Safety and PK Study of BIBF 1120 in Japanese Patients With IPF

• ClinicalTrials.gov Identifier: NCT01136174
• Recruitment Status: Completed
• First Posted: June 3, 2010
• Results First Posted: January 6, 2015
• Last Update Posted: January 6, 2015
• Sponsor: Boehringer Ingelheim
• Information provided by: Boehringer Ingelheim

Study Description

Brief Summary:

To investigate safety of BIBF 1120 in Japanese patients with idiopathic pulmonary fibrosis (IPF), with and without pirfenidone background treatment.

To assess pharmacokinetics of BIBF 1120 in Japanese patients, with and without pirfenidone background treatment.

To assess pharmacokinetics of pirfenidone in Japanese patients, alone and in combination with BIBF 1120 treatment.

Condition or disease	Intervention/treatment	Phase
Idiopathic Pulmonary Fibrosis	Drug: Placebo; Drug: BIBF 1120	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Official Title: A Double-blind, Randomised, Placebo-controlled (Within a Dose Group) Study to Evaluate Safety and Pharmacokinetics of Multiple Rising Doses of BIBF 1120 at 50 mg Bid (14 Days), 100 mg Bid (14 Days), and 150 mg Bid (28 Days) p.o., on Top of Standard Medical Care With Stratification According to Pirfenidone Use, in Japanese Patients With Idiopathic Pulmonary Fibrosis.
• Study Start Date: May 2010
• Actual Primary Completion Date: March 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: BIBF 1120 50 mg; Low dose for cohort 1	Drug: BIBF 1120; 50 mg, 100 mg, 150 mg BID will be used for Cohort 1, 2, and 3 respectively
Experimental: BIBF 1120 100 mg; Middle dose for cohort 2	Drug: BIBF 1120; 50 mg, 100 mg, 150 mg BID will be used for Cohort 1, 2, and 3 respectively
Experimental: BIBF 1120 150 mg; High dose for cohort 3	Drug: BIBF 1120; 50 mg, 100 mg, 150 mg BID will be used for Cohort 1, 2, and 3 respectively
Placebo Comparator: Placebo; Placebo for cohort 1,2,3	Drug: Placebo; Placebo BID for cohort 1,2,3

Outcome Measures

Primary Outcome Measures :

1. Drug-related Adverse Events [ Time Frame: after the first drug intake until 28 days from the last treatment administration, up to 60 days ]
   The number of patients with drug-related adverse events stratified according to pirfenidone use in each group

Secondary Outcome Measures :

1. AUCτ,ss After Multiple Doses of BIBF 1120 Without Pirfenidone [ Time Frame: pre-dose, then 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose on days 14 to 17 (BIBF 1120 50 mg and 100 mg) or on days 28 to 31 (BIBF 1120 150 mg) ]

   AUCτ,ss was calculated as the area under the concentration-time curve of the concentration-time profile of the analyte in plasma at steady state over a uniform dosing interval τ after multiple doses of BIBF 1120 without pirfenidone in the time frame mentioned.

   Detailed outcome measure time frame:

   In 50 mg and 100 mg dose group:

   BIBF 1120:

   days 14 (-1, +3) to 17 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

   In 150 mg dose group:

   BIBF 1120:

   days 28 (-1, +3) to 31 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

2. Cmax,ss After Multiple Doses of BIBF 1120 Without Pirfenidone [ Time Frame: pre-dose, then 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose on days 14 to 17 (BIBF 1120 50 mg and 100 mg) or on days 28 to 31 (BIBF 1120 150 mg) ]

   Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points over a uniform dosing interval τ after multiple doses of BIBF 1120 without pirfenidone.

   Detailed outcome measure time frame:

   In 50 mg and 100 mg dose group:

   BIBF 1120:

   days 14 (-1, +3) to 17 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

   In 150 mg dose group:

   BIBF 1120:

   days 28 (-1, +3) to 31 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

3. AUCτ,ss After Multiple Doses of BIBF 1120 With Pirfenidone [ Time Frame: pre-dose, then 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose on days 14 to 17 (BIBF 1120 50 mg and 100 mg) or on days 28 to 31 (BIBF 1120 150 mg) ]

   AUCτ,ss was calculated as the area under the concentration-time curve of the concentration-time profile of the analyte in plasma at steady state over a uniform dosing interval τ after multiple doses of BIBF 1120 with pirfenidone in the time frame mentioned.

   Detailed outcome measure time frame:

   In 50 mg and 100 mg dose group:

   BIBF 1120:

   days 14 (-1, +3) to 17 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

   In 150 mg dose group:

   BIBF 1120:

   days 28 (-1, +3) to 31 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

4. Cmax,ss After Multiple Doses of BIBF 1120 With Pirfenidone [ Time Frame: pre-dose, then 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose on days 14 to 17 (BIBF 1120 50 mg and 100 mg) or on days 28 to 31 (BIBF 1120 150 mg) ]

   Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points over a uniform dosing interval τ after multiple doses of BIBF 1120 with pirfenidone

   Detailed outcome measure time frame:

   In 50 mg and 100 mg dose group:

   BIBF 1120:

   days 14 (-1, +3) to 17 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

   In 150 mg dose group:

   BIBF 1120:

   days 28 (-1, +3) to 31 at Visit 5: At pre-dose and 0.5 h, 1 h, 2 h, 3 h, 3.92 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h after morning dose

5. AUC0-4,ss After Multiple Doses of Pirfenidone 600 mg Without BIBF 1120 (After Breakfast) [ Time Frame: Day -1 at Visit 1: At pre-dose and 0.5 h, 1 h, 2 h, 3 h after morning dose and pre-dose after lunch dose ]
   AUC0-4,ss was calculated as the area under the curve of the concentration-time profile of the analyte in plasma at steady state over the time interval from 0 to 4 hours after multiple doses of Pirfenidone 600 mg without BIBF 1120 (after breakfast) in the time frame mentioned.
6. Cmax,ss After Multiple Doses of Pirfenidone 600 mg Without BIBF 1120 (After Breakfast) [ Time Frame: Day -1 at Visit 1: At pre-dose and 0.5 h, 1 h, 2 h, 3 h after morning dose and pre-dose after lunch dose ]
   Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points after multiple doses of Pirfenidone 600 mg without BIBF 1120 (after breakfast)
7. AUC0-4,ss After Multiple Doses of Pirfenidone 600 mg With BIBF 1120 (After Breakfast) [ Time Frame: Day 14 at Visit 5 (BIBF 1120 50mg and 100mg) and day 28 (visit 7) (BIBF 1120 150mg): At pre-dose and 0.5 h, 1 h, 2 h, 3 h after morning dose and pre-dose after lunch dose ]
   AUC0-4,ss was calculated as the area under the concentration-time curve of the concentration-time profile of the analyte in plasma at steady state over the time interval from 0 to 4 hours after multiple doses of Pirfenidone 600 mg with BIBF 1120 (after breakfast) in the time frame mentioned.
8. Cmax,ss After Multiple Doses of Pirfenidone 600 mg With BIBF 1120 (After Breakfast) [ Time Frame: Day 14 at Visit 5 (BIBF 1120 50mg and 100mg) and day 28 (visit 7) (BIBF 1120 150mg): At pre-dose and 0.5 h, 1 h, 2 h, 3 h after morning dose and pre-dose after lunch dose ]
   Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points after multiple doses of Pirfenidone 600 mg with BIBF 1120 (after breakfast)
9. AUC0-8,ss After Multiple Doses of Pirfenidone 600 mg Without BIBF 1120 (After Lunch) [ Time Frame: Day -1 at Visit 1: at pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h after lunch dose ]
   AUC0-8,ss was calculated as the area under the concentration-time curve of the concentration-time profile of the analyte in plasma at steady state over the time interval from 0 to 8 hours after multiple doses of Pirfenidone 600 mg without BIBF 1120 (after lunch) in the time frame mentioned.
10. Cmax,ss After Multiple Doses of Pirfenidone 600 mg Without BIBF 1120 (After Lunch) [ Time Frame: Day -1 at Visit 1: at pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h after lunch dose ]
    Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points after multiple doses of Pirfenidone 600 mg Without BIBF 1120 (after lunch)
11. AUC0-8,ss After Multiple Doses of Pirfenidone 600 mg With BIBF 1120 (After Lunch) [ Time Frame: Day 14 at Visit 5 (BIBF 1120 50mg and 100mg) and day 28 (visit 7) (BIBF 1120 150mg): at pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h after lunch dose ]
    AUC0-8,ss was calculated as the area under the concentration-time curve of the concentration-time profile of the analyte in plasma at steady state over the time interval from 0 to 8 hours after multiple doses of Pirfenidone 600 mg with BIBF 1120 (after lunch) in the time frame mentioned.
12. Cmax,ss After Multiple Doses of Pirfenidone 600 mg With BIBF 1120 (After Lunch) [ Time Frame: Day 14 at Visit 5 (BIBF 1120 50mg and 100mg) and day 28 (visit 7) (BIBF 1120 150mg): at pre-dose and 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h after lunch dose ]
    Maximum measured concentration of the analyte in plasma at steady state was identified from measurements obtained at multiple time points after multiple doses of Pirfenidone 600 mg with BIBF 1120 (after lunch)
13. Withdrawal Due to Adverse Event [ Time Frame: after the first drug intake until 28 days from the last treatment administration, up to 60 days ]
    Number of patients prematurely discontinued from trial medication due to adverse event.
14. Clinical Relevant Abnormalities in Laboratory Parameters- No Pirfenidone Background [ Time Frame: after the first drug intake until 28 days from the last treatment administration, up to 60 days ]
    Number of patients with Clinical Relevant Abnormalities in laboratory parameters reported as adverse events - No pirfenidone background
15. Clinical Relevant Abnormalities in Laboratory Parameters- With Pirfenidone Background [ Time Frame: after the first drug intake until 28 days from the last treatment administration, up to 60 days ]
    Number of patients with Clinical Relevant Abnormalities in laboratory parameters reported as adverse events - With pirfenidone background
16. Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: baseline and day 35 ]
    Change from baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
17. Change From Baseline in Pulse Rate [ Time Frame: baseline and day 35 ]
    Change from baseline in pulse rate at day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
18. Lung Function Measurement: Diffusing Capacity for Carbon Monoxide (DLco) [ Time Frame: baseline and day 35 ]
    Change in diffusing capacity for carbon monoxide (DLco) from baseline to day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
19. Lung Function Measurement: Diffusing Capacity for Carbon Monoxide Percent of Predicted (%DLco) [ Time Frame: baseline and day 35 ]
    Change in Diffusing Capacity for Carbon Monoxide percent of predicted (%DLco) from baseline to day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
20. Lung Function Measurement: Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: baseline and day 35 ]
    Change in forced expiratory volume in 1 second (FEV1) from baseline to day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
21. Lung Function Measurement: Forced Vital Capacity (FVC) [ Time Frame: baseline and day 35 ]
    Change in forced vital capacity (FVC) from baseline to day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.
22. Lung Function Measurement: Forced Vital Capacity Percent of Predicted (%FVC) [ Time Frame: baseline and day 35 ]
    Change in Forced Vital Capacity percent of predicted (%FVC) from baseline to day 35. Only the results for placebo and Nintedanib 150mg arm were reported for this endpoint as nintedanib 150mg is the target dose.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. Diagnosis of idiopathic pulmonary fibrosis (IPF) according to American Thoracic Society (ATS) /European Respiratory Society (ERS) guideline
2. Forced vital capacity (FVC) 50-90%
3. Diffusing capacity for carbon monoxide (DLCO) 30-79%
4. For patients on pirfenidone, have been on a steady dose for at least 3 months

Exclusion criteria:

1. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 x upper limit of normal range (ULN) at screening.
2. Bilirubin > 1.5 x ULN at screening.
3. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7) at screening.
4. Continuous oxygen supplementation.
5. Active infection at screening or randomisation.

6. Being treated with any of the following concomitant medications.

   • Oral corticosteroid medication at unstable dose
   • ketoconazole or atazanavir
7. Patients who are expected to go on to lung transplantation, have rapidly deteriorating disease, or have a life expectancy less than 3 months from screening

Contacts and Locations

Locations

Japan

1199.31.002 Boehringer Ingelheim Investigational Site

Bunkyo-ku,Tokyo, Japan

1199.31.004 Boehringer Ingelheim Investigational Site

Hamamatsu, Shizuoka, Japan

1199.31.008 Boehringer Ingelheim Investigational Site

Himeji, Hyogo, Japan

1199.31.006 Boehringer Ingelheim Investigational Site

Nagoya, Aichi, Japan

1199.31.007 Boehringer Ingelheim Investigational Site

Sakai, Osaka, Japan

1199.31.005 Boehringer Ingelheim Investigational Site

Seto, Aichi, Japan

1199.31.001 Boehringer Ingelheim Investigational Site

Shimotsuke,Tochigi, Japan

1199.31.003 Boehringer Ingelheim Investigational Site

Yokohama, Kanagawa, Japan

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando M, Abe S, Mochizuki Y, Chida K, Klüglich M, Fujimoto T, Okazaki K, Tadayasu Y, Sakamoto W, Sugiyama Y. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2015 May;45(5):1382-92. doi: 10.1183/09031936.00198013. Epub 2014 Dec 10.

• Responsible Party: Boehringer Ingelheim, Study Chair, Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01136174
• Other Study ID Numbers: 1199.31
• First Posted: June 3, 2010
• Results First Posted: January 6, 2015
• Last Update Posted: January 6, 2015
• Last Verified: December 2014

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Nintedanib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action