Efficacy and Safety of Danazol in Pulmonary Fibrosis Associated With Short Telomeres: A Phase 2 Randomized Clinical Trial

Abstract RATIONALE: Telomere attrition is identified in a significant number of patients with pulmonary fibrosis (PF) and is predictive of worse survival. Danazol, a synthetic sex hormone, has shown promise in telomere biology disorders but lacks randomized evidence in PF with short telomeres (PF-ST). The objective of the phase II TELO-SCOPE trial was to assess the ability of danazol to attenuate telomere attrition in PF-ST, to demonstrate biological plausibility for possible benefit in PF-ST. METHODS: TELO-SCOPE was a multi-centre, randomized, double-blind, placebo-controlled trial comparing danazol (up to 800mg daily) to placebo in adults and children with PF and peripheral blood lymphocyte telomere length ≤10th centile by flow fluorescent in situ hybridization (FISH). Participants were randomized 2:1 to danazol or placebo for 12 months. The primary endpoint was change in absolute telomere length at 12 months measured by the telomere shortest length assay (TeSLA). Secondary endpoints included safety data and clinical outcomes. RESULTS: Twenty-nine adults (24 male, median age 67 years) were randomized (danazol n=19, placebo n=10), 23 of whom had a diagnosis of idiopathic pulmonary fibrosis. Median baseline FVC% and DLCO% were 75% and 54% respectively. Seventeen participants completed the study to the 12 month endpoint, with 8 participants discontinuing treatment early, including 4 participants who underwent lung transplantation before 12 months, three of whom were on danazol. No participants died during follow-up. The study was terminated by the Data Safety and Monitoring Board for futility following analysis of the first 16 participants to complete 12-months of follow-up. At 12 months, median telomere length change was -80bp (IQR -28, 320) in the danazol group versus +115bp (IQR -110, 780) in the placebo group. The most common adverse event was ALT/AST elevation which occurred in 16 participants (15 on danazol). Two participants on danazol discontinued the study due to moderate-severe ALT/AST elevation. At 12 months, median change in FVC was -0.18L (IQR -0.44, 0.06) in the danazol group versus -0.13L (IQR -0.32, 0.08) in the placebo group. CONCLUSIONS: In this randomized trial of danazol in PF-ST, danazol did not attenuate telomere attrition compared to placebo at 12 months. The absence of a biological effect of danazol on telomere length in patients with PF, together with recent open label data, suggests that danazol is ineffective in PF-ST.