J. Maringwa (1), E. Cox (1), L. Harnisch (2) and X. Gao (3)
(1) Quantitative Solutions BV, Breda, The Netherlands (2) Global Pharmacometrics, Pfizer Inc, Sandwich, UK; (3) Clinical Pharmacology, Pfizer Inc, Groton, USA.
Objectives: (1) To perform a model-based meta-analysis of comparative effectiveness of various drugs investigated in treating IPF patients, and to assess the effect of trial- and patient disease variables on drug treatment effect. (2) To simulate expected treatment- and trial performance in IPF.
Methods: Publicly available longitudinal summary level data of clinical efficacy outcomes (forced vital capacity, FVC % predicted) from 7 drugs in 11 placebo-controlled IPF trials (2,834 patients) were analyzed using an asymptotic repeated measures regression model to describe the time course of treatment effect (drug, dose) on FVC. A non-parametric placebo model was used to account for heterogeneity in the time course of placebo effect, both between- and within trials.
Results: Significant, time-dependent treatment effects on FVC were identified for pirfenidone and the investigational compound BIBF1120 and for the latter so in a linear dose dependent manner. No statistically significant treatment effect was observed for the other drugs (etanercept, interferon-gamma, sildenafil, bosentan, and azathioprine). Patient disease variables such as baseline FVC values did not appear to impact treatment effect in a significant manner. The maximum estimated treatment effect is 3.29- and 5.14% for pirfenidone and 300mg/day BIBF1120, respectively, while the estimated time to achieve 50% of this maximum effect for both drugs is ~15 weeks. For BIBF1120 doses of 200mg/day and higher, a larger treatment effect on FVC compared to pirfenidone is expected. Trial simulations suggest that a trial with mean baseline FVC of 70%, duration of 52 weeks, and enrolling 40 patients per group will have a power of ~80% to detect a treatment effect of 1.53%.
Conclusions: Pirfenidone and BIBF1120 slow down the decline of lung function (FVC) in IPF patients in a significant manner. At doses of 200mg/day and higher, the effect of BIBF1120 on FVC decline is expected to be larger than for pirfenidone. Model-based simulations allowed exploring several trial design aspects.
Reference: PAGE 21 (2012) Abstr 2422 [www.page-meeting.org/?abstract=2422]
Poster: Study Design