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

Scleroderma, Systemic Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02597933
• Other study ID #: 1199.214
• Secondary ID: 2015-000392-28
• Status: Completed
• Phase: Phase 3
• Start date: November 12, 2015
• Est. completion date: November 28, 2018

Study information

• Verified date: November 2019
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 580
• Est. completion date: November 28, 2018
• Est. primary completion date: October 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Scleroderma, Diffuse
• Scleroderma, Systemic

Intervention

Drug:
• Nintedanib

• Placebo

Locations

Country	Name	City	State
Argentina	Hospital Militar Central Cirujano Mayor Dr. Cosme Argerich	Buenos Aires
Argentina	APRILLUS-Asistencia e Investigación	Ciudad Autonoma Buenos Aires
Argentina	CEMER-Centro Medico De Enfermedades Respiratorias	Florida
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	St Vincent's Hospital Melbourne	Fitzroy	Victoria
Australia	Liverpool Hospital	Sydney	New South Wales
Austria	LKH-Univ. Hospital Graz	Graz
Austria	Medical University of Innsbruck	Innsbruck
Belgium	Brussels - UNIV Saint-Luc	Bruxelles
Belgium	ULB Hopital Erasme	Bruxelles
Belgium	UNIV UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liège	Liège
Brazil	Edumed - Educacao e Saude SA	Curitiba
Canada	Saint Joseph's Healthcare	Hamilton	Ontario
Canada	HSCM	Montreal	Quebec
Canada	Mount Sinai Hospital	Toronto	Ontario
Chile	Hospital Clínico Reg. de Concepción "Dr. G. Grant Benavente"	Concepción
Chile	Centro de Investigación del Maule	Talca
China	Beijing Chao-Yang Hospital	Beijing
China	Beijing Hospital	Beijing
China	Peking Union Medical College Hospital	Beijing
China	First Hospital of Jilin University	Changchun
China	West China Hospital	Chengdu
China	The First Affiliated Hospital of Anhui Medical University	Hefei
China	Huashan Hospital, Fudan University	Shanghai
China	The First Hospital of Chinese Medical University	Shenyang
China	Zhuzhou Central Hospital	Zhuzhou
Czechia	Institute of Rheumathology Prague	Prague
Czechia	Thomayer Hospital	Praha 4
Denmark	Aarhus Universitets Hospital	Århus
Denmark	Odense Universitetshospital	Odense
Finland	HYKS Keuhkosairauksien	Helsinki
Finland	TYKS, Keuhkosairauksien klinikka, Turku	Turku
France	HOP Avicenne	Bobigny
France	HOP Louis Pradel	Bron
France	HOP Calmette	Lille
France	HOP Claude Huriez	Lille
France	HOP Arnaud de Villeneuve	Montpellier
France	HOP Hôtel-Dieu	Nantes
France	HOP Pasteur	Nice
France	HOP Bichat	Paris
France	HOP Cochin	Paris
France	HOP Pontchaillou	Rennes
France	HOP Charles Nicolle	Rouen
France	HOP Larrey	Toulouse
France	HOP Bretonneau	Tours
Germany	Kerckhoff-Klinik, Bad Nauheim	Bad Nauheim
Germany	Klinik Donaustauf	Donaustauf
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	Asklepios Klinik Altona	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Schleswig-Holstein, Campus Kiel	Kiel
Germany	Universitätsklinikum Köln (AöR)	Köln
Germany	Klinikum der Universität München - Campus Großhadern	München
Germany	Universitätsklinikum Münster	Münster
Germany	Universitätsklinikum Tübingen	Tübingen
Greece	General Hospital of Athens "Laiko"	Athens
Greece	General Hospital of Athens "Laiko"	Athens
Hungary	Semmelweis University, Dept. Pulmonology	Budapest
India	Mazumdar Shaw Medical centre	Bangalore
India	Ramaiah Medical College and Hospitals	Bangalore
India	St John's Medical College	Bangalore
India	Postgraduate Institute of Medical Education And Research	Chandigarh
India	Care Hospital	Hyderabad
India	Nizam's Institute of Medical Sciences	Hyderabad
India	Asthma Bhawan	Jaipur
India	P.D. Hinduja National Hospital	Mumbai
India	Getwell Hospital & Research Institute	Nagpur
India	All India Institute of Medical Science	New Delhi
India	Sir Gangaram Hospital	New Delhi
India	B.J. Medical College and Sasoon General Hospital	Pune
India	Inamdar Multispeciality Hospital	Pune
India	Jehangir Clinical Development Centre Pvt. Ltd.	Pune
India	Christian Medical College	Vellore
Ireland	Cork University Hospital	Cork
Ireland	Mater Misericordiae University Hospital	Dublin 7
Israel	Bnei Zion Medical Center, Haifa	Haifa
Israel	Rambam Medical Center	Haifa
Israel	Rabin Medical Center Beilinson	Petah Tiqwa
Israel	Sourasky Medical Center	Tel Aviv
Italy	Az. Ospedaliere Umberto I di Ancona	Ancona
Italy	Università degli Studi di Genova	Genova
Italy	A.O. San Gerardo di Monza	Monza
Italy	A.O Universitaria - Università degli Studi della Campania Luigi Vanvitelli	Napoli
Italy	Università degli Studi Padova	Padova
Italy	Azienda Universitaria-Universita' La Sapienza	Roma
Japan	Tosei General Hospital	Aichi, Seto
Japan	Kurume University Hospital	Fukuoka, Kurume
Japan	Sapporo Medical University Hospital	Hokkaido, Sapporo
Japan	National Hospital Organization Himeji Medical Center	Hyogo, Himeji
Japan	Iwate Medical University Hospital	Iwate, Morioka
Japan	St. Marianna University School of Medicine Hospital	Kanagawa, Kawasaki
Japan	Kitasato University Hospital	Kanagawa, Sagamihara
Japan	Kanagawa Cardiovascular and Respiratory Center	Kanagawa, Yokohama
Japan	Kyoto University Hospital	Kyoto, Kyoto
Japan	Nagasaki University Hospital	Nagasaki, Nagasaki
Japan	Kindai University Hospital	Osaka, Osakasayama
Japan	National Hospital Organization Kinki-Chuo Chest Medical Center	Osaka, Sakai
Japan	Osaka Medical College Hospital	Osaka, Takatsuki
Japan	Saitama Medical University Hospital	Saitama, Iruma-gun
Japan	Hamamatsu University Hospital	Shizuoka, Hamamatsu
Japan	Tokushima University Hospital	Tokushima, Tokushima
Japan	Juntendo University Hospital	Tokyo, Bunkyo-Ku
Japan	Nippon Medical School Hospital	Tokyo, Bunkyo-Ku
Japan	Toho University Omori Medical Center	Tokyo, Ota-ku
Japan	Institute of Rheumatology Tokyo Women's Medical University	Tokyo, Shinjyuku-ku
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Hospital Pulau Pinang	Pulau Pinang
Malaysia	Hospital Selayang	Selangor
Malaysia	Hospital Tuanku Ja'afar	Seremban
Mexico	Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas	Ciudad de México
Netherlands	VU Medisch Centrum	Amsterdam
Netherlands	Leids Universitair Medisch Centrum (LUMC)	Leiden
Netherlands	Radboud Universitair Medisch Centrum	Nijmegen
Netherlands	Erasmus Medisch Centrum	Rotterdam
Norway	Oslo Universitetssykehus HF, Rikshospitalet	Oslo
Norway	Universitetssykehuset Nord-Norge, Tromsø	Tromsø
Poland	Dr.Biziel UnivHosp#2,Rheumat&Connec.Tissue Disease,Bydgoszcz	Bydgoszcz
Poland	Dobry Lekarz,Spec.Med.Clinics,Private Prac,Krakow	Krakow
Poland	EMED, Center of Medical Services,Private Prac,Rzeszow	Rzeszow
Poland	Indep.Pblic Clin.Hosp#1,Dermatol,Venereol&Allerg.dep,Wroclaw	Wroclaw
Portugal	Hospital Garcia de Orta, EPE	Almada
Portugal	Hospital Fernando Fonseca, EPE	Amadora
Portugal	CHUC - Centro Hospitalar e Universitário de Coimbra, EPE	Coimbra
Portugal	ULSAM, EPE - Hospital Conde de Bertiandos	Ponte de Lima
Portugal	Centro Hospitalar São João,EPE	Porto
Portugal	Centro Hospitalar de Vila Nova de Gaia	Vila Nova de Gaia
Spain	Hospital Santa Creu i Sant Pau	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Marqués de Valdecilla	Santander
Spain	Hospital Dr. Peset	Valencia
Spain	Hospital Politècnic La Fe	Valencia
Spain	Hospital Álvaro Cunqueiro	Vigo
Sweden	Clinical Rheumatology Research Center Sahlgrenska	Gothenburg
Switzerland	Kantonspital St. Gallen, Rheumatologie Department	St. Gallen
Switzerland	Universitätsspital Zürich	Zürich
Thailand	Songklanagarind Hospital	Hat Yai
Thailand	Srinagarind Hospital	Muang
Thailand	Ramathibodi Hospital	Ratchathewi
United Kingdom	Glasgow Royal Infirmary	Glasgow
United Kingdom	Guy's Hospital	London
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	Salford Royal Hospital	Salford
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	The Emory Clinic	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	The Lung Research Center, LLC	Chesterfield	Missouri
United States	Northwestern University	Chicago	Illinois
United States	University of Cincinnati Health	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of South Carolina	Columbia	South Carolina
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Inova Fairfax Medical Campus	Falls Church	Virginia
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	The University Of Texas at Houston	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	University of Florida College of Medicine	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California Los Angeles	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Froedtert and The Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota Masonic Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt Pulmonary Clinic	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Tulane University Hospital and Clinic	New Orleans	Louisiana
United States	Columbia University Medical Center-New York Presbyterian Hospital	New York	New York
United States	Hospital for Special Surgery	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic-Rochester	Rochester	Minnesota
United States	University of California Davis	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah Health Sciences Center	Salt Lake City	Utah
United States	University of California San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Stanford University Medical Center	Stanford	California
United States	University of Toledo	Toledo	Ohio
United States	Georgetown University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Chile,  China,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Hungary,  India,  Ireland,  Israel,  Italy,  Japan,  Malaysia,  Mexico,  Netherlands,  Norway,  Poland,  Portugal,  Spain,  Sweden,  Switzerland,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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