Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis, Cytisine versus Nicotine for Smoking Cessation, and FACED Score for Non–Cystic Fibrosis Bronchiectasis
Authors: Aaron Mulhall, Adam Cole, Sanjeevkumar Patel
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Idiopathic pulmonary fibrosis (IPF) is chronic, and ultimately fatal, lung scarring of unknown etiology characterized by dyspnea and progressive loss of lung function. Nintedanib is an intracellular inhibitor of various tyrosine kinases shown in a phase 2 trial to decrease the rate of decline of FVC in IPF (2). The INPULSIS study group conducted two replicate phase 3 trials (INPULSIS-1 and INPULSIS-2) to determine the efficacy and safety of nintedanib (150 mg twice daily) in patients with IPF. These trials were multinational, randomized, double-blind, placebo-controlled, parallel-group studies. Patients (1,066) were randomized in a 3:2 fashion (309 nintedanib and 204 placebo in INPULSIS-1; 329 nintedanib and 219 placebo in INPULSIS-2) to receive either nintedanib or placebo for 52 weeks. Inclusion criteria included the following: patient age, at least 40 years; high-resolution computed tomography (HRCT) within the previous 12 months; a diagnosis of IPF within the past 5 years, confirmed centrally by a single radiologist and single pathologist who reviewed the HRCT images (all patients) and lung biopsies (if available); FVC not exceeding 50% predicted, and diffusing capacity of the lung for carbon monoxide (DLCO) of 30–79% predicted. The primary end point was decline in FVC over 12 months, and secondary end points included time to first IPF exacerbation and change in the St. George’s Respiratory Questionnaire (SGRQ) score over 12 months. After 52 weeks, the annual rate of decline in FVC for INPULSIS-1 was 2114.7 ml with nintedanib versus 2239.9 ml with placebo (absolute difference, 125.3 ml; P , 0.001); for INPULSIS-2 it was 2113.6 ml with nintedanib versus 2207.3 ml with placebo (absolute difference, 93.7 ml; P , 0.001). In INPULSIS-1, there was no difference between groups in time to first IPF exacerbation (hazard ratio, 1.15; P = 0.67) or in the number of patients with an IPF exacerbation (6.1 vs. 5.4%). For INPULSIS-2, the nintedanib group had a significant increase in time to first IPF exacerbation (hazard ratio, 0.38; P = 0.005) and a smaller number of patients with at least one exacerbation (3.6 vs. 9.6%). In the pooled analysis there was no significant difference in exacerbations between INPULSIS and placebo groups (4.9 vs. 7.6%; P = 0.08). There was no difference in SGRQ scores in INPULSIS-1, but a significantly smaller increase in the SGRQ score in the nintedanib group (2.80 vs. 5.48 points; P = 0.02) was observed in INPULSIS-2. In the pooled analysis there was no significant difference in SGRQ scores between the INPULSIS and placebo groups (difference, 1.43; P = 0.09). The most frequent adverse event reported was diarrhea in both INPULSIS-1 (61.5%) and INPULSIS-2 (63.2%), leading to study drug discontinuation in 4.5% of INPULSIS-1 and 4.3% of INPULSIS-2 patients. This study was well designed, hit its primary end point, and supported the findings noted in the TOMORROW (To Improve Pulmonary Fibrosis with BIBF 1120) trial (2). There was, however, an inconsistent effect of nintedanib on exacerbation rates and SGRQ scores between INPULSIS-1 and INPULSIS-2, with the pooled analysis showing no significant difference between treatment and placebo groups. The differences in these secondary end points, unfortunately, cannot be explained by the patients’ baseline characteristics as they were similar. The variability in exacerbation rates can be explained by the paucity of exacerbations that occur in patients enrolled in clinical trials, as well as the difficulties with diagnosing and categorizing them; however, this reason does not account for the differences in SGRQ scores. Whereas almost two-thirds of patients receiving nintedanib had gastrointestinal side effects, less than 5% discontinued the drug. These data suggest that gastrointestinal side effects have little effect