Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients

Pulmonary Fibrosis Clinical Trial

Official title:

A 52 Weeks, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of Oral BIBF 1120, 150 mg Twice Daily, on Annual Forced Vital Capacity Decline, in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01335464
• Other study ID #: 1199.32
• Secondary ID: 2010-024251-87
• Status: Completed
• Phase: Phase 3
• First received: April 13, 2011
• Last updated: January 29, 2015
• Start date: April 2011
• Est. completion date: October 2013

Study information

• Verified date: January 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Dept of Health and Ageing Therapeutic Goods AdminBelgium: Federal Agency for Medicinal and Health ProductsChina: Food and Drug AdministrationCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesIndia: Drugs Controller General of IndiaIreland: Medical Ethics Research CommitteeIsrael: Ministry of HealthItaly: Ethics CommitteeJapan: Ministry of Health, Labor and WelfareUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Idiopathic Pulmonary Fibrosis (IPF) is a chronic disease of unknown cause that results in scarring of the lung and there is a high unmet medical need for effective treatment to halt lung function decline, delay or avoid exacerbation (flare-ups), and ultimately to reduce the death rate.

In a large Phase 2 trial (1199.30) (NCT00514683), investigating the effects of 52 weeks of treatment with BIBF 1120 in patients with IPF, a positive effect was seen on lung function of patients treated with high dose of BIBF 1120 compared to placebo.

Hence it is the purpose of this trial to investigate and confirm the efficacy and safety of BIBF 1120 at a high dose in treating patients with IPF, compared with placebo. The trial will be conducted as a prospective, randomised design with the aim to collect safety and efficacy data.

Respiratory function is globally accepted for assessment of treatment effects in IPF patients. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in IPF patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 515
• Est. completion date: October 2013
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion criteria:

1. Age >= 40 years;

2. IPF diagnosed, according to most recent American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Latin American Thoracic Association (ALAT) IPF guideline for diagnosis and management, within 5 years;

3. Combination of High Resolution Computerized Tomography (HRCT) pattern, and if available surgical lung biopsy pattern, as assessed by central reviewers, are consistent with diagnosis of IPF

4. Dlco (corrected for Hb): 30%-79% predicted of normal;

5. FVC>= 50% predicted of normal

Exclusion criteria:

1. Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) > 1.5 x Upper Limit of Normal (ULN)

2. Bilirubin > 1.5 x ULN;

3. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC < 0.7);

4. Patient likely to have lung transplantation during study (being on transplantation list is acceptable for participation);

5. Myocardial infarction within 6 months;

6. Unstable angina within 1 month;

7. Bleeding risk (genetic predisposition; fibrinolysis or full-dose therapeutic anticoagulation or high dose antiplatelet therapy; history of hemorrhagic CNS event within 12 months; haemoptysis or haematuria or active gastro-intestinal bleeding or ulcers or major injury or surgery within 3 months);

8. Thrombotic risk (inherited predisposition; history of thrombotic event (including stroke and transient ischemic attacks) within 12 months;

9. International normalised ratio (INR) > 2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by > 50% of institutional ULN);

10. N-ACetyl Cystein, prednisone > 15mg/day or equivalent received within 2 weeks of visit 1;

11. Pirfenidone, azathioprine, cyclophosphamide, cyclosporine A received within 8 weeks of visit 1;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• placebo
placebo matching BIBF1120, BID
• BIBF 1120
BIBF1120 BID (twice daily)

Locations

Country	Name	City	State
Australia	1199.32.61001 Boehringer Ingelheim Investigational Site	Camperdown	New South Wales
Australia	1199.32.61002 Boehringer Ingelheim Investigational Site	Concord	New South Wales
Australia	1199.32.61003 Boehringer Ingelheim Investigational Site	Daw Park	South Australia
Australia	1199.32.61005 Boehringer Ingelheim Investigational Site	Frankston	Victoria
Australia	1199.32.61004 Boehringer Ingelheim Investigational Site	Prahran	Victoria
Belgium	1199.32.32004 Boehringer Ingelheim Investigational Site	Bruxelles
Belgium	1199.32.32005 Boehringer Ingelheim Investigational Site	Jette
Belgium	1199.32.32001 Boehringer Ingelheim Investigational Site	Leuven
Belgium	1199.32.32002 Boehringer Ingelheim Investigational Site	Yvoir
China	1199.32.86001 Boehringer Ingelheim Investigational Site	Beijing
China	1199.32.86002 Boehringer Ingelheim Investigational Site	Beijing
China	1199.32.86005 Boehringer Ingelheim Investigational Site	Changsha
China	1199.32.86004 Boehringer Ingelheim Investigational Site	Chengdu
China	1199.32.86003 Boehringer Ingelheim Investigational Site	Nanchang
China	1199.32.86006 Boehringer Ingelheim Investigational Site	Xi'An
Czech Republic	1199.32.42003 Boehringer Ingelheim Investigational Site	Prague 4
Czech Republic	1199.32.42002 Boehringer Ingelheim Investigational Site	Prague 8
Czech Republic	1199.32.42001 Boehringer Ingelheim Investigational Site	Usti nad Labem
France	1199.32.33002 Boehringer Ingelheim Investigational Site	Bobigny
France	1199.32.33003 Boehringer Ingelheim Investigational Site	Nice Cedex 1
France	1199.32.33006 Boehringer Ingelheim Investigational Site	Paris Cedex 15
France	1199.32.33001 Boehringer Ingelheim Investigational Site	Paris Cedex 18
France	1199.32.33005 Boehringer Ingelheim Investigational Site	Paris cedex 20
France	1199.32.33007 Boehringer Ingelheim Investigational Site	Reims cedex
France	1199.32.33004 Boehringer Ingelheim Investigational Site	Rennes Cedex 9
Germany	1199.32.49008 Boehringer Ingelheim Investigational Site	Bamberg
Germany	1199.32.49005 Boehringer Ingelheim Investigational Site	Donaustauf
Germany	1199.32.49001 Boehringer Ingelheim Investigational Site	Essen
Germany	1199.32.49002 Boehringer Ingelheim Investigational Site	Freiburg/Breisgau
Germany	1199.32.49006 Boehringer Ingelheim Investigational Site	Gießen
Germany	1199.32.49003 Boehringer Ingelheim Investigational Site	Großhansdorf
Germany	1199.32.49007 Boehringer Ingelheim Investigational Site	Heidelberg
Germany	1199.32.49004 Boehringer Ingelheim Investigational Site	Mainz
India	1199.32.91003 Boehringer Ingelheim Investigational Site	Ahmedabad
India	1199.32.91002 Boehringer Ingelheim Investigational Site	Coimbatore
India	1199.32.91006 Boehringer Ingelheim Investigational Site	Jaipur
India	1199.32.91005 Boehringer Ingelheim Investigational Site	Kolkatta
India	1199.32.91001 Boehringer Ingelheim Investigational Site	Mumbai
Ireland	1199.32.35301 Boehringer Ingelheim Investigational Site	Dublin
Israel	1199.32.97004 Boehringer Ingelheim Investigational Site	Haifa
Israel	1199.32.97001 Boehringer Ingelheim Investigational Site	Petah Tiqwa
Israel	1199.32.97002 Boehringer Ingelheim Investigational Site	Rehovot
Italy	1199.32.39012 Boehringer Ingelheim Investigational Site	Catania
Italy	1199.32.39004 Boehringer Ingelheim Investigational Site	Chieti Scalo
Italy	1199.32.39008 Boehringer Ingelheim Investigational Site	Forli'
Italy	1199.32.39005 Boehringer Ingelheim Investigational Site	Milano
Italy	1199.32.39001 Boehringer Ingelheim Investigational Site	Modena
Italy	1199.32.39007 Boehringer Ingelheim Investigational Site	Monza
Italy	1199.32.39011 Boehringer Ingelheim Investigational Site	Napoli
Italy	1199.32.39002 Boehringer Ingelheim Investigational Site	Padova
Italy	1199.32.39006A Boehringer Ingelheim Investigational Site	Pisa
Italy	1199.32.39006B Boehringer Ingelheim Investigational Site	Pisa
Italy	1199.32.39010 Boehringer Ingelheim Investigational Site	Roma
Italy	1199.32.39009 Boehringer Ingelheim Investigational Site	Siena
Japan	1199.32.81005 Boehringer Ingelheim Investigational Site	Bunkyo-ku,Tokyo
Japan	1199.32.81006 Boehringer Ingelheim Investigational Site	Bunkyo-ku,Tokyo
Japan	1199.32.81007 Boehringer Ingelheim Investigational Site	Kiyose, Tokyo
Japan	1199.32.81004 Boehringer Ingelheim Investigational Site	Kumagaya, Saitama
Japan	1199.32.81009 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo
Japan	1199.32.81003 Boehringer Ingelheim Investigational Site	Naka-gun, Ibaraki
Japan	1199.32.81011 Boehringer Ingelheim Investigational Site	Ota-ku, Tokyo
Japan	1199.32.81001 Boehringer Ingelheim Investigational Site	Sendai, Miyagi
Japan	1199.32.81010 Boehringer Ingelheim Investigational Site	Shibuya-ku, Tokyo
Japan	1199.32.81002 Boehringer Ingelheim Investigational Site	Shimotsuke,Tochigi
Japan	1199.32.81008 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo
Japan	1199.32.81012 Boehringer Ingelheim Investigational Site	Yokohama, Kanagawa
United Kingdom	1199.32.44006 Boehringer Ingelheim Investigational Site	Aberdeen
United Kingdom	1199.32.44003 Boehringer Ingelheim Investigational Site	Birmingham
United Kingdom	1199.32.44005 Boehringer Ingelheim Investigational Site	Birmingham
United Kingdom	1199.32.44009 Boehringer Ingelheim Investigational Site	Leeds
United Kingdom	1199.32.44004 Boehringer Ingelheim Investigational Site	Liverpool
United Kingdom	1199.32.44002 Boehringer Ingelheim Investigational Site	London
United Kingdom	1199.32.44008 Boehringer Ingelheim Investigational Site	Oxford
United Kingdom	1199.32.44001 Boehringer Ingelheim Investigational Site	Westbury on Trym
United States	1199.32.10007 Boehringer Ingelheim Investigational Site	Birmingham	Alabama
United States	1199.32.10004 Boehringer Ingelheim Investigational Site	Cincinnati	Ohio
United States	1199.32.10001 Boehringer Ingelheim Investigational Site	Council Bluffs	Iowa
United States	1199.32.10009 Boehringer Ingelheim Investigational Site	Dallas	Texas
United States	1199.32.10022 Boehringer Ingelheim Investigational Site	Danbury	Connecticut
United States	1199.32.10021 Boehringer Ingelheim Investigational Site	Falls Church	Virginia
United States	1199.32.10029 Boehringer Ingelheim Investigational Site	Jasper	Alabama
United States	1199.32.10005 Boehringer Ingelheim Investigational Site	Los Angeles	California
United States	1199.32.10003 Boehringer Ingelheim Investigational Site	Lynchburg	Virginia
United States	1199.32.10018 Boehringer Ingelheim Investigational Site	McKinney	Texas
United States	1199.32.10016 Boehringer Ingelheim Investigational Site	Minneapolis	Minnesota
United States	1199.32.10015 Boehringer Ingelheim Investigational Site	Nashville	Tennessee
United States	1199.32.10024 Boehringer Ingelheim Investigational Site	New Brunswich	New Jersey
United States	1199.32.10019 Boehringer Ingelheim Investigational Site	New York	New York
United States	1199.32.10025 Boehringer Ingelheim Investigational Site	Newark	Delaware
United States	1199.32.10013 Boehringer Ingelheim Investigational Site	Phoenix	Arizona
United States	1199.32.10002 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania
United States	1199.32.10033 Boehringer Ingelheim Investigational Site	Pittsburgh	Pennsylvania
United States	1199.32.10020 Boehringer Ingelheim Investigational Site	Portland	Oregon
United States	1199.32.10008 Boehringer Ingelheim Investigational Site	Providence	Rhode Island
United States	1199.32.10034 Boehringer Ingelheim Investigational Site	Shelbyville	Tennessee
United States	1199.32.10038 Boehringer Ingelheim Investigational Site	Tacoma	Washington
United States	1199.32.10023 Boehringer Ingelheim Investigational Site	Weston	Florida
United States	1199.32.10028 Boehringer Ingelheim Investigational Site	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  China,  Czech Republic,  France,  Germany,  India,  Ireland,  Israel,  Italy,  Japan,  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	52 weeks	No
Secondary	Change From Baseline in Saint-George's Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks	This is a key secondary endpoint.; SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact.; The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status.; Means provided are the adjusted means based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	baseline and 52 weeks	No
Secondary	Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation	Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and represented as a key secondary endpoint. An acute exacerbation (reported as an AE by the investigator) was defined as follows: Otherwise unexplained clinical features including all of the following: Unexplained worsening or development of dyspnoea within 30 days; New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit; Exclusion of infection as per routine clinical practice and microbiological studies; Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury.; Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks, based on all investigator-reported AEs .	52 weeks	No
Secondary	Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks	Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).	Baseline and 52 weeks	No
Secondary	Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks	Percentage change from baseline in FVC over 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).	Baseline and 52 weeks	No
Secondary	Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks	Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).	Baseline and 52 weeks	No
Secondary	Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks	Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).	Baseline and 52 weeks	No
Secondary	Absolute Categorical Change of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold	Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 5% threshold (decrease by >5%, increase by >5%, and change within =5%).	Baseline and 52 weeks	No
Secondary	Absolute Categorical Change of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold	Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 10% threshold (decrease by 10%, increase by >10%, and change within =10%)	Baseline and 52 weeks	No
Secondary	FVC Responders Using 10% Threshold at 52 Weeks	FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC evaluation at 52 weeks.	52 weeks	No
Secondary	Proportion of FVC Responders Using 5% Threshold at 52 Weeks	Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks.	52 weeks	No
Secondary	Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs)	Proportion of SGRQ responders at 52 weeks; Responders defined as <= -4 points change in change from baseline in SGRQ total score at 52 weeks.	Baseline and 52 weeks	No
Secondary	Change From Baseline in SGRQ Symptom Score at 52 Weeks: Patient Reported Outcomes (PROs)	SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life.; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and 52 weeks	No
Secondary	Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better impact-related quality of life.; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and 52 weeks	No
Secondary	Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life.; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	baseline and 52 weeks	No
Secondary	Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score.; The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale.	Baseline and 52 weeks	No
Secondary	Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs)	Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome).; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	baseline and 52 weeks	No
Secondary	Change From Baseline in Cough Symptoms Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)	The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome).; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and 52 weeks	No
Secondary	Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks : Patient Reported Outcomes (PROs)	The cough domains of the Cough and Sputum Assessment Questionnaire (CASA-Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome).; Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).	Baseline and 52 weeks	No
Secondary	Proportion of Patient's Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs)	Patient's Global Impression of Change (PGI-C) responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'.	52 weeks	No
Secondary	Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs)	The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale.	baseline, 12 weeks, 24 weeks and 52 weeks	No
Secondary	Risk of an Acute IPF Exacerbation Over 52 Weeks	The incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk in years*100)	52 weeks	No
Secondary	Time to Death Over 52 Weeks	Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.; Failure is the proportion of patients who died over 52 weeks (373 days time-period) .	52 weeks	No
Secondary	Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated)	Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.; Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (373 days time-period).	52 weeks	No
Secondary	Time to On-treatment Death	Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial medication intake + 28 days were censored at last trial medication intake + 28 days and reported.; Failure is the the proportion of patients who died on-treatment.	52 weeks	No
Secondary	Time to Death or Lung Transplant Over 52 Weeks	Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.; Failure is the proportion of patients who died or had lung transplant over 52 weeks (373 days time-period).	52 weeks	No
Secondary	Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks.	Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria: FVC <45% predicted or Carbon monoxide diffusion capacity (DL(CO)) <30% pred or Oxygen saturation on pulse oximetry (SpO2) <88% at rest, at sea level (to be adapted for other heights).; These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (373 days time-period).	52 weeks	No
Secondary	Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks	Means presented are the adjusted means. Adjusted mean is based on all analyzed patients in the model (not only patients with a change from baseline to week 52)	Baseline and 52 weeks	No
Secondary	Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks	Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).	Baseline and 52 weeks	No

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