23265205, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.41576 by Readcube (Labtiva Inc.), Wiley Online Library on [13/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Arthritis & Rheumatology Vol. 73, No. 4, April 2021, pp 671–676 DOI 10.1002/art.41576 © 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Effect of Nintedanib on Lung Function in Patients With Systemic Sclerosis−Associated Interstitial Lung Disease: Further Analyses of a Randomized, Double-Blind, ­ Placebo-Controlled Trial Toby M. Maher,1 Maureen D. Mayes,2 Michael Kreuter,3 Elizabeth R. Volkmann,4 Martin Aringer,5 6 7 Ivan Castellvi, Maurizio Cutolo, Christian Stock, Nils Schoof, Margarida Alves, and Ganesh Raghu,10 8 9 9 on behalf of the SENSCIS Trial Investigators Objective. In the SENSCIS trial in subjects with systemic sclerosis–associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. Methods. In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death. Results. A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to ≤10% predicted, and 3.5% and 5.2% had a decline in FVC of >10% to ≤15% predicted; 34.5% and 43.8% had a decrease in FVC of ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66−1.06) (P = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43−0.95) (P = 0.029). Conclusion. These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD. INTRODUCTION progressive fibrosis of the skin and internal organs (1). Interstitial lung disease (ILD) is a common manifestation of SSc and the lead- Systemic sclerosis (SSc) is a rare and heterogeneous auto- ing cause of death in subjects with SSc (2). The course of SSc-­ immune disease characterized by microvascular damage and associated ILD (SSc-ILD) is unpredictable, but a decline in forced ClinicalTrials.gov identifier: NCT02597933. speaking fees, and/or honoraria from Boehringer Ingelheim, Corbus, Eicos Supported by Boehringer Ingelheim. Sciences, Galápagos, and Mitsubishi Tanabe (less than $10,000 each). Dr. 1 Toby M. Maher, MD: National Heart and Lung Institute, Imperial College Kreuter has received consulting fees, speaking fees, and/or honoraria from London and NIHR Clinical Research Facility, Royal Brompton Hospital, London, Boehringer Ingelheim and Roche (less than $10,000 each). Dr. Volkmann has UK, and Keck School of Medicine, University of Southern California, Los Angeles; received consulting fees, speaking fees, and/or honoraria from Boehringer 2 Maureen D. Mayes, MD: University of Texas McGovern Medical School, Houston; Ingelheim (more than $10,000). Dr. Aringer has received consulting fees, 3 Michael Kreuter, MD: Thoraxklinik University of Heidelberg, and the German speaking fees, and/or honoraria from Boehringer Ingelheim (less than Center for Lung Research, Heidelberg, Germany; 4Elizabeth R. Volkmann, MD: $10,000). Dr. Castellvi has received consulting fees, speaking fees, and/or University of California, David Geffen School of Medicine, Los Angeles; 5Martin honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Janssen-Cilag, Aringer, MD: University Medical Center and Faculty of Medicine Carl Gustav Carus, Roche, and Sanofi (less than $10,000 each). Dr. Cutolo has received consulting TU Dresden, Dresden, Germany; 6Ivan Castellvi, MD: Hospital de la Santa Creu i fees, speaking fees, and/or honoraria from Bristol Myers Squibb (less than Sant Pau, Barcelona, Spain; 7Maurizio Cutolo, MD: University of Genova, IRCCS $10,000). Drs. Stock, Schoof, and Alves are employees of Boehringer Ingelheim. San Martino Polyclinic Hospital, Genova, Italy; 8Christian Stock, PhD: Boehringer Dr. Raghu has received consulting fees, speaking fees, and/or honoraria from Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 9Nils Schoof, Roche-Genentech (less than $10,000) and from Boehringer Ingelheim (more PhD, Margarida Alves, MD: Boehringer Ingelheim International GmbH, Ingelheim than $10,000). am Rhein, Germany; 10Ganesh Raghu, MD: University of Washington, Seattle. Address correspondence to Toby M. Maher, Keck School of Medicine, Dr. Maher has received consulting fees, speaking fees, and/or honoraria University of Southern California, Los Angeles, CA 90033. Email: toby.maher@ from AstraZeneca, Blade Therapeutics, Boehringer Ingelheim, Bristol Myers med.usc.edu. Squibb, Galápagos, GlaxoSmithKline, Indalo, Pliant, Respivant, Roche, and Submitted for publication March 17, 2020; accepted in revised form Theravance (less than $10,000 each). Dr. Mayes has received consulting fees, October 29, 2020. 671 23265205, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.41576 by Readcube (Labtiva Inc.), Wiley Online Library on [13/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 672 | MAHER ET AL vital capacity (FVC) in subjects with SSc-ILD is an indicator of ILD End points. The following were assessed in the nintedanib progression and is associated with mortality (3−7). While there is and placebo groups based on data at week 52: the proportion of no established definition for progression of ILD, in 2015, the Out- subjects with categorical absolute declines or increases in FVC come Measures in Rheumatology (OMERACT) connective tissue % predicted or categorical relative declines or increases in FVC disease−associated ILD (CTD-ILD) Working Group agreed that a (milliliters) (as listed in the Results section); the proportion of sub- relative decline in FVC % predicted of ≥10%, or a relative decline jects who met proposed thresholds for minimal clinically important in FVC % predicted of ≥5% to <10% with a relative decline in dif- differences (MCID) for improvement in FVC (absolute increase of fusing capacity for carbon monoxide (DLco) % predicted ≥15%, ≥3.0% predicted), stable FVC (absolute increase of <3.0% pre- represents clinically meaningful progression of SSc-ILD (8). dicted or decrease of <3.3% predicted), and worsening of FVC Nintedanib, an intracellular inhibitor of tyrosine kinases (9), has (absolute decrease of ≥3.3% predicted) based on data from been approved in many countries for the treatment of idiopathic Sclero­derma Lung Studies I and II, anchored to the health tran- pulmonary fibrosis (IPF) and SSc-ILD. Clinical trials in subjects with sition question from the Medical Outcomes Study Short Form-36 IPF (INPULSIS) (10), with SSc-ILD (SENSCIS) (11), and with vari- (16); and time to 1) an absolute decline in FVC of ≥5% predicted or ous forms of progressive fibrosing ILDs (INBUILD) (12), including death; 2) an absolute decline in FVC of ≥10% predicted or death; progressive autoimmune disease-related ILDs (13), have shown and 3) an absolute decline in FVC of ≥10% predicted or absolute that nintedanib reduces the rate of decline in FVC (milliliters/year). decline in FVC of ≥5% to <10% predicted with an absolute decline The objective of the current analyses was to investigate the effects in DLco of ≥15% predicted, or death. The proportions of subjects of nintedanib on categorical changes in FVC and other measures who met proposed thresholds for improvement in FVC, stable of ILD progression in subjects with SSc-ILD in the SENSCIS trial. FVC, and worsening of FVC at week 52 were also assessed in subgroups defined by the following baseline characteristics: FVC of <80% versus ≥80% predicted, extent of fibrotic ILD on HRCT of PATIENTS AND METHODS <20% versus ≥20%, time since onset of first non−Raynaud’s phe- Trial design. The design of the SENSCIS trial (ClinicalTrials.­ nomenon symptom ≤3 versus >3 years, and glucocorticoid use. gov identifier: NCT02597933) has been published previously, together with the trial protocol (11). Briefly, eligible subjects had Statistical analysis. Analyses were conducted post hoc in SSc with onset of first non−Raynaud’s phenomenon symptom <7 subjects who received ≥1 dose of trial medication (intention-to-treat). years before screening, extent of fibrotic ILD ≥10% on a high-­ The proportions of subjects with categorical declines or increases resolution computed tomography (HRCT) scan (based on assess- in FVC % predicted and FVC measured in milliliters at week 52, ment of the whole lung), FVC ≥40% predicted, and DLco of the lung and the proportions of subjects who met proposed thresholds for (corrected for hemoglobin) 30–89% predicted. Subjects receiv- improvement in FVC, stable FVC, and worsening of FVC at week ing prednisone ≤10 mg/day or equivalent and/or stable therapy 52 were compared between treatment groups using a Cochran- with mycophenolate or methotrexate for ≥6 months prior to ran­ Mantel-Haenszel test, stratified by anti–topo I antibody status. domization were allowed to participate. Spirometers were provided In the subgroup analyses, the proportions of subjects who met to the sites and the results were confirmed centrally. Spirometry proposed thresholds for improvement in FVC, stable FVC, and was performed in accordance with guidelines issued by the Amer- worsening of FVC at week 52 were compared between treatment ican Thoracic Society and European Respiratory Society (14), groups using a logistic regression model, including trial medication including daily calibration of the spirometer. Percent predicted (nintedanib/placebo), anti–topo I antibody status, subgroup, and values for FVC were calculated using the Global Lung Initiative treatment-by-subgroup interaction as terms. Missing values were equations based on the subject’s age, sex, race, and height (15). imputed using a worst value carried forward approach. Exploratory The method used to measure DLco and the equation used to cal- interaction P values were calculated to assess potential heteroge- culate percent predicted values for DLco were chosen by the site. neity in the treatment effect of nintedanib versus placebo across the Subjects were randomized 1:1 to receive nintedanib subgroups. Time-to-event end points were analyzed based on data 150 mg twice a day or placebo, stratified by the presence of anti− from 52 weeks (± 7 days) using a Cox regression model with a term topoisomerase I (anti–topo I) antibodies. Subjects could con- for treatment and stratified by anti–topo I antibody status. Analyses tinue to receive treatment in a blinded manner until the last subject were not adjusted for multiplicity. Hazard ratios (HRs) or odds ratios had reached week 52, but for ≤100 weeks. Subjects who dis- and 95% confidence intervals (95% CIs) were calculated. continued treatment prematurely were asked to remain in the trial and attend visits as originally planned. The trial was conducted in RESULTS accordance with the trial protocol, the principles of the Declara- tion of Helsinki, and the International Council for Harmonisation Characteristics of the study subjects. A total of Guidelines for Good Clinical Practice, and was approved by local 576 subjects received ≥1 dose of trial medication (288 authorities. All subjects provided written informed consent. received nintedanib and 288 received placebo). The baseline 23265205, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.41576 by Readcube (Labtiva Inc.), Wiley Online Library on [13/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EFFECT OF NINTEDANIB ON LUNG FUNCTION IN SSc-ILD | 673 Figure 1. Proportions of subjects with systemic sclerosis–associated interstitial lung disease (SSc-ILD) treated with nintedanib or placebo in the SENSCIS trial who had the indicated absolute increases and declines in forced vital capacity (FVC) % predicted at week 52. A post-baseline FVC measurement was not available for 1 patient. characteristics of subjects in the SENSCIS trial have been placebo group with an absolute decline in FVC of >5% to ≤10% described previously (11). The mean ± SD age was 54.0 ± 12.2 predicted and an absolute decline in FVC of >10% to ≤15% years, 75.2% of subjects were female, and 67.2% were White. predicted were 20.1% and 5.2%, respectively (Figure 1). The The mean ± SD FVC was 2,500 ± 777 milliliters and 72.5 ± 16.7 proportions of subjects who met thresholds for relative declines % predicted, and the mean ± SD DLco was 53.0 ± 15.1 % pre- or increases in FVC (in milliliters) are shown in Supplementary dicted. Baseline characteristics were similar between the treat- Figure 1 (available on the Arthritis & Rheumatology website at ment groups (11). http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41576/​abstract). In the nintedanib and placebo groups, respectively, 34.5% Categorical changes in FVC % predicted. In total, 46 versus 43.8% of subjects had an absolute decrease in FVC of subjects (16.0%) in the nintedanib group and 31 subjects (10.8%) ≥3.3% predicted at week 52 (the proposed MCID for worsening in the placebo group had missing FVC data at week 52. At week of FVC), while 23.0% versus 14.9% had an absolute increase 52, 55.7% of subjects in the nintedanib group and 66.3% of sub- in FVC of ≥3.0% predicted at week 52 (the proposed MCID for jects in the placebo group had a decline in FVC % predicted. At improvement in FVC) (Figure 2). Exploratory interaction P values week 52 the proportions of subjects in the nintedanib group with did not indicate heterogeneity in the effect of nintedanib versus an absolute decline in FVC of >5% to ≤10% predicted and an placebo between subgroups classified by FVC % predicted, absolute decline in FVC of >10% to ≤15% predicted were 13.6% extent of fibrotic ILD on HRCT, time since onset of first non−­ and 3.5%, respectively, while the proportions of subjects in the Raynaud’s phenomenon symptom at baseline, or glucocorticoid Figure 2. Proportions of subjects with SSc-ILD treated with nintedanib or placebo in the SENSCIS trial who met the proposed threshold for worsening of FVC (decrease of ≥3.3% predicted), stable FVC (increase of <3.0% predicted or decrease of <3.3% predicted), or improvement in FVC (increase of ≥3.0% predicted) at week 52. A post-baseline FVC measurement was not available for 1 patient. OR = odds ratio; 95% CI = 95% confidence interval (see Figure 1 for other definitions). 23265205, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.41576 by Readcube (Labtiva Inc.), Wiley Online Library on [13/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 674 | MAHER ET AL Table 1. Proportions of subjects with absolute declines in FVC % predicted or death over 52 weeks in the SENSCIS trial* Nintedanib (n = 288) Placebo (n = 288) Absolute decline in FVC ≥5% predicted or death Subjects with event, no. (%) 124 (43.1) 145 (50.3) Hazard ratio (95% confidence interval) 0.83 (0.66−1.06) P 0.14 Absolute decline in FVC ≥10% predicted or death Subjects with event, no. (%) 40 (13.9) 62 (21.5) Hazard ratio (95% confidence interval) 0.64 (0.43−0.95) P 0.03 Absolute decline in FVC ≥10% predicted or absolute decline in FVC ≥5% to <10% predicted with absolute decline in DLco ≥15% predicted, or death Subjects with event, no. (%) 39 (13.5) 69 (22.9) Hazard ratio (95% confidence interval) 0.58 (0.39−0.87) P 0.008 * FVC = forced vital capacity; DLco = diffusing capacity for carbon monoxide. use (P > 0.05 for treatment-by-subgroup interactions) (Sup- progression of SSc-ILD. Although there is no established defi- plementary Figure 2, available on the Arthritis & Rheumatology nition for the progression of ILD, declines in FVC of >10% pre- website at http://onlin​elibr​ary.wiley.com/doi/10.1002/art.41576/​ dicted have been used to assess the proportion of subjects with abstract). clinically relevant ILD progression in previous studies of SSc-ILD (6,7) and other ILDs (17−20), based on the association between Time to lung function decline or death. Over 52 weeks, decline in FVC and mortality. In addition, thresholds for improve- an absolute decline in FVC of ≥5% predicted or death occurred ment and worsening of FVC, derived based on anchoring to the in 43.1% of the subjects in the nintedanib group and 50.3% of health transition question from the Medical Outcomes Study the subjects in the placebo group (HR 0.83 [95% CI 0.66−1.06]; Short Form-36 in the Scleroderma Lung Studies I and II, have P = 0.14), and an absolute decline in FVC of ≥10% predicted or been proposed as MCIDs at a population level (16). In a recent death occurred in 13.9% of the subjects in the nintedanib group European Delphi consensus study, physicians experienced in and 21.5% of the subjects in the placebo group (HR 0.64 [95% the management of SSc-ILD agreed that the progression of SSc- CI 0.43−0.95]; P = 0.029) (Table 1 and Figure 3). Over 52 weeks, ILD can be assessed using changes in % predicted values for an absolute decline in FVC of ≥10% predicted, absolute decline in FVC and DLco and that measurement of lung function is an effec- FVC of ≥5% to <10% predicted with an absolute decline in DLco tive tool in long-term follow-up of ILD progression in patients with of ≥15% predicted, or death occurred in 13.5% and 22.9% of SSc-ILD (21). subjects in the nintedanib and placebo groups, respectively (HR Several studies have shown that a decline in FVC is associ- 0.58 [95% CI 0.39−0.87]; P = 0.008) (Table 1). ated with mortality in patients with SSc-ILD. A study of 171 patients at a single center showed that patients who died within 4 years of SSc-ILD diagnosis had a higher annual rate of decline in FVC than DISCUSSION those who died between 4 and 8 years after their SSc-ILD diagno- These findings from the SENSCIS trial provide further evi- sis or who survived for >8 years (22). Data from Sclero­derma Lung dence that nintedanib has a clinically relevant effect on the Study I (n = 158) showed that absolute declines in FVC of ≥10% Figure 3. Time to A, absolute decline in FVC of ≥5% predicted or death and B, absolute decline in FVC of ≥10% predicted or death, over 52 weeks in patients with SSc-ILD treated with nintedanib or placebo in the SENSCIS trial. See Figure 1 for definitions. 23265205, 2021, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.41576 by Readcube (Labtiva Inc.), Wiley Online Library on [13/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License EFFECT OF NINTEDANIB ON LUNG FUNCTION IN SSc-ILD | 675 predicted or DLco of ≥15% predicted over 2 years were asso- In conclusion, these further analyses of FVC decline in the ciated with mortality over a median follow-up period of 8 years, SENSCIS trial support a clinically meaningful effect of nintedanib while data from Scleroderma Lung Study II (n = 142) showed that on slowing the progression of SSc-ILD. an absolute decline in FVC of ≥10% predicted at 1 year was asso- ciated with mortality over a median follow-up period of 4 years ACKNOWLEDGMENTS (7). In a large cohort of subjects in the European Scleroderma We would like to thank the subjects who participated in this trial. Trials and Research (EUSTAR) database (n = 857), an absolute decline in FVC of ≥10% predicted, or an absolute decline in FVC AUTHOR CONTRIBUTIONS of ≥5% predicted with a decline in DLco of ≥15% predicted, over All authors were involved in drafting the article or revising it critically 12 months was predictive of mortality over a maximum follow-up for important intellectual content, and all authors approved the final version period of 5 years (5). Recent data from a well-characterized Nor- to be published. Dr. Maher had full access to all of the data in the study wegian cohort (n = 391) showed that ILD progression defined and takes responsibility for the integrity of the data and the accuracy of the data analysis. as severe (absolute decline in FVC of >10% predicted or decline Study conception and design. Maher, Mayes, Stock, Schoof, Alves, Raghu. in FVC of 5−10% predicted with decline in DLco of ≥15% pre- Acquisition of data. Maher, Mayes, Kreuter, Aringer, Castellvi, Cutolo. dicted) or moderate (absolute decline in FVC of 5−10% predicted Analysis and interpretation of data. Maher, Mayes, Kreuter, Volkmann, Aringer, Castellvi, Cutolo, Stock, Schoof, Alves, Raghu. with decline in DLco of <15% predicted) over a mean follow-up period of almost 4 years was associated with lower survival com- pared with stable FVC (change <5% predicted), with 10-year ROLE OF THE STUDY SPONSOR survival rates of 59% versus 78% (6). In a long-term UK study of Boehringer Ingelheim was involved in the design of the study, the 162 patients, a relative decline in FVC (in milliliters) of ≥10%, or a interpretation of the data, and the writing of the manuscript. The au­­thors had relative decline in FVC (in milliliters) of 5–9% with a relative decline the final decision to submit the manuscript for publication. Writing assistance was provided by Julie Fleming and Wendy Morris (FleishmanHillard Fishburn, in DLco of >15% at 1 year was strongly associated with mortality London, UK; supported financially by Boehringer Ingelheim). over 15 years (4). Subgroup analyses of the data from the SENSCIS trial suggest that the proportions of subjects who met proposed REFERENCES thresholds for worsening and improvement in FVC were con- 1. Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall sistent across subgroups based on FVC % predicted, time A, et al. 2013 classification criteria for systemic sclerosis: an American since onset of first non−Raynaud’s phenomenon symptom, College of Rheumatology/European League against Rheumatism ­collaborative initiative. Arthritis Rheum 2013;65:2737–47. extent of fibrotic ILD on HRCT, and glucocorticoid use at base- 2. Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman line. Previous analyses have shown that the proportions of sub- A, et al. 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