Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects

Abstract

Background: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references.

Methods: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative.

Results: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001).

Conclusions: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 weeks. The decline in FVC in the placebo group was four-fold greater than in a hypothetical group of matched healthy references, whereas the decline in FVC in patients who received nintedanib was two-fold greater than in hypothetical healthy references. These data highlight the clinical relevance of the slowing of FVC decline provided by nintedanib. Trial registration Registered 5 November 2015, https://ichgcp.net/clinical-trials-registry/NCT02597933 .

Keywords: Connective tissue diseases; Pulmonary fibrosis; Scleroderma, systemic; Vital capacity.

Conflict of interest statement

TMM reports consulting fees from AstraZeneca, Bayer, Blade Therapeutics, BI, Bristol Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant Sciences, Roche/Genentech, Theravance Biopharma, Veracyte and payment for presentations from BI and Roche/Genentech. AB reports grants from AstraZeneca and BI; consulting fees from Amgen, AstraZeneca, BI, Chiesi, GlaxoSmithKline, Novartis, Regeneron, Sanofi; payment for presentations, speakers bureaus, or educational events, and support for attending meetings from AstraZeneca, BI, Chiesi, GlaxoSmithKline, Novartis, Regeneron; and participation on a Data Safety Monitoring Board or advisory board for AB Science. ERV reports grants from BI, Forbius, Kadmon, Horizon and fees from BI for serving on advisory boards and for presentations. SV reports consulting fees from BI. JHWD reports grants, consulting fees and payment for presentations, speakers bureaus, or educational events from BI and stock in 4D Science. MA and CS are employees of Boehringer Ingelheim. OD has received grants BI, Kymera, Mitsubishi Tanabe; consultancy fees from AbbVie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Bayer, Beacon, Blade Therapeutics, BI, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark Pharmaceuticals, Horizon Therapeutics (Curzion), Inventiva, Kymera, Lupin, Merck Sharp & Dohme, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Pfizer, Prometheus Biosciences, Roivant Sciences, Sanofi, Topadur; speaking fees from Bayer, BI, Janssen, Medscape; he holds patent US8247389 for the treatment of SSc; he is Chair of the Executive Committee of the FOREUM Foundation, co-chair of a ERS/EULAR guidelines committee, President of EUSTAR, a Member of the Board of Trustees for the Swiss Clinical Quality Management in Rheumatic Diseases and the Hartmann Müller Foundation, and a Senate member of the Swiss Academy of Medical Sciences.

© 2022. The Author(s).

Figures

Fig. 1

Schematic illustration of a the course of FVC decline in patients in the SENSCIS trial and healthy reference subjects and b the difference between effective lung age and actual age in subjects in the SENSCIS trial. In figure a, the black dashed line denotes the decline in FVC in the hypothetical healthy reference population; the coloured lines denote the decline in FVC in the nintedanib (blue) and placebo (grey) groups in the SENSCIS trial; the coloured vertical arrows denote the differences in FVC between the nintedanib (blue) and placebo (grey) groups in the SENSCIS trial and the hypothetical healthy reference population at week 52. In figure b, the black horizontal line denotes the difference between actual age and effective lung age at baseline; the coloured horizontal arrows denote the differences between actual age and effective lung age at week 52 in the nintedanib (orange) and placebo (purple) groups in the SENSCIS trial

Fig. 2

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched hypothetical healthy references. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height

Fig. 3

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched hypothetical healthy references in subgroups by mycophenolate use at baseline. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height

Fig. 4

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched hypothetical healthy references in subgroups by time since first non-Raynaud symptom. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height

Fig. 5

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched hypothetical healthy references in subgroups by FVC % predicted at baseline. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height

Fig. 6

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched healthy reference subjects in subgroups by cough at baseline. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height

Fig. 7

Change from baseline in FVC (mL) at week 52 in subjects in the SENSCIS trial versus matched hypothetical healthy references in subgroups by dyspnoea at baseline. Reference subjects were matched to the SENSCIS subjects for age, sex, ethnicity and height