A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis

A Double Blind, Randomised, Placebo-controlled Trial Evaluating Efficacy and Safety of Oral Nintedanib Treatment for at Least 52 Weeks in Patients With Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)

Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. Patients suffer from multiple organ fibrosis whereas lung fibrosis (interstitial lung disease, ILD) is one of the main driver for mortality. There is preclinical evidence for efficacy of nintedanib in SSc and associated ILD (SSc-ILD) and the anti-fibrotic efficacy of nintedanib was proven in idiopathic pulmonary fibrosis patients, who are presenting a similar pattern regarding lung fibrosis. Hence it is the purpose of the trial to confirm the efficacy and safety of nintedanib 150 mg bid in treating patients with SSc-ILD, compared with placebo. The trial will be conducted as a double blind, randomised, placebo-controlled trial with primary efficacy evaluation at week 52 and placebo-controlled treatment until last patient out (up to a maximum of 100 weeks). Respiratory function is globally accepted for assessment of treatment effects in patients with lung fibrosis. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in patients with SSc-ILD.

Study Overview

• Status: Completed
• Conditions: Scleroderma, Systemic
• Intervention / Treatment: Drug: Placebo; Drug: Nintedanib

• Study Type: Interventional
• Enrollment (Actual): 580
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1426BOR
    • Hospital Militar Central Cirujano Mayor Dr. Cosme Argerich
  • Ciudad Autonoma Buenos Aires, Argentina, C1046AAQ
    • APRILLUS-Asistencia e Investigación
  • Florida, Argentina, B1602DQD
    • CEMER-Centro Medico De Enfermedades Respiratorias
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Sydney, New South Wales, Australia, 2170
      • Liverpool Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
• Austria
  • Graz, Austria, 8036
    • LKH-Univ. Hospital Graz
  • Innsbruck, Austria, 6020
    • Medical University of Innsbruck
• Belgium
  • Bruxelles, Belgium, 1200
    • Brussels - UNIV Saint-Luc
  • Bruxelles, Belgium, 1070
    • ULB Hopital Erasme
  • Gent, Belgium, 9000
    • UNIV UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire de Liège
• Brazil
  • Curitiba, Brazil, 80440-080
    • Edumed - Educacao e Saude SA
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4A6
      • Saint Joseph's Healthcare
    • Toronto, Ontario, Canada, M5T 3L9
      • Mount Sinai Hospital
  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
      • HSCM
• Chile
  • Concepción, Chile, 4070038
    • Hospital Clínico Reg. de Concepción "Dr. G. Grant Benavente"
  • Talca, Chile, 3465586
    • Centro de Investigación del Maule
• China
  • Beijing, China
    • Beijing Hospital
  • Beijing, China, 100032
    • Peking Union Medical College Hospital
  • Beijing, China
    • Beijing Chao-Yang Hospital
  • Changchun, China
    • First Hospital of Jilin University
  • Chengdu, China, 610041
    • West China Hospital
  • Hefei, China, 230022
    • The First affiliated Hospital of Anhui Medical University
  • Shanghai, China, 200040
    • Huashan Hospital, Fudan University
  • Shenyang, China
    • The First Hospital of Chinese Medical University
  • Zhuzhou, China, 412007
    • ZhuZhou Central Hospital
• Czechia
  • Prague, Czechia, 12850
    • Institute of Rheumathology Prague
  • Praha 4, Czechia, 14059
    • Thomayer Hospital
• Denmark
  • Odense, Denmark, 5000 C
    • Odense Universitetshospital
  • Århus, Denmark, 8000
    • Aarhus Universitets Hospital
• Finland
  • Helsinki, Finland, 00290
    • HYKS Keuhkosairauksien
  • Turku, Finland, 20520
    • TYKS, Keuhkosairauksien klinikka, Turku
• France
  • Bobigny, France, 93009
    • HOP Avicenne
  • Bron, France, 69677
    • HOP Louis Pradel
  • Lille, France, 59037
    • HOP Claude Huriez
  • Lille, France, 59037
    • HOP Calmette
  • Montpellier, France, 34295
    • HOP Arnaud de Villeneuve
  • Nantes, France, 44000
    • HOP Hôtel-Dieu
  • Nice, France, 06001
    • HOP Pasteur
  • Paris, France, 75018
    • HOP Bichat
  • Paris, France, 75014
    • HOP Cochin
  • Rennes, France, 35033
    • HOP Pontchaillou
  • Rouen, France, 76000
    • HOP Charles Nicolle
  • Toulouse, France, 31059
    • HOP Larrey
  • Tours, France, 37044
    • HOP Bretonneau
• Germany
  • Bad Nauheim, Germany, 61231
    • Kerckhoff-Klinik, Bad Nauheim
  • Donaustauf, Germany, 93093
    • Klinik Donaustauf
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus Dresden
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen
  • Greifswald, Germany, 17475
    • Universitätsmedizin Greifswald
  • Hamburg, Germany, 22763
    • Asklepios Klinik Altona
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany, 69126
    • Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein, Campus Kiel
  • Köln, Germany, 50937
    • Universitätsklinikum Köln (AöR)
  • München, Germany, 80336
    • Klinikum der Universität München - Campus Großhadern
  • Münster, Germany, 48149
    • Universitätsklinikum Münster
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens "Laiko"
  • Athens, Greece, 115 27
    • General Hospital of Athens "Laiko"
• Hungary
  • Budapest, Hungary, 1125
    • Semmelweis University, Dept. Pulmonology
• India
  • Bangalore, India, 560099
    • Mazumdar Shaw Medical Centre
  • Bangalore, India, 560054
    • Ramaiah Medical College and Hospitals
  • Bangalore, India, 560 034
    • St John's Medical College
  • Chandigarh, India, 160012
    • Postgraduate Institute of Medical Education and Research
  • Hyderabad, India, 500082
    • Nizam's Institute of Medical Sciences
  • Hyderabad, India, 500034
    • Care Hospital
  • Jaipur, India, 302039
    • Asthma Bhawan
  • Mumbai, India, 400016
    • P.D. Hinduja National Hospital
  • Nagpur, India, 440012
    • Getwell Hospital & Research Institute
  • New Delhi, India, 110060
    • Sir Gangaram Hospital
  • New Delhi, India, 110029
    • All India Institute of Medical Science
  • Pune, India, 411001
    • B.J. Medical College and Sasoon General Hospital
  • Pune, India, 411 001
    • Jehangir Clinical Development Centre Pvt. Ltd.
  • Pune, India, 411040
    • Inamdar Multispeciality Hospital
  • Vellore, India, 632 004
    • Christian medical college
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Dublin 7, Ireland
    • Mater Misericordiae University Hospital
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Haifa, Israel, 31048
    • Bnei Zion Medical Center, Haifa
  • Petah Tiqwa, Israel, 49100
    • Rabin Medical Center Beilinson
  • Tel Aviv, Israel, 64239
    • Sourasky Medical Center
• Italy
  • Ancona, Italy, 60126
    • Az. Ospedaliere Umberto I di Ancona
  • Genova, Italy, 16132
    • Università degli Studi di Genova
  • Monza, Italy, 20900
    • A.O. San Gerardo di Monza
  • Napoli, Italy, 80138
    • A.O Universitaria - Università degli Studi della Campania Luigi Vanvitelli
  • Padova, Italy, 35128
    • Università degli Studi Padova
  • Roma, Italy, 00161
    • Azienda Universitaria-Universita' La Sapienza
• Japan
  • Aichi, Seto, Japan, 489-8642
    • Tosei General Hospital
  • Fukuoka, Kurume, Japan, 830-0011
    • Kurume University Hospital
  • Hokkaido, Sapporo, Japan, 060-8543
    • Sapporo Medical University Hospital
  • Hyogo, Himeji, Japan, 670-8520
    • National Hospital Organization Himeji Medical Center
  • Iwate, Morioka, Japan, 020-8505
    • Iwate Medical University Hospital
  • Kanagawa, Kawasaki, Japan, 216-8511
    • St. Marianna University School of Medicine Hospital
  • Kanagawa, Sagamihara, Japan, 252-0375
    • Kitasato University Hospital
  • Kanagawa, Yokohama, Japan, 236-0051
    • Kanagawa Cardiovascular and Respiratory Center
  • Kyoto, Kyoto, Japan, 606-8507
    • Kyoto University Hospital
  • Nagasaki, Nagasaki, Japan, 852-8501
    • Nagasaki University Hospital
  • Osaka, Osakasayama, Japan, 589-8511
    • Kindai University Hospital
  • Osaka, Sakai, Japan, 591-8555
    • National Hospital Organization Kinki-chuo Chest Medical Center
  • Osaka, Takatsuki, Japan, 569-8686
    • Osaka Medical College Hospital
  • Saitama, Iruma-gun, Japan, 350-0495
    • Saitama Medical University Hospital
  • Shizuoka, Hamamatsu, Japan, 431-3192
    • Hamamatsu University Hospital
  • Tokushima, Tokushima, Japan, 770-8503
    • Tokushima University Hospital
  • Tokyo, Bunkyo-Ku, Japan, 113-8431
    • Juntendo University Hospital
  • Tokyo, Bunkyo-Ku, Japan, 113-8603
    • Nippon Medical School Hospital
  • Tokyo, Ota-ku, Japan, 143-8541
    • Toho University Omori Medical Center
  • Tokyo, Shinjyuku-ku, Japan, 162-0054
    • Institute of Rheumatology Tokyo Women's Medical University
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Pulau Pinang, Malaysia, 10990
    • Hospital Pulau Pinang
  • Selangor, Malaysia, 68100
    • Hospital Selayang
  • Seremban, Malaysia, 70300
    • Hospital Tuanku Ja'afar
• Mexico
  • Ciudad de México, Mexico, 14080
    • Instituto Nacional De Enfermedades Respiratorias Ismael Cosio Villegas
• Netherlands
  • Amsterdam, Netherlands, 1081HV
    • VU Medisch Centrum
  • Leiden, Netherlands, 2333 ZA
    • Leids Universitair Medisch Centrum (LUMC)
  • Nijmegen, Netherlands, 6525 GA
    • Radboud Universitair Medisch Centrum
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus Medisch Centrum
• Norway
  • Oslo, Norway, N-0372
    • Oslo Universitetssykehus HF, Rikshospitalet
  • Tromsø, Norway, N-9038
    • Universitetssykehuset Nord-Norge, Tromsø
• Poland
  • Bydgoszcz, Poland, 85168
    • Dr.Biziel UnivHosp#2,Rheumat&Connec.Tissue Disease,Bydgoszcz
  • Krakow, Poland, 31011
    • Dobry Lekarz,Spec.Med.Clinics,Private Prac,Krakow
  • Rzeszow, Poland, 35205
    • EMED, Center of Medical Services,Private Prac,Rzeszow
  • Wroclaw, Poland, 50 368
    • Indep.Pblic Clin.Hosp#1,Dermatol,Venereol&Allerg.dep,Wroclaw
• Portugal
  • Almada, Portugal, 2801-951
    • Hospital Garcia de Orta, EPE
  • Amadora, Portugal, 2720-276
    • Hospital Fernando Fonseca, EPE
  • Coimbra, Portugal, 3000-075
    • CHUC - Centro Hospitalar e Universitário de Coimbra, EPE
  • Ponte de Lima, Portugal, 4990-041
    • ULSAM, EPE - Hospital Conde de Bertiandos
  • Porto, Portugal, 4200-319
    • Centro Hospitalar São João,EPE
  • Vila Nova de Gaia, Portugal, 4434-502
    • Centro Hospitalar de Vila Nova de Gaia
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau
  • Madrid, Spain, 28041
    • Hospital Universitario 12 De Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla
  • Valencia, Spain, 46026
    • Hospital Politècnic La Fe
  • Valencia, Spain, 46017
    • Hospital Dr. Peset
  • Vigo, Spain, 36312
    • Hospital Álvaro Cunqueiro
• Sweden
  • Gothenburg, Sweden, 413 45
    • Clinical Rheumatology Research Center Sahlgrenska
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Kantonspital St. Gallen, Rheumatologie Department
  • Zürich, Switzerland, 8091
    • Universitätsspital Zürich
• Thailand
  • Hat Yai, Thailand, 90110
    • Songklanagarind hospital
  • Muang, Thailand, 40002
    • Srinagarind Hospital
  • Ratchathewi, Thailand, 10400
    • Ramathibodi Hospital
• United Kingdom
  • Glasgow, United Kingdom, G4 0SF
    • Glasgow Royal Infirmary
  • London, United Kingdom, SE1 9RT
    • Guy's Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • Salford, United Kingdom, M6 8HD
    • Salford Royal Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Sacramento, California, United States, 95817
      • University of California Davis
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • Stanford, California, United States, 94305-5236
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine
    • Miami, Florida, United States, 33125
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Hospital and Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic-Rochester
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • The Lung Research Center, LLC
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • New York, New York, United States, 10032
      • Columbia University Medical Center-New York Presbyterian Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Health
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Toledo, Ohio, United States, 43614
      • University of Toledo
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232-5735
      • Vanderbilt Pulmonary Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • The University of Texas at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Health Sciences Center
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Medical Campus
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Age >= 18 years
• 2013 American College of Rheumatology (ACR) / EULAR classification criteria for SSc fulfilled
• SSc disease onset (defined by first non-Raynaud symptom) within 7 years
• SSc related Interstitial Lung Disease confirmed by High Resolution Computer Tomography (HRCT); Extent of fibrotic disease in the lung >= 10%
• FVC >= 40% of predicted normal
• Carbon Monoxide Diffusion Capacity (DLCO) 30% to 89% of predicted normal

Exclusion criteria:

• Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) >1.5 x ULN
• Bilirubin >1.5 x ULN
• Creatinine clearance <30 mL/min
• Airway obstruction (pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/FVC <0.7)
• Other clinically significant pulmonary abnormalities
• Significant Pulmonary Hypertension (PH)
• Cardiovascular diseases
• More than 3 digital fingertip ulcers or a history of severe digital necrosis requiring hospitalization or severe other ulcers
• Bleeding risk (such as predisposition to bleeding, fibrinolysis, full-dose anticoagulation, high dose antiplatelet therapy, history of hemorrhagic central nervous system (CNS) event within last year
• international normalised ratio (INR) >2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN)
• History of thrombotic event within last year
• Clinical signs of malabsorption or needing parenteral nutrition
• Previous treatment with nintedanib or pirfenidone
• Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine, cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, newer anti-arthritic treatments like tofacitinib and cyclosporine A, potassium para-aminobenzoate
• Unstable background therapy with either mycophenolate mofetil or methotrexate
• Previous or planned hematopoietic stem cell transplantation
• Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nintedanib; patient receives capsules containing nintedanib twice a day	Drug: Nintedanib
Placebo Comparator: Placebo; patient receives capsules identical to those containing active drug	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks	Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.	up to week (wk) 52 after the start of administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in the Modified Rodnan Skin Score (mRSS) at Week 52	This is the first key secondary endpoint. The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold. The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).	Baseline and up to 52 weeks after the start of administration
Absolute Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at Week 52.	This is the second key secondary endpoint. The Saint George's Respiratory Questionnaire measures the health status in patients with chronic airflow limitation. It consists of 2 parts that cover 3 domains: symptoms, activities, and impacts. The symptom domain relates to the effect, frequency and severity of respiratory symptoms. The activity domain relates to activities that cause or are limited by breathlessness. The impact domain evaluates a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. The scores of these domains range from 0 (no impairment) to 100 (worst possible). The calculated total score summarises the impact of the disease on overall health status. A high score corresponds to worse health. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).	Baseline and up to 52 weeks after the start of administration
Annual Rate of Decline in FVC in Percentage (%) Predicted Over 52 Weeks	Annual rate of decline in FVC in percentage (%) predicted over 52 weeks. For this endpoint reported means represent the adjusted rate.	up to 52 weeks after the start of administration
Absolute Change From Baseline in FVC in mL at Week 52	Absolute change from baseline in FVC in mL at Week 52. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).	Baseline and up to 52 weeks after the start of administration
Relative Change From Baseline [%] of mRSS at Week 52	Relative change from baseline [%] of mRSS at Week 52. The modified Rodnan Skin Score (mRSS) is an evaluation of the patient's skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold. The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).	Baseline and up to 52 weeks after the start of administration
Time to Death	Time to event analysis of patients with death. The number of observed patients with death are reported.	From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
The Percentage (%) of Responder Based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52	The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52. This is a composite endpoint, based on the mRSS, FVC percent predicted, HAQ-DI, patient's global impression of overall health Visual Analogue Scale (VAS) and physician's global impression of patient's overall health VAS, as well as the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension. The CRISS index score represents a probability of improvement and ranges between 0 and 1. This is a 2 stage process to predict probability of improvement: Step 1 - absence of major organ progression (SRC etc.) - score "0" Step 2 - predicted probability of improvement - (score "0 - 1")	Week 52
Absolute Change From Baseline in Carbon Monoxide Diffusion Capacity (DLco) in % Predicted at Week 52	Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and up to 52 weeks after the start of administration
Absolute Change From Baseline in Digital Ulcer Net Burden at Week 52	Absolute change from baseline in digital ulcer net burden (defined as the number of new digital ulcers (DUs) plus the number of DUs that have been verified at any earlier assessment during the trial) at Week 52. It is calculated at a visit by counting the total number of fingertips with ulcers (i.e. number of fingers with presence of digital ulcer ticked "Yes") at the corresponding visit Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and up to 52 weeks after the start of administration
Absolute Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52	Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52. The HAQ-DI score is calculated as follows: Each question is scored 0-3 (where 0= "without difficulty" & 3= "unable to do"). There are 8 categories (Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, Activities), each including 2 or 3 questions. The score for each category corresponds to maximum question score within each category. Finally, HAQ-DI score corresponds to sum of the sub-scores of all 8 categories divided by number of categories completed. Please note that if there are fewer than 6 categories with responses, then a score cannot be calculated. The HAQ-DI score scale has 25 possible values (i.e., 0, 0.125, 0.250, 0.375 … 3). A high score corresponds to worse impairment. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and up to 52 weeks after the start of administration
Absolute Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Dyspnoea Score at Week 52	Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52. FACIT-Dyspnoea (Dyspnoea) 10 Item Short Form include a 4-point rating scale (no shortness of breath=0; mildly short of breath=1; moderately short of breath = 2; severely short of breath =3; or I did not do this in the past 7 days =4). A raw score is calculated as: Sum individual item scores * 10 / number of items answered. Raw scores are then converted to scale scores using the table included in the FACIT Dyspnoea Scale Short Form Scoring Guideline. FACIT dyspnea scale score ranges between 0 and 75.9. The FACIT-Dyspnea short forms are scored such that a high score represents high levels of dyspnea. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and up to 52 weeks after the start of administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Denton CP, Goh NS, Humphries SM, Maher TM, Spiera R, Devaraj A, Ho L, Stock C, Erhardt E, Alves M, Wells AU; SENSCIS trial investigators. Extent of fibrosis and lung function decline in patients with systemic sclerosis and interstitial lung disease: data from the SENSCIS trial. Rheumatology (Oxford). 2022 Sep 16:keac535. doi: 10.1093/rheumatology/keac535. Online ahead of print.
• Maher TM, Bourdin A, Volkmann ER, Vettori S, Distler JHW, Alves M, Stock C, Distler O. Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects. Respir Res. 2022 Jul 5;23(1):178. doi: 10.1186/s12931-022-02095-6.
• Kreuter M, Hoffmann-Vold AM, Matucci-Cerinic M, Saketkoo LA, Highland KB, Wilson H, Alves M, Erhardt E, Schoof N, Maher TM. Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease. Rheumatology (Oxford). 2022 May 31:keac325. doi: 10.1093/rheumatology/keac325. Online ahead of print.
• Volkmann ER, Kreuter M, Hoffmann-Vold AM, Wijsenbeek M, Smith V, Khanna D, Denton CP, Wuyts WA, Miede C, Alves M, Sambevski S, Allanore Y. Dyspnoea and cough in patients with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial. Rheumatology (Oxford). 2022 Nov 2;61(11):4397-4408. doi: 10.1093/rheumatology/keac091.
• Kreuter M, Del Galdo F, Miede C, Khanna D, Wuyts WA, Hummers LK, Alves M, Schoof N, Stock C, Allanore Y. Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis. Arthritis Res Ther. 2022 Jan 10;24(1):19. doi: 10.1186/s13075-021-02710-9.
• Highland KB, Distler O, Kuwana M, Allanore Y, Assassi S, Azuma A, Bourdin A, Denton CP, Distler JHW, Hoffmann-Vold AM, Khanna D, Mayes MD, Raghu G, Vonk MC, Gahlemann M, Clerisme-Beaty E, Girard M, Stowasser S, Zoz D, Maher TM; SENSCIS trial investigators. Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial. Lancet Respir Med. 2021 Jan;9(1):96-106. doi: 10.1016/S2213-2600(20)30330-1.
• Roennow A, Sauve M, Welling J, Riggs RJ, Kennedy AT, Galetti I, Brown E, Leite C, Gonzalez A, Portales Guiraud AP, Houyez F, Camp R, Gilbert A, Gahlemann M, Moros L, Luna Flores JL, Schmidt F, Sauter W, Finnern H. Collaboration between patient organisations and a clinical research sponsor in a rare disease condition: learnings from a community advisory board and best practice for future collaborations. BMJ Open. 2020 Dec 16;10(12):e039473. doi: 10.1136/bmjopen-2020-039473.
• Azuma A, Chung L, Behera D, Chung M, Kondoh Y, Ogura T, Okamoto M, Swarnakar R, Zeng X, Zou H, Meng X, Gahlemann M, Alves M, Kuwana M; SENSCIS trial investigators. Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial. Respir Investig. 2021 Mar;59(2):252-259. doi: 10.1016/j.resinv.2020.10.005. Epub 2020 Nov 19.
• Maher TM, Mayes MD, Kreuter M, Volkmann ER, Aringer M, Castellvi I, Cutolo M, Stock C, Schoof N, Alves M, Raghu G; SENSCIS Trial Investigators. 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. Arthritis Rheumatol. 2021 Apr;73(4):671-676. doi: 10.1002/art.41576. Epub 2021 Mar 8.
• Kuwana M, Ogura T, Makino S, Homma S, Kondoh Y, Saito A, Ugai H, Gahlemann M, Takehara K, Azuma A. Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial. Mod Rheumatol. 2021 Jan;31(1):141-150. doi: 10.1080/14397595.2020.1751402. Epub 2020 Apr 23.
• Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, Raghu G, Sauter W, Girard M, Alves M, Clerisme-Beaty E, Stowasser S, Tetzlaff K, Kuwana M, Maher TM; SENSCIS Trial Investigators. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun 27;380(26):2518-2528. doi: 10.1056/NEJMoa1903076. Epub 2019 May 20.
• Distler O, Brown KK, Distler JHW, Assassi S, Maher TM, Cottin V, Varga J, Coeck C, Gahlemann M, Sauter W, Schmidt H, Highland KB; SENSCIS trial investigators. Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS). Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 106(4):75-81. Epub 2017 Jun 29.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2015
• Primary Completion (Actual): October 31, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: November 4, 2015
• First Posted (Estimate): November 5, 2015

Study Record Updates

• Last Update Posted (Actual): December 13, 2019
• Last Update Submitted That Met QC Criteria: November 26, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1199.214; 2015-000392-28 (EudraCT Number)