Transdermal 17β-Estradiol for the Treatment of COVID-19: Protocol of an Early Terminated Phase 2 Randomized Controlled Trial.

TL;DR

Early-terminated Phase 2 RCT of transdermal 17β-estradiol for COVID-19 in 29 men and postmenopausal women demonstrated good tolerability with no safety signals, but recruitment fell far short of targets due to declining disease severity and vaccination rates, preventing efficacy assessment.

Key findings

• Study was terminated early with only 29 enrolled participants (13 standard care, 16 estradiol plus standard care) versus anticipated larger sample size, due to reduced hospitalized COVID-19 cases from widespread vaccination and policy changes
• Transdermal 17β-estradiol was well tolerated with no adverse safety signals or thromboembolic events reported in the treatment group
• Theoretical rationale for estrogen therapy included immunomodulation and ACE2 downregulation, based on initial epidemiological observations of better outcomes in women on estrogen therapy
• Study was underpowered to assess efficacy outcomes; adequately powered trials would be needed to determine therapeutic potential of estrogen for COVID-19 or other ACE2-mediated viral illnesses

Why this matters at the bedside

Limited clinical relevance due to early termination and lack of efficacy data. Findings are primarily supportive of transdermal estradiol's safety profile in acute COVID-19, with potential operational lessons for pandemic trial conduct.