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In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. Suppl 1 ( 2022-06), p. 1457.1-1457

Abstract: Unfavourable effects observed after administration of placebo that may be attributed to factors such as expectation or conditioning are known as nocebo effects. Prior to initiation of the SENSCIS trial, diarrhoea was a known side-effect of nintedanib. Objectives To investigate whether a nocebo effect contributed to reporting of diarrhoea in the SENSCIS trial. Methods The SENSCIS trial enrolled patients with systemic sclerosis (SSc) with first non-Raynaud symptom in the prior ≤7 years and ≥10% extent of fibrotic ILD on high-resolution computed tomography. Patients were randomised to receive nintedanib or placebo until the last patient had reached week 52 but for ≤100 weeks. A follow-up visit was conducted 28 days after the end of treatment. Adverse events were reported by investigators irrespective of causality and coded according to the Medical Dictionary for Regulatory Activities. We analysed the incidence of diarrhoea adverse events in the on-treatment period ( i.e., events with onset between the first intake of trial drug intake and the last intake plus 7 days) and in the post-discontinuation period ( i.e., events with onset between the first day after the on-treatment period and the end of the follow-up period) in the nintedanib and placebo groups. Incidence rates were calculated as the number of patients with diarrhoea adverse events divided by the time at risk. Results In the on-treatment period (time at risk: 277.8 patient-years), the rate of diarrhoea adverse events in the placebo group (n=288) was 33.1 per 100 patient-years. In the post-discontinuation period (time at risk: 41.9 patient-years), the rate of diarrhoea adverse events in the placebo group (n=284) was 19.1 per 100 patient-years. In the on-treatment period (time at risk: 105.1 patient-years), the rate of diarrhoea adverse events in the nintedanib group (n=288) was 209.3 per 100 patient-years. In the post-discontinuation period (time at risk: 53.7 patient-years), the rate of diarrhoea adverse events in the nintedanib group (n=283) was 5.6 per 100 patient-years. Conclusion In the SENSCIS trial in patients with SSc-ILD, the rate of diarrhoea adverse events in the placebo group fell after trial drug was discontinued. This suggests that a nocebo effect may have contributed to the diarrhoea adverse events reported in the SENSCIS trial. Acknowledgements The SENSCIS trial was funded by Boehringer Ingelheim. Oliver Distler, Kristin B Highland and Arata Azuma were members of the SENSCIS trial Steering Committee. Disclosure of Interests Oliver Distler Speakers bureau: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Speaker fee: Bayer, Boehringer Ingelheim, Janssen, Medscape , Consultant of: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Consultancy fee: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur OD has/had relationships with the following companies in the area of potential treatments for arthritides in the last three calendar years: Consultancy fee: Abbvie , Grant/research support from: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Research Grants: Boehringer Ingelheim, Kymera, Mitsubishi Tanabe , Kristin Highland Speakers bureau: Actelion Pharmaceuticals (Jansen), Bayer Healthcare, Boehringer Ingelheim, United Therapeutics, Paid instructor for: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Gilead Sciences, United Therapeutics, Consultant of: Boehringer Ingelheim, Forsee Pharmaceuicals, Genentech, United Therapeutics, Grant/research support from: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Genentech, Gossamer Bio, Eiger Pharmaceuticlas, Lilly Pharmaceuticals, Reata Pharmaceuticals, United Therapeutics, Viela Bio (Horizon Pharmaceuticals), Arata Azuma Speakers bureau: AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Consultant of: Boehringer Ingelheim, Kyorin Pharma, Taiho Co., Toray Medical Co., Grant/research support from: Boehringer Ingelheim, Taiho Co., Corinna Miede Employee of: Corinna Miede is an employee of mainanalytics GmbH that is contracted by Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Petros Sfikakis: None declared

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2022-eular.749

Language: English

Publisher: BMJ

Publication Date: 2022

detail.hit.zdb_id: 1481557-6

In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. Suppl 1 ( 2022-06), p. 1456-1456

Abstract: Gastrointestinal (GI) involvement is a common manifestation of systemic sclerosis (SSc) and a frequent side-effect of drugs used to treat SSc. In the SENSCIS trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease (SSc-ILD), with an adverse event profile characterised predominantly by GI events. Objectives To assess the severity and impact of GI symptoms on quality of life in patients treated with nintedanib in the open-label extension trial, SENSCIS-ON. Methods Patients with SSc-ILD who completed the SENSCIS trial or a drug–drug interaction (DDI) study of nintedanib and oral contraceptive were eligible to enter SENSCIS-ON. Patients who received nintedanib in SENSCIS (up to 100 weeks) and continued nintedanib in SENSCIS-ON comprised the “continued nintedanib” group. Patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON, or who received nintedanib for a short time in the DDI study, comprised the “initiated nintedanib” group. We assessed changes in scores on the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) questionnaire v2.0 from baseline to week 52. This questionnaire comprises 7 scales measuring the severity and impact of GI symptoms: reflux, distension or bloating, faecal soilage, diarrhoea, constipation, emotional well-being, social functioning. Each scale is scored from 0 to 3 except for the diarrhoea scale (0 to 2) and constipation scale (0 to 2.5). The total score, the mean of the scores for the scales except constipation, ranges from 0 to 2.83, with higher scores indicating worse symptoms. Results The “continued nintedanib” group comprised 197 patients and the “initiated nintedanib” group comprised 247 patients (231 from SENSCIS). Of these, 178 and 218 patients, respectively, provided a total UCLA SCTC GIT score at baseline. At baseline, mean (SD) total scores were 0.33 (0.33) and 0.33 (0.34) in the continued nintedanib and initiated nintedanib groups, respectively. Mean (SD) scores on the 7 scales ranged from 0.16 (0.52) to 0.70 (0.73) in the continued nintedanib group and from 0.13 (0.43) to 0.64 (0.68) in the initiated nintedanib group. Increases (worsening) in scores were observed in both groups from baseline to week 52, except for on the constipation scale (Figure 1). Based on the total score, between baseline and week 52, the proportion of patients with moderate or severe or very severe GI symptoms increased, but 45.7% and 39.7% of patients in the continued nintedanib and initiated nintedanib groups, respectively, had no or mild GI symptoms at week 52 (Table 1). Table 1. Changes in severity and impact of gastrointestinal symptoms based on UCLA SCTC GIT total score between baseline and week 52 of SENSCIS-ON Baseline Week 52 None or mild Moderate Severe or very severe Missing Total Continued nintedanib None or mild 81 (41.1) 5 (2.5) 0 4 (2.0) 90 (45.7) Moderate 38 (19.3) 10 (5.1) 0 1 (0.5) 49 (24.9) Severe or very severe 13 (6.6) 14 (7.1) 7 (3.6) 1 (0.5) 35 (17.8) Missing 6 (3.0) 3 (1.5) 1 (0.5) 13 (6.6) 23 (11.7) Total 138 (70.1) 32 (16.2) 8 (4.1) 19 (9.6) 197 (100) Initiated nintedanib None or mild 87 (35.2) 6 (2.4) 1 (0.4) 4 (1.6) 98 (39.7) Moderate 35 (14.2) 12 (4.9) 2 (0.8) 3 (1.2) 52 (21.1) Severe or very severe 8 (3.2) 7 (2.8) 4 (1.6) 1 (0.4) 20 (8.1) Missing 37 (15.0) 15 (6.1) 4 (1.6) 21 (8.5) 77 (31.2) Total 167 (67.6) 40 (16.2) 11 (4.5) 29 (11.7) 247 (100) Data are n (%) of patients. None or mild=scores of 0 to 0.49; moderate=scores of 0.5 to 1; severe or very severe=scores of 1.01 to 3. Figure 1. Changes in UCLA SCTC GIT scores from baseline to week 52 of SENSCIS-ON Conclusion In the SENSCIS-ON trial, the majority of patients with SSc-ILD treated with nintedanib had no or mild GI symptoms at baseline. A small worsening in GI symptoms was observed over 52 weeks. Diarrhoea had the greatest impact, reflecting the adverse event profile of nintedanib. Recommendations for the management of diarrhoea in patients treated with nintedanib should be implemented in clinical practice. Acknowledgements The SENSCIS-ON trial was funded by Boehringer Ingelheim. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc - stocks, Consultant of: AbbVie, Acceleron, Actelion, Amgen, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos NV, Genentech/Roche, Gilead, GlaxoSmithKline, Horizon Therapeutics, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Sanofi-Aventis, United Therapeutics, Prometheus, Theraly, AstraZeneca, Grant/research support from: Bayer, Bristol-Myers Squibb, Horizon Therapeutics, Immune Tolerance Network, National Institutes of Health, Pfizer, Employee of: CiviBioPharma/Eicos Sciences, Inc - Leadership/Equity position – Chief Medical Officer, Elizabeth Volkmann Speakers bureau: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Grant/research support from: Boehringer Ingelheim, Corbus, Forbius, Horizon, Kadmon, Kristin Highland Speakers bureau: Actelion Pharmaceuticals (Jansen), Bayer Healthcare, Boehringer Ingelheim, United Therapeutics, Paid instructor for: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Gilead Sciences, United Therapeutics, Consultant of: Boehringer Ingelheim, United Therapeutics, Genentech, Forsee Pharmaceuticals, Grant/research support from: Acceleron Pharmaceuticals, Actelion Pharmaceuticals, Bayer Healthcare, Boehringer Ingelheim, Genentech, Gossamer Bio, Eiger Pharmaceuticlas, Lilly Pharmaceuticals, Reata Pharmaceuticals, United Therapeutics, Viela Bio (Horizon Pharmaceuticals), Yannick Allanore Consultant of: Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, Medsenic, Mylan, Prometheus, Roche, Sanofi, Grant/research support from: Alpine Immunosciences, Medsenic, OSE Immunotherapeutics, Stéphane Jouneau Paid instructor for: Cours, formations - Actelion, AIRB, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, LVL, Mundipharma, Novartis, Pfizer, Roche, Consultant of: Advisory Boards, consultancy - AIRB, Boehringer Ingelheim, Roche, Grant/research support from: Recherche Clinique - AIRB, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Galactic, Gilead, LVL, Roche, Savara Aides pour des recherches - AIRB, Boehringer Ingelheim, LVL, Novartis, Roche, James Seibold Shareholder of: Prometheus Biosciences, Speakers bureau: Boehringer Ingelheim, Consultant of: Alexion, Blade, Camurus AB, GlaxoSmithKline, Prometheus Biosciences, Sironax, Sojournix, Xenikos, Employee of: Prometheus Biosciences, Alexandra James Employee of: Alexandra James is an employee of Elderbrook solutions GmbH that is contracted by Boehringer Ingelheim, Margarida Alves Employee of: Margarida Alves is an employee of Boehringer Ingelheim, Oliver Distler Speakers bureau: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Speaker fee: Bayer, Boehringer Ingelheim, Janssen, Medscape , Consultant of: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Consultancy fee: Abbvie, Acceleron, Alcimed, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, 4P Science, Galapagos, Glenmark, Horizon, Inventiva, Kymera, Lupin, Miltenyi Biotec, Mitsubishi Tanabe, MSD, Novartis, Prometheus, Roivant, Sanofi and Topadur OD has/had relationships with the following companies in the area of potential treatments for arthritides in the last three calendar years: Consultancy fee: Abbvie , Grant/research support from: OD has/had relationships with the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: Research Grants: Boehringer Ingelheim, Kymera, Mitsubishi Tanabe

Type of Medium: Online Resource

ISSN: 0003-4967 , 1468-2060

URL: Article

DOI: 10.1136/annrheumdis-2022-eular.714

Language: English

Publisher: BMJ

Publication Date: 2022

detail.hit.zdb_id: 1481557-6