Progesterone in Addition to Standard of Care Versus Standard of Care Alone in the Treatment of Men Admitted to the Hospital with Moderate to Severe COVID-19: A Randomised Control Phase 1 Trial

Background: Severity of illness and mortality from coronavirus disease 2019 (COVID-19) is consistently lower in women than in men. While this outcome difference is not well understood, focus on sex as a biologic factor may suggest potential therapeutic intervention for this disease. We assessed whether adding progesterone, a steroid hormone with immune-modulatory properties, to standard of care, would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. Method: We conducted a Phase 1, randomised, open-label, controlled trial at a large academic hospital in Los Angeles, CA, USA, of subcutaneous progesterone in men hospitalized with confirmed COVID-19 and evidence of lower respiratory tract involvement. Patients were randomly assigned (1:1), using block randomization and a computer-generated randomization sequence, to receive standard of care (SOC) plus progesterone (100 mg subcutaneously twice daily for up to five days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status based on a 7-point ordinal scale noted at baseline compared to that on Day 7 of the trial. Control patients with significant clinical deterioration or absence of clinical improvement by Day 7 were permitted to cross over to receive progesterone therapy. Intention to treat analysis was performed and the patient’s last clinical assessment prior to receiving the study drug was imputed as the Day 7 assessment. Findings: Forty-two patients were enrolled in the study from April 27 to August 20, 2020; 22 were randomised to the control group and 20 to the progesterone group. Of the 20 patients in the progesterone group, two withdrew from the study prior to receiving progesterone and were excluded from analysis. There was an overall improvement in clinical status from baseline to Day 7 in patients in the progesterone group as compared to controls (95% CI: 0-2; P = 0·010). There were no serious adverse events attributable to progesterone. Interpretation: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to standard of care may represent a safe and novel approach for the treatment in men with moderate to severe COVID-19. Trial Registration: This trial was registered at ClinicalTrials.gov, NCT04365127. Funding Statement: The Institut Biochimique SA (IBSA, Lugano, Switzerland) Declaration of Interests: SG, YM, SP, TK, DN, JH, SC, RIG, JM, CB, ML, VT report grants and nonfinancial support from Institut Biochimique SA (IBSA, Lugano, Switzerland), during the conduct of the study; SG,SP report patent pending on method of use of progesterone agonist for treatment of COVID-19 VT reports grants from NIH/NIAID ACTT (ACTT 1-3), outside the submitted work. DS, HG declare no competing interests. Ethics Approval Statement: This study was approved by the Cedars-Sinai Institutional Review Board (IRB).