Randomized controlled trial of pirfenidone XR for patients with COVID-19 and exploration of effects on long-COVID incidence.

Abstract

Objective: Evaluate safety and efficacy of extended-release pirfenidone (pirfenidone-XR), an anti-inflammatory and anti-fibrotic agent, as an early treatment for acute and long-term effects of COVID-19.

Methods: This double-blinded, placebo-controlled trial randomized hospitalized and ambulatory COVID-19 patients in Mexico City 2:1 to pirfenidone-XR or placebo. The primary endpoint was recovery dynamics using a clinical severity 7-point ordinal scale; secondary and exploratory endpoints included long COVID incidence and safety. Planned enrollment was 801 patients to detect a 50% relative-risk reduction in key clinical outcomes.

Results: Between May 2020 and May 2021, 367 patients were enrolled, approximately 50% of the target. Evolving standards of care resulted in early termination and lower-than-anticipated event rates, limiting statistical power. Time-to-recovery analyses suggested improved dynamics with pirfenidone-XR: both groups had 53% full recovery by week 1; an additional 33% vs 21% achieved it during week 2, and 97% vs 90% by week 4. Long-term follow-up showed a numerically lower incidence of long COVID symptoms in 1, 2, 3 and 4 symptom domains in the pirfenidone-XR group: symptoms in ≥4 domains were reported in 5% vs 21% of hospitalized patients. There were no unexpected safety signals.

Conclusions: Pirfenidone-XR was well tolerated and, although underpowered, demonstrated numerical trends of improved recovery and reduced long COVID risk. These findings support further investigation of pirfenidone-XR in patients infected with SARS-CoV-2 and similar post-infectious syndromes characterized by persistent immune activation and tissue remodeling.