Background: In this phase 2 randomised placebo-controlled clinical trial, we hypothesised that blocking mineralocorticoid receptors with spironolactone in patients with COVID-19 is safe and may reduce illness severity.
Methods: Hospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50mg day 1, then 25mg once daily for 21 days) or standard care in a 2:1 ratio. Both groups received dexamethasone 6mg for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF). Results: 120 patients were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had lower aldosterone levels on day 7 and lower D-dimer levels on days 4 and 7 (day 7 D-dimer mean SpiroDex 1.15μg/mL, Dex 3.15 μg/mL, p = 0.0004). There was no increase in adverse events in patients receiving SpiroDex. Post hoc analysis demonstrated reduced clinical deterioration (pre specified as escalating to WHO OS category >4) in the SpiroDex group vs Dex group (5.4% vs 19.6%).
Conclusion: Low dose oral spironolactone in addition to dexamethasone was safe and reduced D-Dimer and aldosterone. Although time to recovery was not significantly reduced, fewer patients progressed to severe disease. Phase 3 randomised controlled trials with spironolactone should be considered.
Author Contributions BW & VM were chief investigators of the study and responsible for all trial related activities. BW, VM, SK, FH, NP, KS, VS contributed to the implementation of the study and all study related activities in Delhi. KF, AM, JA, AB, contributed to study support and resource allocation. TQ, LF analysed the blinded data. TQ, LF, BM, MS-H, CE and KD contributed to the interpretation of the data. All authors assisted with the writing of the paper and reviewed and approved the final manuscript.
Conflict of interests The authors have no conflict of interests.
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