Clinical trial NCT00514683: Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis
Official title: A 12 Month, Double Blind, Randomized, Placebo-controlled Trial Evaluating the Effect of BIBF 1120 Administered at Oral Doses of 50 mg qd, 50 mg Bid, 100 mg Bid and 150 mg Bid on Forced Vital Capacity Decline During One Year, in Patients With Idiopathic Pulmonary Fibrosis, With Optional Active Treatment Extension Until Last Patient Out.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Fibrosis
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2007-08-10
Enrollment: 432
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The general purpose of this trial is to investigate the efficacy and safety of 4 dose strategies of BIBF 1120 treatment for 12 months, compared to placebo in patients with idiopathic pulmonary fibrosis.

The primary objective of this study is to demonstrate whether at least one dose strategy is superior to placebo in patients with IPF, in modifying the rate of decline of Forced Vital Capacity (FVC).

As a secondary objective, additional parameters will be assessed in order to differentiate between dose strategies on the basis of safety and efficacy


Eligibility criteria: Inclusion Criteria:

1. Patient \>40 years
2. Written informed consent signed prior to entry into the study
3. IPF diagnosed (according to ATS / ERS criteria) less than 5 years prior to screening visit.
4. HRCT within 12 months of randomisation and biopsy (the latter if needed to fulfil ATS/ERS criteria) centrally reviewed and consistent with diagnosis.
5. FVC\>50 % of predicted value

   Predicted normal values will be calculated according to ESCS (R94-1408):

   Males :

   FVC predicted (L) = 5.76 x height (meters)- 0.026 x age (years) -4.34

   Females :

   FVC predicted (L) = 4.43 x height (meters)- 0.026 x age (years) -2.89
6. Single breath DLCO (corrected for Hb) 30 - 79% inclusive of predicted .

   Different sites may use different prediction formulas, based on the method used to measure DLco. In any case, the method used must be in compliance with the ATS/ERS guideline on DLCO measurements (R06-2002), and the prediction formula appropriate for that method. Raw data (gas mixture, equation used for prediction of normal, further adjustments made if so) must be traced.

   Adjustment for haemoglobin (R06-2002):

   Males :

   DLCO predicted for Hb = DLCO predicted x (1.7Hb/\[10.22+Hb\])

   Females :

   DLCO predicted for Hb = DLCO predicted x (1.7Hb/\[9.38+Hb\]) where Hb is expressed in g/dL-1
7. PaO2 \>= 55 mmHg (sea level to 1500 m) or 50 mmHg (above 1500 m) room air

Exclusion Criteria:

1. AST, ALT \> 1.5 x ULN ;
2. Bilirubin \> 1.5 x ULN
3. Relevant airways obstruction
4. Continuous oxygen supplementation at randomisation (defined as \> 15 hours supplemental oxygen per day).
5. Active infection at screening or randomisation.
6. Neutrophils \< 1500 / mm3
7. International normalised ratio (INR) \> 1.5 and/or Partial thromboplastin time (PTT) \> 1.5 x ULN ;
8. Platelets \< 100 000 /mL
9. Haemoglobin \< 9.0 g/dL
10. In the opinion of the Investigator, patient is likely to have lung transplantation during study
11. Life expectancy for disease other than IPF \< 2.5 years (Investigator assessment).
12. Other disease that may interfere with testing procedures or in judgement of Investigator may interfere with trial participation or may put the patient at risk when participating to this trial.

    * Myocardial infarction during the previous 6 months
    * Unstable angina during the previous month
13. Other investigational therapy received within 8 weeks prior to screening visit.
14. Pregnant women or women who are breast feeding or of child bearing potential not using a highly effective method of birth control for at least one month prior to enrolment.
15. Sexually active males not committing to using condoms during the course of the study (except if their partner is not of childbearing potential).
16. Known or suspected active alcohol or drug abuse.
17. Bleeding risk : Known inherited predisposition to bleeding, patients who require full-dose anticoagulation, Patients who require full-dose antiplatelet therapy, History of hemorrhagic CNS event within 12 months prior to screening , Any of the following within 3 months prior to screening : Gross / frank haemoptysis or haematuria, Active gastro-intestinal bleeding or ulcers, Major injury or surgery
18. Thrombotic risk
19. Surgical procedures planned to occur during trial period.
20. Coagulopathy
21. Uncontrolled systemic arterial hypertension
22. known hypersensitivity to lactose or any component of the study medication

Primary outcomes:
measure: Rate of Decline in FVC
timeFrame: Baseline until 52 weeks
Secondary outcomes:
measure: Absolute Change From Baseline in FVC%Pred
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in FVC
timeFrame: Baseline and 52 weeks
measure: Relative Change From Baseline in FVC%Pred
timeFrame: Baseline and 52 weeks
measure: Relative Change From Baseline in FVC
timeFrame: Baseline and 52 weeks
measure: Number of Participants With Change From Baseline in FVC by Categories
timeFrame: Baseline and 52 weeks
measure: Survival (All Causes of Death and Lung-transplant Free)
timeFrame: 52 weeks
measure: Absolute Change From Baseline in SpO2 at Rest
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in SpO2 at Rest by Categories
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in PaO2
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in P(A-a)O2
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in PaCO2
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in PaO2 by Categories
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in P(A-a) O2 by Categories
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in DLCO
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in DLCO by Categories
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in Distance Walk (6-MWT)
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in Dyspnoea Rating on Borg Scale Before Exercise (6-MWT)
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in Dyspnoea Rating on Borg Scale After Exercise (6-MWT)
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in MRC Dyspnea Scale by Categories
timeFrame: Baseline and 52 weeks
measure: Absolute Change From Baseline in FEV1/FVC
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in SGRQ Total Score
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in SGRQ Domain Score Symptoms
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in SGRQ Domain Score Impacts
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Domain Score Activities
timeFrame: Baseline and 52 weeks
measure: St George's Respiratory Questionnaire (SGRQ) Responder
timeFrame: 52 weeks
measure: Change From Baseline in TLC
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in RV
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in TGV
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in VC
timeFrame: Baseline and 52 weeks
measure: Change From Baseline in IC
timeFrame: Baseline and 52 weeks
measure: Number of Patients With at Least One IPF Exacerbation
timeFrame: 52 weeks
measure: Occurrences of IPF Exacerbations Per Patient Per Year
timeFrame: 52 weeks
measure: Time to First Occurrence of IPF Exacerbation
timeFrame: 52 weeks
measure: Survival (Death Due to Respiratory Cause, and Lung-transplant Free)
timeFrame: 52 weeks
measure: Time to Progression
timeFrame: 52 weeks
measure: Pre-dose Plasma Concentration of Nintedanib in Plasma at Steady State on Day 365 (Cpre,ss,365) and Day 729 (Cpre,ss,729).
timeFrame: day 365 and day 729
Other outcomes:
Locations:
city: Mendoza
country: Argentina
facility: 1199.30.54002 Boehringer Ingelheim Investigational Site
city: South Brisbane
country: Australia
facility: 1199.30.61005 Boehringer Ingelheim Investigational Site
state: Queensland
city: Toorak Gardens
country: Australia
facility: 1199.30.61003 Boehringer Ingelheim Investigational Site
state: South Australia
city: Woodville
country: Australia
facility: 1199.30.61004 Boehringer Ingelheim Investigational Site
state: South Australia
city: Perth
country: Australia
facility: 1199.30.61001 Royal Perth Hospital
state: Western Australia
city: Bruxelles
country: Belgium
facility: 1199.30.32004 Boehringer Ingelheim Investigational Site
city: Leuven
country: Belgium
facility: 1199.30.32001 Boehringer Ingelheim Investigational Site
city: Yvoir
country: Belgium
facility: 1199.30.32002 Boehringer Ingelheim Investigational Site
city: Porto Alegre
country: Brazil
facility: 1199.30.55002 Boehringer Ingelheim Investigational Site
city: Vila Clementino
country: Brazil
facility: 1199.30.55001 Boehringer Ingelheim Investigational Site
city: Sofia
country: Bulgaria
facility: 1199.30.06004 Boehringer Ingelheim Investigational Site
city: Sofia
country: Bulgaria
facility: 1199.30.06005 Boehringer Ingelheim Investigational Site
city: Halifax
country: Canada
facility: 1199.30.01003 Division of Respirology
state: Nova Scotia
city: Hamilton
country: Canada
facility: 1199.30.01002 St. Joseph's Healthcare
state: Ontario
city: Providencia
country: Chile
facility: 1199.30.56001 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1199.30.86001 Boehringer Ingelheim Investigational Site
city: Beijing
country: China
facility: 1199.30.86002 Boehringer Ingelheim Investigational Site
city: Nanjing
country: China
facility: 1199.30.86005 Boehringer Ingelheim Investigational Site
city: Shanghai
country: China
facility: 1199.30.86003 Boehringer Ingelheim Investigational Site
city: Shenyang
country: China
facility: 1199.30.86004 Boehringer Ingelheim Investigational Site
city: Prague 8
country: Czech Republic
facility: 1199.30.42002 Boehringer Ingelheim Investigational Site
city: Usti nad Labem
country: Czech Republic
facility: 1199.30.42001 Boehringer Ingelheim Investigational Site
city: Bobigny
country: France
facility: 1199.30.3302A Boehringer Ingelheim Investigational Site
city: Dijon
country: France
facility: 1199.30.3306A Boehringer Ingelheim Investigational Site
city: Grenoble
country: France
facility: 1199.30.3303A Boehringer Ingelheim Investigational Site
city: Lille Cedex
country: France
facility: 1199.30.3305A Boehringer Ingelheim Investigational Site
city: Lille Cedex
country: France
facility: 1199.30.3305B Boehringer Ingelheim Investigational Site
city: Lille Cedex
country: France
facility: 1199.30.3305C Boehringer Ingelheim Investigational Site
city: Montpellier
country: France
facility: 1199.30.3304C Boehringer Ingelheim Investigational Site
city: Nice Cedex 1
country: France
facility: 1199.30.3307A Boehringer Ingelheim Investigational Site
city: Paris Cedex 18
country: France
facility: 1199.30.3301A Boehringer Ingelheim Investigational Site
city: Bad Berka
country: Germany
facility: 1199.30.49008 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1199.30.49007 Boehringer Ingelheim Investigational Site
city: Donaustauf
country: Germany
facility: 1199.30.49006 Boehringer Ingelheim Investigational Site
city: Essen
country: Germany
facility: 1199.30.49001 Boehringer Ingelheim Investigational Site
city: Freiburg/Breisgau
country: Germany
facility: 1199.30.49002 Boehringer Ingelheim Investigational Site
city: Großhansdorf
country: Germany
facility: 1199.30.49003 Boehringer Ingelheim Investigational Site
city: Leipzig
country: Germany
facility: 1199.30.49009 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1199.30.49004 Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: 1199.30.49005 Boehringer Ingelheim Investigational Site
city: Alexandroupolis
country: Greece
facility: 1199.30.30004 Boehringer Ingelheim Investigational Site
city: Heraklion
country: Greece
facility: 1199.30.30001 Boehringer Ingelheim Investigational Site
city: Larisa
country: Greece
facility: 1199.30.30002 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 1199.30.36002 Boehringer Ingelheim Investigational Site
city: Budapest
country: Hungary
facility: 1199.30.36003 Boehringer Ingelheim Investigational Site
city: Deszk
country: Hungary
facility: 1199.30.36004 Boehringer Ingelheim Investigational Site
city: Pecs
country: Hungary
facility: 1199.30.36001 Boehringer Ingelheim Investigational Site
city: Szekesfehervar
country: Hungary
facility: 1199.30.36005 Boehringer Ingelheim Investigational Site
city: Dublin 7
country: Ireland
facility: 1199.30.35301 Mater Misericordiae Hospital
city: Ascoli Piceno
country: Italy
facility: 1199.30.39008 Boehringer Ingelheim Investigational Site
city: Busto Arsizio (va)
country: Italy
facility: 1199.30.39013 Boehringer Ingelheim Investigational Site
city: Milano
country: Italy
facility: 1199.30.39007 Boehringer Ingelheim Investigational Site
city: Modena
country: Italy
facility: 1199.30.39001 Boehringer Ingelheim Investigational Site
city: Napoli
country: Italy
facility: 1199.30.39012 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 1199.30.39009 Boehringer Ingelheim Investigational Site
city: Roma
country: Italy
facility: 1199.30.39011 Boehringer Ingelheim Investigational Site
city: Siena
country: Italy
facility: 1199.30.39010 Boehringer Ingelheim Investigational Site
city: Terni
country: Italy
facility: 1199.30.39003 Boehringer Ingelheim Investigational Site
city: Trieste
country: Italy
facility: 1199.30.39004 Boehringer Ingelheim Investigational Site
city: Gyunggido
country: Korea, Republic of
facility: 1199.30.82002 Boehringer Ingelheim Investigational Site
city: Incheon
country: Korea, Republic of
facility: 1199.30.82004 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1199.30.82001 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1199.30.82003 Boehringer Ingelheim Investigational Site
city: Seoul
country: Korea, Republic of
facility: 1199.30.82005 Boehringer Ingelheim Investigational Site
city: Distrito Federal
country: Mexico
facility: 1199.30.52001 Boehringer Ingelheim Investigational Site
city: Nieuwegein
country: Netherlands
facility: 1199.30.31002 Boehringer Ingelheim Investigational Site
city: Coimbra
country: Portugal
facility: 1199.30.35105 Boehringer Ingelheim Investigational Site
city: Coimbra
country: Portugal
facility: 1199.30.35106 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1199.30.35107 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1199.30.35108 Boehringer Ingelheim Investigational Site
city: Lisboa
country: Portugal
facility: 1199.30.35109 Boehringer Ingelheim Investigational Site
city: Porto
country: Portugal
facility: 1199.30.35101 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 1199.30.07001 Boehringer Ingelheim Investigational Site
city: Moscow
country: Russian Federation
facility: 1199.30.07002 Boehringer Ingelheim Investigational Site
city: St. Petersburg
country: Russian Federation
facility: 1199.30.07003 Boehringer Ingelheim Investigational Site
city: Bellville
country: South Africa
facility: 1199.30.27001 Boehringer Ingelheim Investigational Site
city: Cape Town
country: South Africa
facility: 1199.30.27003 Boehringer Ingelheim Investigational Site
city: Tygerberg
country: South Africa
facility: 1199.30.27002 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1199.30.34001 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1199.30.34002 Boehringer Ingelheim Investigational Site
city: Taichung
country: Taiwan
facility: 1199.30.88605 Boehringer Ingelheim Investigational Site
city: Taipei
country: Taiwan
facility: 1199.30.88601 National Taiwan University
city: Taipei
country: Taiwan
facility: 1199.30.88603 Tri-service General Hospital
city: Taipei
country: Taiwan
facility: 1199.30.88606 Boehringer Ingelheim Investigational Site
city: Taoyuan
country: Taiwan
facility: 1199.30.88604 Chang Gung Memorial Hosp-Linkou
city: Ankara
country: Turkey
facility: 1199.30.90001 Boehringer Ingelheim Investigational Site
city: Istanbul
country: Turkey
facility: 1199.30.90002 Boehringer Ingelheim Investigational Site
city: Aberdeen
country: United Kingdom
facility: 1199.30.44006 Boehringer Ingelheim Investigational Site
city: Birmingham
country: United Kingdom
facility: 1199.30.44003 Boehringer Ingelheim Investigational Site
city: Birmingham
country: United Kingdom
facility: 1199.30.44005 Boehringer Ingelheim Investigational Site
city: Manchester
country: United Kingdom
facility: 1199.30.44007 Boehringer Ingelheim Investigational Site
city: Westbury on Trym
country: United Kingdom
facility: 1199.30.44001 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Glaspole I, Bonella F, Bargagli E, Glassberg MK, Caro F, Stansen W, Quaresma M, Orsatti L, Bendstrup E. Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities. Respir Res. 2021 Apr 26;22(1):125. doi: 10.1186/s12931-021-01695-y.
citation: Richeldi L, Kreuter M, Selman M, Crestani B, Kirsten AM, Wuyts WA, Xu Z, Bernois K, Stowasser S, Quaresma M, Costabel U. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax. 2018 Jun;73(6):581-583. doi: 10.1136/thoraxjnl-2016-209701. Epub 2017 Oct 9.
citation: Paterniti MO, Bi Y, Rekic D, Wang Y, Karimi-Shah BA, Chowdhury BA. Acute Exacerbation and Decline in Forced Vital Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc. 2017 Sep;14(9):1395-1402. doi: 10.1513/AnnalsATS.201606-458OC.
citation: Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Kluglich M, du Bois RM. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011 Sep 22;365(12):1079-87. doi: 10.1056/NEJMoa1103690.