Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial

Abstract

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Keywords: antifibrotic medication; forced vital capacity; futility analysis; interstitial lung disease; linear mixed-effects model.

Figure 1.

CONSORT flow diagram. *One patient in the placebo arm received a partial dose of zinpentraxin alfa. This patient was included in the full analysis set in the zinpentraxin alfa group for safety analyses and in the placebo group for the efficacy analyses.

Figure 2.

Absolute change from baseline to Week 52 in (A) FVC, (B) percent predicted FVC (%FVC), and (C) 6-minute-walk distance (6MWD) (full analysis set). Estimates for 6MWD are from analyses with a random coefficient regression model using unstructured covariance matrix of random intercept and random slope. The following terms are included in the model: age, sex, height, time, treatment × time, concurrent idiopathic pulmonary fibrosis (IPF) treatment, and region for FVC and 6MWD; time, treatment × time, concurrent IPF treatment, and region for %FVC. CI = confidence interval.

Figure 3.

Post hoc analysis of phase II FVC data: distribution of FVC slopes (ml/yr) by assigned treatment arm. Boxplots show the interquartile range of FVC slope (ml/yr), and data points in the boxplots represent individual patients who were treated with placebo or zinpentraxin alfa. Horizontal lines represent the median FVC slope in each arm. Circled data points show the three patients (two from the placebo arm, one from the zinpentraxin alfa arm) who had an FVC decline of >1,000 ml/yr. IPF = idiopathic pulmonary fibrosis.