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Abstract
Introduction The 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.
Methods To 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.
Results 723 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.
Conclusion Decline 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.