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

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: NCT01335477
• Other study ID #: 1199.34
• Secondary ID: 2010-024252-29
• Status: Completed
• Phase: Phase 3
• First received: April 13, 2011
• Last updated: January 29, 2015
• Start date: May 2011
• Est. completion date: October 2013

Study information

• Verified date: January 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health CanadaChile: Instituto de Salud Pública de ChileChina: Food and Drug AdministrationFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: Ethics CommitteeIndia: Drugs Controller General of IndiaJapan: Ministry of Health, Labor and WelfareMexico: Ministry of HealthNetherlands: Central Committee Research Involving Human SubjectsPortugal: National Pharmacy and Medicines InstituteRussia: Pharmacological Committee, Ministry of HealthSouth Korea: Ministry of Food and Drug Safety (MFDS)Spain: Spanish Agency of MedicinesTurkey: Ministry of HealthUnited 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: 551
• 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 BIBF 1120 BID
• BIBF 1120
BIBF 1120 BID (twice daily)

Locations

Country	Name	City	State
Canada	1199.34.02001 Boehringer Ingelheim Investigational Site	Calgary	Alberta
Canada	1199.34.02003 Boehringer Ingelheim Investigational Site	Halifax	Nova Scotia
Canada	1199.34.02002 Boehringer Ingelheim Investigational Site	Hamilton	Ontario
Chile	1199.34.56001 Boehringer Ingelheim Investigational Site	Santiago de Chile
China	1199.34.86056 Boehringer Ingelheim Investigational Site	Beijing
China	1199.34.86052 Boehringer Ingelheim Investigational Site	Shanghai
China	1199.34.86054 Boehringer Ingelheim Investigational Site	Shanghai
China	1199.34.86055 Boehringer Ingelheim Investigational Site	Shanghai
China	1199.34.86058 Boehringer Ingelheim Investigational Site	Shanghai
China	1199.34.86051 Boehringer Ingelheim Investigational Site	Shenyang
China	1199.34.86053 Boehringer Ingelheim Investigational Site	Shenyang
China	1199.34.86057 Boehringer Ingelheim Investigational Site	Yinchuan
Finland	1199.34.35801 Boehringer Ingelheim Investigational Site	Helsinki
France	1199.34.33004 Boehringer Ingelheim Investigational Site	Dijon Cedex
France	1199.34.33003 Boehringer Ingelheim Investigational Site	Lille Cedex
France	1199.34.33005 Boehringer Ingelheim Investigational Site	Lyon Cedex
France	1199.34.33007 Boehringer Ingelheim Investigational Site	Marseille
France	1199.34.33002 Boehringer Ingelheim Investigational Site	Montpellier cedex 5
France	1199.34.33006 Boehringer Ingelheim Investigational Site	Toulouse cedex 9
Germany	1199.34.49003 Boehringer Ingelheim Investigational Site	Bad Berka
Germany	1199.34.49002 Boehringer Ingelheim Investigational Site	Berlin
Germany	1199.34.49010 Boehringer Ingelheim Investigational Site	Berlin-Buch
Germany	1199.34.49005 Boehringer Ingelheim Investigational Site	Coswig
Germany	1199.34.49001 Boehringer Ingelheim Investigational Site	Essen
Germany	1199.34.49007 Boehringer Ingelheim Investigational Site	Greifswald
Germany	1199.34.49009 Boehringer Ingelheim Investigational Site	Immenhausen
Germany	1199.34.49011 Boehringer Ingelheim Investigational Site	Köln
Germany	1199.34.49006 Boehringer Ingelheim Investigational Site	München
Germany	1199.34.49004 Boehringer Ingelheim Investigational Site	Münster
Greece	1199.34.30005 Boehringer Ingelheim Investigational Site	Athens
Greece	1199.34.30001 Boehringer Ingelheim Investigational Site	Heraklion
Greece	1199.34.30004 Boehringer Ingelheim Investigational Site	Larisa
Greece	1199.34.30002 Boehringer Ingelheim Investigational Site	Maroussi, Athens
Greece	1199.34.30003 Boehringer Ingelheim Investigational Site	Nikaia
India	1199.34.91051 Boehringer Ingelheim Investigational Site	Ahmedabad
India	1199.34.91053 Boehringer Ingelheim Investigational Site	Banglore
India	1199.34.91056 Boehringer Ingelheim Investigational Site	Jaipur
India	1199.34.91054 Boehringer Ingelheim Investigational Site	Pune
India	1199.34.91055 Boehringer Ingelheim Investigational Site	Pune
Japan	1199.34.81059 Boehringer Ingelheim Investigational Site	Himeji, Hyogo
Japan	1199.34.81063 Boehringer Ingelheim Investigational Site	Kawasaki, Kanagawa
Japan	1199.34.81060 Boehringer Ingelheim Investigational Site	Kobe, Hyogo
Japan	1199.34.81051 Boehringer Ingelheim Investigational Site	Minato-ku, Tokyo
Japan	1199.34.81054 Boehringer Ingelheim Investigational Site	Nagoya, Aichi
Japan	1199.34.81055 Boehringer Ingelheim Investigational Site	Ogaki, Gifu
Japan	1199.34.81058 Boehringer Ingelheim Investigational Site	Osaka-Sayama, Osaka
Japan	1199.34.81057 Boehringer Ingelheim Investigational Site	Sakai, Osaka
Japan	1199.34.81053 Boehringer Ingelheim Investigational Site	Seto, Aichi
Japan	1199.34.81052 Boehringer Ingelheim Investigational Site	Shinjuku-ku, Tokyo
Japan	1199.34.81056 Boehringer Ingelheim Investigational Site	Tenri, Nara
Japan	1199.34.81062 Boehringer Ingelheim Investigational Site	Tokushima, Tokushima
Japan	1199.34.81061 Boehringer Ingelheim Investigational Site	Yonago, Tottori
Korea, Republic of	1199.34.82002 Boehringer Ingelheim Investigational Site	Bucheon
Korea, Republic of	1199.34.82004 Boehringer Ingelheim Investigational Site	Incheon
Korea, Republic of	1199.34.82001 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1199.34.82003 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1199.34.82006 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1199.34.82007 Boehringer Ingelheim Investigational Site	Seoul
Mexico	1199.34.52001 Boehringer Ingelheim Investigational Site	Mexico DF
Netherlands	1199.34.31002 Boehringer Ingelheim Investigational Site	Amsterdam
Netherlands	1199.34.31001 Boehringer Ingelheim Investigational Site	Nieuwegein
Netherlands	1199.34.31003 Boehringer Ingelheim Investigational Site	Rotterdam
Portugal	1199.34.35107 Boehringer Ingelheim Investigational Site	Amadora
Portugal	1199.34.35105 Boehringer Ingelheim Investigational Site	Coimbra
Portugal	1199.34.35102 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1199.34.35103 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1199.34.35101 Boehringer Ingelheim Investigational Site	Porto
Portugal	1199.34.35106 Boehringer Ingelheim Investigational Site	Vila Nova de Gaia
Russian Federation	1199.34.07001 Boehringer Ingelheim Investigational Site	Kazan
Russian Federation	1199.34.07003 Boehringer Ingelheim Investigational Site	St. Petersburg
Spain	1199.34.34001 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1199.34.34003 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1199.34.34004 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1199.34.34005 Boehringer Ingelheim Investigational Site	Hospitalet de Llobregat
Spain	1199.34.34009 Boehringer Ingelheim Investigational Site	Madrid
Spain	1199.34.34008 Boehringer Ingelheim Investigational Site	Sevilla
Turkey	1199.34.90003 Boehringer Ingelheim Investigational Site	Ankara
Turkey	1199.34.90001 Boehringer Ingelheim Investigational Site	Istanbul
Turkey	1199.34.90005 Boehringer Ingelheim Investigational Site	Istanbul
Turkey	1199.34.90002 Boehringer Ingelheim Investigational Site	Izmir
Turkey	1199.34.90004 Boehringer Ingelheim Investigational Site	Izmir
United States	1199.34.10085 Boehringer Ingelheim Investigational Site	Albany	New York
United States	1199.34.10100 Boehringer Ingelheim Investigational Site	Austell	Georgia
United States	1199.34.10082 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	1199.34.10067 Boehringer Ingelheim Investigational Site	Chesterfield	Missouri
United States	1199.34.10075 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1199.34.10101 Boehringer Ingelheim Investigational Site	Colchester	Vermont
United States	1199.34.10074 Boehringer Ingelheim Investigational Site	Durham	North Carolina
United States	1199.34.10092 Boehringer Ingelheim Investigational Site	Jamaica	New York
United States	1199.34.10066 Boehringer Ingelheim Investigational Site	Lebanon	New Hampshire
United States	1199.34.10090 Boehringer Ingelheim Investigational Site	Lexington	Kentucky
United States	1199.34.10095 Boehringer Ingelheim Investigational Site	Longview	Texas
United States	1199.34.10073 Boehringer Ingelheim Investigational Site	Madison	Wisconsin
United States	1199.34.10069 Boehringer Ingelheim Investigational Site	Olathe	Kansas
United States	1199.34.10064 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1199.34.10089 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1199.34.10070 Boehringer Ingelheim Investigational Site	Portland	Oregon
United States	1199.34.10079 Boehringer Ingelheim Investigational Site	Rochester	Minnesota
United States	1199.34.10084 Boehringer Ingelheim Investigational Site	Salt Lake City	Utah
United States	1199.34.10060 Boehringer Ingelheim Investigational Site	San Antonio	Texas
United States	1199.34.10086 Boehringer Ingelheim Investigational Site	San Francisco	California
United States	1199.34.10093 Boehringer Ingelheim Investigational Site	Santa Barbara	California
United States	1199.34.10078 Boehringer Ingelheim Investigational Site	Scottsdale	Arizona
United States	1199.34.10087 Boehringer Ingelheim Investigational Site	South Miami	Florida
United States	1199.34.10080 Boehringer Ingelheim Investigational Site	Stamford	Connecticut
United States	1199.34.10077 Boehringer Ingelheim Investigational Site	Stanford	California
United States	1199.34.10088 Boehringer Ingelheim Investigational Site	Toledo	Ohio
United States	1199.34.10083 Boehringer Ingelheim Investigational Site	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Canada,  Chile,  China,  Finland,  France,  Germany,  Greece,  India,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Portugal,  Russian Federation,  Spain,  Turkey, 

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 From Baseline 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 From Baseline 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 (Points): 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 Symptom 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 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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