Progesterone in Addition to Standard of Care vs Standard of Care Alone in the Treatment of Men Hospitalized With Moderate to Severe COVID-19: A Randomized, Controlled Pilot Trial

Abstract

Background: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19.

Research question: Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19?

Study design and methods: We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes.

Results: Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects.

Interpretation: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19.

Trial registry: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.

Keywords: COVID-19; progesterone; sex difference in COVID-19 outcomes.

Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Participant flow in a randomized clinical trial of progesterone vs standard of care in men with moderate to severe COVID-19.

Figure 2

Cumulative probability of improvement or discharge on day 7. During the first seven study days, the cumulative probability of clinical improvement (an increase of at least one point on the seven-point scale or live discharge) was significantly higher in the progesterone group, 0.76 (95% CI, 0.55-0.93) vs 0.55 (95% CI, 0.28-0.68) in the control group (log-rank P = .014), by Kaplan-Meier estimation. One patient in the progesterone group showed improvement on day 2 but was subsequently noncompliant with study protocols and was transferred to another facility. For the purpose of this analysis, this patient was excluded.