ASPIRE Trial in Idiopathic Pulmonary Fibrosis: A Patient Experience-focused Phase 2b Randomized, Double-blind, Placebo-controlled, Multicenter Trial of the Novel Angiotensin II Type 2 Receptor Agonist Buloxibutid

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a severe, progressive respiratory illness. Despite available antifibrotics, the high morbidity is still a major burden to people affected and mortality is increasing, reflecting the need for new therapies. In the absence of novel validated endpoints, phase 2 trials in IPF require repeated lung function measures to determine efficacy. Frequent site visits are a burden to patients and may discourage trial participation. Buloxibutid (C21) is an oral, selective angiotensin II type 2 receptor agonist, driving an upstream repair pathway that improves alveolar epithelial type 2 cell function, triggers anti-fibrotic pathways, and resolves disease-associated vascular remodeling. In a phase 2a clinical trial (AIR), buloxibutid increased forced vital capacity (FVC) over 36 weeks. With the aim to reduce hurdles for participation, a patient and caregiver panel was established during design of the phase 2b trial of buloxibutid to advise on trial design, conduct and patient-facing materials. Here we report the effect on trial design of engaging a patient-caregiver panel. Methods and Results: ASPIRE (NCT06588686) is a randomized, double-blind, placebo-controlled, 52-week trial investigating efficacy and safety of two doses of buloxibutid with placebo. The trial will include 270 participants with IPF confirmed by central read of high-resolution computed tomography (HRCT), FVC ≥50% predicted and diffusing capacity of carbon monoxide ≥35% predicted, who are on a stable dose of nintedanib or currently not treated. The trial schedule, combining site and remote visits, is shown below. Participants will receive randomized treatment with buloxibutid 50 mg, buloxibutid 100 mg, or placebo given orally twice daily. The primary endpoint is change in FVC from baseline and the key secondary endpoint is a composite of ≥10 FVC % predicted decline, respiratory hospitalization, or death. Other secondary endpoints include acute exacerbations, health-related quality of life and symptoms, and quantitative analyses of HRCT parameters. Semi-structured interviews will be conducted by an independent interviewer for a subgroup of participants to provide feedback on the trial participation experience and, if applicable, amend operational aspects, and provide insights to be considered in future trials. Conclusions: The ASPIRE trial is designed to provide robust evidence of efficacy and safety of the novel angiotensin II type 2 receptor agonist buloxibutid in IPF, while using patient and caregiver experiences to enable easy participation. Collecting direct participant feedback on trial experience is a novel approach to provide insights that may support patients’ wishes to enroll and remain in clinical trials.