IntroductionThe two replicate, randomised, placebo-controlled, 52-week INPULSIS® trials assessed the efficacy and safety of nintedanib 150 mg twice daily (bid) in patients with IPF. The primary endpoint was met in both trials; nintedanib significantly reduced the annual rate of decline in FVC compared with placebo, consistent with a slowing of disease progression.MethodsTo qualify for the INPULSIS® trials if a surgical lung biopsy was unavailable, patients needed to have a high-resolution computed tomography (HRCT) scan showing honeycombing and/or a combination of reticular abnormality and traction bronchiectasis, without features suggestive of alternative causes. Surgical lung biopsies, if available, were used to confirm eligibility. A post-hoc subgroup analysis of patients with diagnosis based on honeycombing and/or confirmation of usual interstitial pneumonia (UIP) by biopsy versus patients with no honeycombing and no biopsy was undertaken using pooled data from both trials.Results723 patients (425 nintedanib, 298 placebo) had honeycombing and/or confirmation by biopsy and 338 (213 nintedanib, 125 placebo) had no honeycombing or biopsy for diagnosis of IPF. Demographics and baseline characteristics were similar between these subgroups. In patients with honeycombing and/or biopsy, the adjusted annual rate of decline in FVC was -108.7 mL/year with nintedanib and -225.7 mL/year with placebo (difference: 117.0 mL/year [95% CI: 76.3, 157.8]); in patients with no honeycombing or biopsy, it was -122.0 mL/year with nintedanib and -221.0 mL/year with placebo (difference: 98.9 mL/year [95% CI: 36.4, 161.5]). The treatment by subgroup interaction p-value was not significant for the primary endpoint (p = 0.81) or for the key secondary endpoints of time to first acute exacerbation (p = 0.37) or change from baseline in St George’s Respiratory Questionnaire total score (p = 0.67), indicating that the treatment effect of nintedanib was not statistically significantly different between the subgroups.Abstract S106 Figure 1 ConclusionDecline in FVC in placebo arms was virtually identical in patients with A) the presence of honeycombing and/or biopsy confirmation of UIP; and B) the absence of both, but features of “possible UIP” on HRCT. Nintedanib slowed FVC decline equally in both sub-groups. These findings have major implications for diagnosis and clinical trial design.
BackgroundSafety data on combined pirfenidone and nintedanib use are limited.MethodsA single-arm, open-label study (NCT02598193) assessed safety and tolerability of 24 weeks’ pirfenidone (1602–2403 mg/day) and nintedanib (200–300 mg/day) in patients with idiopathic pulmonary fibrosis (IPF) with forced vital capacity (FVC) ≥50% and diffusing capacity of the lung for carbon monoxide (DLco) ≥30%. Before initiating nintedanib, patients had received pirfenidone for ≥16 weeks and tolerated a stable dose of ≥1602 mg/day pirfenidone for ≥28 days. Investigators recorded treatment-emergent adverse events (TEAEs), attributing them to pirfenidone, nintedanib, both or neither. Change from baseline FVC, DLco and King’s Brief Interstitial Lung Disease (K-BILD) score were assessed at 24 weeks. The study is monitored by a data monitoring committee.ResultsEighty-nine patients were enrolled. A pre-specified interim analysis was conducted once 63 patients (mean age 68.7 years, 85.7% male) completed (n=50) or discontinued (n=13) 24 weeks’ combination treatment. Fifty patients had 330 treatment-related TEAEs (Table); 11 patients discontinued due to TEAEs. Two patients had serious treatment-related TEAEs (Table) but none led to death. Final Results for all 89 patients, including change from baseline FVC, DLco and K-BILD score, will be presented at BTS.ConclusionsCombined pirfenidone and nintedanib use for 24 weeks did not reveal a different safety profile to that expected for either treatment alone. Patients had tolerated a stable dose of pirfenidone before initiation of nintedanib, which may explain why investigators attributed more TEAEs to nintedanib than pirfenidone.FundingF. Hoffmann-La Roche, Ltd./Genentech, Inc.Abstract M31 Table 1Summary of safety profile at the pre-specified interim analysis
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