Introduction Nintedanib slows disease progression in patients with idiopathic pulmonary fibrosis (IPF) by reducing the rate of decline in forced vital capacity, with an adverse event profile that is manageable for most patients. We used data from six clinical trials to characterise the safety and tolerability profile of nintedanib and to investigate its effects on survival.
Methods Data from patients treated with ≥1 dose of nintedanib 150 mg two times per day or placebo in the 52-week TOMORROW trial and/or its open-label extension; the two 52-week INPULSIS trials and/or their open-label extension, INPULSIS-ON; and a Phase IIIb trial with a placebo-controlled period of ≥6 months followed by open-label nintedanib were pooled. All adverse events, irrespective of causality, were included in descriptive analyses. Parametric survival distributions were fit to pooled Kaplan-Meier survival data from the trials and extrapolated to estimate long-term survival.
Results There were 1126 patients in the pooled nintedanib group and 565 patients in the pooled placebo group. The mean duration of nintedanib treatment was 28 months. No new safety signals were observed. Incidence rates of bleeding, liver enzyme elevations and cardiovascular events were consistent with those observed in the INPULSIS trials. Diarrhoea was reported at a lower event rate in the pooled nintedanib group than in nintedanib-treated patients in the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years) and infrequently led to permanent treatment discontinuation (3.6 events per 100 patient exposure-years). Based on the Weibull distribution, mean (95% CI) survival was estimated as 11.6 (9.6, 14.1) years in nintedanib-treated patients and 3.7 (2.5, 5.4) years in placebo-treated patients.
Conclusions Based on pooled data from six clinical trials, the adverse event profile of nintedanib was manageable for most patients. Exploratory analyses based on extrapolation of survival data suggest that nintedanib extends life expectancy in patients with IPF.
- interstitial fibrosis
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Contributors All authors were involved in planning the analyses, in the interpretation of data and in drafting the manuscript.
Funding The trials that provided data for these analyses were funded by Boehringer Ingelheim.
Competing interests LLa has served on advisory boards for Genentech, Global Blood Therapeutics, Boehringer Ingelheim, Veracyte, Theravance, Magnolia Therapeutics, Galapagos and Bellerophon; has provided disease state education for Genentech and Boehringer Ingelheim; has served as a principal investigator in clinical trials in IPF and other ILDs for Genentech, Global Blood Therapeutics, Celgene, FibroGen, Stromedix, Veracyte, Afferent, Merck, Bellerophon, Novartis, Galapagos, Galecto, the National Institutes of Health and Boehringer Ingelheim. BC has received grants from Apellis and MedImmune; grants and personal fees from Boehringer Ingelheim and Roche; and personal fees from AstraZeneca and Sanofi. PH has served on advisory boards for Actelion, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Teva and Trudell; served as a principal investigator in clinical trials in IPF for Boehringer Ingelheim and Prometic; and provided disease state education in IPF/ILDs for Boehringer Ingelheim and Roche. YI has served on advisory boards for Boehringer Ingelheim and reports lecture and advisory fees from Boehringer Ingelheim, Shionogi & Co, Ltd, Takeda, Nobel Pharma, Novartis, Serendex, Bayer, Chugai and Daiichi Sankyo. LR has served on advisory boards for Anthera, Asahi-Kasei, AstraZeneca, Bayer, Boehringer Ingelheim, Biogen Idec, FibroGen, GlaxoSmithKline, ImmuneWorks, InterMune, MedImmune, PatientsLikeMe, Promedior, Roche, Sanofi-Aventis, Takeda and UCB; received grants from InterMune, the Italian Ministry of Health, the National Drug Agency (Italy), the National Research Council (Italy) and Roche; and received speaker fees from Boehringer Ingelheim, Cipla, InterMune and Roche. DW, LLo, MQ and SS are employees of Boehringer Ingelheim.
Patient consent for publication Not required.
Ethics approval All clinical trial protocols were approved by an independent ethics committee or institutional review board at every participating institution.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data are available uponon request. A request can be submitted via https://trials.boehringer-ingelheim.com/trial_results/clinical_submission_documents.html.
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