Op0124 effects of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease Associated With Rheumatoid Arthritis (Ra-Ild) in the Inbuild Trial

Abstract

Background:In the INBUILD trial in subjects with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 57% compared with placebo.Objectives:To assess the rate of decline in FVC in subjects with RA-ILD in the INBUILD trial.Methods:Subjects in the INBUILD trial had a chronic fibrosing ILD other than IPF, reticular abnormality with traction bronchiectasis (with or without honeycombing) of >10% extent on high-resolution computed tomography (HRCT), forced vital capacity (FVC) ≥45% predicted, diffusing capacity of the lungs for carbon monoxide ≥30%–<80% predicted, and met criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Patients taking stable doses of approved medications to treat RA or connective tissue disease could participate, except that the protocol excluded those taking azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, rituximab, cyclophosphamide, or oral glucocorticoids >20 mg/day. We analysed the rate of decline in FVC (mL/year) over 52 weeks and adverse events in subjects with RA-ILD.Results:Of 663 subjects who received trial medication, 89 had RA-ILD (42 nintedanib, 47 placebo), of whom 60.7% were male, 64.0% were current or former smokers, 86.5% had a usual interstitial pneumonia (UIP)-like pattern on HRCT; 93.3% had received confirmation of their RA diagnosis from a rheumatologist. At baseline, 21.3% of subjects were taking biologic disease-modifying anti-rheumatic drugs (DMARDs), 53.9% were taking non-biologic DMARDs and 73.0% were taking glucocorticoids (≤20 mg/day prednisone or equivalent). At baseline, mean (SD) age was 66.9 (9.6) years, time since RA diagnosis was 9.9 (9.4) years, time since ILD diagnosis was 3.6 (3.2) years, FVC was 71.5 (16.2) % predicted and C-reactive protein was 13.7 (22.5) mg/L. The adjusted mean (SE) rate of decline in FVC over 52 weeks was -82.6 (41.3) mL/year in the nintedanib group versus -199.3 (36.2) mL/year in the placebo group (difference 116.7 mL/year [95% CI 7.4, 226.1]; nominal p=0.037), consistent with findings in the overall trial population (Figure). As in the overall trial population, the most common adverse event in subjects with RA-ILD was diarrhoea (reported in 54.8% of the nintedanib group and 25.5% of the placebo group). Adverse events led to permanent discontinuation of trial drug in 19.0% of subjects in the nintedanib group and 12.8% of subjects in the placebo group.Conclusion:In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing RA-ILD, with adverse events that were manageable for most patients. The efficacy and safety of nintedanib in subjects with RA-ILD were consistent with those observed in the overall trial population.Acknowledgements:The INBUILD trial was funded by Boehringer Ingelheim. Medical writing support was provided by Fleishman Hillard Fishburn, London, UK. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Disclosure of Interests:Clive Kelly Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Eric Matteson Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim and Gilead Sciences, Grant/research support from: Sun Pharmaceuticals and Pfizer, Martin Aringer Speakers bureau: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Gilead, GlaxoSmithKline, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB, Consultant of: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and UCB, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp & Dohme, Pfizer, Roche and Sanofi, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Lilly, Merck Sharp & Dohme, Pfizer, Roche and Sanofi, Heiko Mueller Employee of: Currently an employee of Boehringer Ingelheim, Lizette Moros Employee of: Currently an employee of Boehringer Ingelheim, Klaus Rohr Employee of: Currently an employee of Boehringer Ingelheim, Martin Kolb Consultant of: Algernon, Boehringer Ingelheim, Pieris Pharmaceuticals and Roche, Grant/research support from: Boehringer Ingelheim, Pieris Pharmaceuticals and Prometic

A Randomized, Double-Blinded, Placebo-Controlled, Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with Rheumatoid Arthritis Interstitial Lung Disease

“…Our placebo group had an average FVC decline of 146 ml over 52 weeks. Though markedly less than subjects with IPF in the placebo groups in ASCEND (428 ml/yr) (14) and INPULSIS (239.9 ml/yr and -207.3 ml/yr in INPULSIS 1 and 2 respectively) (50), this decline is closer to that seen in INBUILD (187.8 ml/yr in all subjects (27) and 199.3 ml/yr in subjects with RA-ILD (51)) and RELIEF (114.4 ml/yr) (52). These two trials enrolled subjects with evidence of progression prior to enrollment, and similar progression over time in our placebo group supports the idea that RA with fibrotic ILD is a progressive fibrosing interstitial lung disease.…”

Interstitial lung disease in rheumatoid arthritis: A multidisciplinary problem in rheumatology and pulmonology

“…Завершены крупные РПКИ нинтеданиба у больных ССД-ИЗЛ (SENSCIS; n=576) [90,[186][187][188][189][190][191][192] и другими СЗСТ-ИЗЛ, включая РА-ИЗЛ (INBUILD; более 600 пациентов) [193][194][195][196] и ИФЛ (TOMORROW, INPULSIS) [197], в которых продемонстрировано замедление отрицательной динамики показателей ФЖЕЛ в группах нинтеданиба по сравнению с плацебо (ПЛ) в общей популяции пациентов с ИЗЛ и ССД-ИЗЛ и в подгруппе пациентов с аутоиммунными заболеваниями. При субанализе данных РПКИ INBUILD была выделена группа пациентов (n=89) с РА-ИЗЛ (42 пациента получали нинтеданиб, 47 -ПЛ).…”

“…Средний возраст пациентов составил 66,9 года, 60,7% были мужчинами, 64% -курильщиками, 85,6% страдали ОИП (по данным КТВР). 21,3% обследованных получали ГИБП, 53,9% -БПВП, 73,0% -ГК (≤20 мг/день) [196]. Как видно из рисунка 1, замедление снижения ФЖЕЛ в такой же степени имело место в группе пациентов с РА-ИЗЛ, как и у всех включенных в РПКИ пациентов.…”

Danggui Niantong decoction ameliorates joint inflammation and cardiopulmonary injury in TNF-Tg mice

“…Currently, in addition to glucocorticoids with or without immunosuppressive therapy, drugs for the primary treatment of cardiopulmonary diseases are used to manage RA complications. For example, the anti-fibrotic drug nintedanib, which is used to treat RA-ILD, has been proven to slow down the rate of decline in forced vital capacity in patients with progressive fibrotic RA-ILD [17] . Similarly, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are primarily used in patients with RA hypertension [18] .…”