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Safety, Tolerability and PK of Nintedanib in Combination With Pirfenidone in IPF

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ClinicalTrials.gov Identifier: NCT02579603
Recruitment Status : Completed
First Posted : October 19, 2015
Results First Posted : February 13, 2018
Last Update Posted : February 13, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Idiopathic Pulmonary Fibrosis
Interventions Drug: Nintedanib
Drug: Pirfenidone
Enrollment 105
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Nintedanib Nintedanib + Pirfenidone
Hide Arm/Group Description Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily). Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily.
Period Title: Overall Study
Started 52 [1] 53 [1]
Number of Patients Treated 51 53
Completed 48 51
Not Completed 4 2
Reason Not Completed
Not treated             1             0
Adverse Event             2             2
Other than stated             1             0
[1]
Started are the randomised patients
Arm/Group Title Nintedanib Nintedanib + Pirfenidone Total
Hide Arm/Group Description Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily). Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily. Total of all reporting groups
Overall Number of Baseline Participants 51 53 104
Hide Baseline Analysis Population Description
Treated Set : The treated set (104 patients) consisted of all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of randomised investigational treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 53 participants 104 participants
68.9  (6.8) 68.9  (6.6) 68.9  (6.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 53 participants 104 participants
Female
7
  13.7%
11
  20.8%
18
  17.3%
Male
44
  86.3%
42
  79.2%
86
  82.7%
1.Primary Outcome
Title Percentage of Patients With On-treatment Gastrointestinal (GI) AEs (SOC GI Disorders) From Baseline to Week 12
Hide Description

Percentage of patients with on-treatment gastrointestinal (GI) Adverse events (AEs) (SOC GI disorders) from baseline to week 12.

On-treatment AEs were defined as AEs with an onset from the first dose of randomised treatment up to the last dose of randomised treatment (inclusive).

Time Frame Baseline to week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Treated set : The treated set (104 patients) consisted of all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of randomised investigational treatment.
Arm/Group Title Nintedanib Nintedanib + Pirfenidone
Hide Arm/Group Description:
Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily).
Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily.
Overall Number of Participants Analyzed 51 53
Measure Type: Number
Unit of Measure: percentage of participants
52.9 69.8
2.Secondary Outcome
Title Predose Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline, Weeks 2 and 4
Hide Description Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline (Visit 3), Week 2 (Visit 4) and Week 4 (Visit 5)
Time Frame baseline, prior to intake of study medication on week 2 and week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Set (PKS): This analysis set included all patients who had been treated with study medication and who provided evaluable data for at least 1 PK endpoint without important protocol violations relevant to the evaluation of PK.
Arm/Group Title Nintedanib Nintedanib + Pirfenidone
Hide Arm/Group Description:
Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily).
Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily.
Overall Number of Participants Analyzed 51 53
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
baseline Number Analyzed 46 participants 46 participants
7.08
(56.0%)
7.65
(72.5%)
Week 2 Number Analyzed 41 participants 35 participants
7.25
(52.7%)
8.17
(69.8%)
Week 4 Number Analyzed 44 participants 30 participants
5.92
(73.5%)
7.13
(63.9%)
3.Secondary Outcome
Title Predose Plasma Concentrations at Steady State (Cpre,ss) of Pirfenidone
Hide Description Predose plasma concentrations at steady state (Cpre,ss) of pirfenidone at Week 2 (Visit 4) and Week 4 (Visit 5)
Time Frame Prior to intake of study medication on week 2 and week 4
Hide Outcome Measure Data
Hide Analysis Population Description
PKS set
Arm/Group Title Nintedanib + Pirfenidone
Hide Arm/Group Description:
Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily.
Overall Number of Participants Analyzed 53
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Week 2 Number Analyzed 32 participants
1120
(122%)
Week 4 Number Analyzed 28 participants
1220
(90.7%)
Time Frame From first dose administration of the study medication to 28 days after last drug administration; up to 124 days.
Adverse Event Reporting Description Treated set was used. The treated set (104 patients) consisted of all randomised patients who were dispensed study medication and were documented to have taken at least 1 dose of randomised investigational treatment
 
Arm/Group Title Nintedanib Nintedanib + Pirfenidone
Hide Arm/Group Description Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily). Patients were orally administered Nintedanib 2x150 mg soft gelatine capsule daily (1 capsule of 150 mg twice daily) with the possibility to reduce to 2x100 mg daily (1 capsule of 100 mg twice daily) in combination with pirfenidone. The pirfenidone dose was titrated up to 2403 mg daily according to the following schedule: 801 mg (1 capsule of 267 mg 3 times daily) from Visit 3 until the phone call visit ; 1602 mg daily (2 capsules of each 267 mg 3 times daily) after the phone call visit; 2403 mg daily (3 capsules of each 267 mg 3 times daily) starting at Visit 4 after the PK sampling had been performed.The dose of pirfenidone could have been reduced to 1 or 2 capsule(s) 3 times daily.
All-Cause Mortality
Nintedanib Nintedanib + Pirfenidone
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Nintedanib Nintedanib + Pirfenidone
Affected / at Risk (%) Affected / at Risk (%)
Total   5/51 (9.80%)   2/53 (3.77%) 
Cardiac disorders     
Atrial flutter  1  1/51 (1.96%)  0/53 (0.00%) 
Gastrointestinal disorders     
Pancreatitis acute  1  1/51 (1.96%)  0/53 (0.00%) 
Infections and infestations     
Pneumonia  1  0/51 (0.00%)  1/53 (1.89%) 
Nervous system disorders     
Transient ischaemic attack  1  1/51 (1.96%)  0/53 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/51 (1.96%)  0/53 (0.00%) 
Idiopathic pulmonary fibrosis  1  0/51 (0.00%)  1/53 (1.89%) 
Vascular disorders     
Circulatory collapse  1  0/51 (0.00%)  1/53 (1.89%) 
Phlebitis  1  1/51 (1.96%)  0/53 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Nintedanib Nintedanib + Pirfenidone
Affected / at Risk (%) Affected / at Risk (%)
Total   36/51 (70.59%)   46/53 (86.79%) 
Gastrointestinal disorders     
Abdominal discomfort  1  0/51 (0.00%)  4/53 (7.55%) 
Abdominal pain  1  3/51 (5.88%)  4/53 (7.55%) 
Abdominal pain upper  1  4/51 (7.84%)  7/53 (13.21%) 
Constipation  1  1/51 (1.96%)  3/53 (5.66%) 
Diarrhoea  1  16/51 (31.37%)  20/53 (37.74%) 
Gastrooesophageal reflux disease  1  1/51 (1.96%)  3/53 (5.66%) 
Nausea  1  6/51 (11.76%)  22/53 (41.51%) 
Vomiting  1  6/51 (11.76%)  15/53 (28.30%) 
General disorders     
Asthenia  1  3/51 (5.88%)  1/53 (1.89%) 
Fatigue  1  6/51 (11.76%)  10/53 (18.87%) 
Pyrexia  1  1/51 (1.96%)  3/53 (5.66%) 
Hepatobiliary disorders     
Hepatocellular injury  1  0/51 (0.00%)  3/53 (5.66%) 
Infections and infestations     
Bronchitis  1  2/51 (3.92%)  5/53 (9.43%) 
Nasopharyngitis  1  2/51 (3.92%)  4/53 (7.55%) 
Injury, poisoning and procedural complications     
Contusion  1  3/51 (5.88%)  0/53 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  1/51 (1.96%)  3/53 (5.66%) 
Aspartate aminotransferase increased  1  1/51 (1.96%)  3/53 (5.66%) 
Gamma-glutamyltransferase increased  1  0/51 (0.00%)  3/53 (5.66%) 
Weight decreased  1  3/51 (5.88%)  4/53 (7.55%) 
Metabolism and nutrition disorders     
Decreased appetite  1  5/51 (9.80%)  6/53 (11.32%) 
Nervous system disorders     
Dizziness  1  3/51 (5.88%)  0/53 (0.00%) 
Dysgeusia  1  0/51 (0.00%)  3/53 (5.66%) 
Headache  1  1/51 (1.96%)  7/53 (13.21%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/51 (5.88%)  4/53 (7.55%) 
Dyspnoea  1  8/51 (15.69%)  2/53 (3.77%) 
Skin and subcutaneous tissue disorders     
Photosensitivity reaction  1  0/51 (0.00%)  3/53 (5.66%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02579603    
Other Study ID Numbers: 1199.222
2015-000640-42 ( EudraCT Number )
First Submitted: October 16, 2015
First Posted: October 19, 2015
Results First Submitted: December 7, 2017
Results First Posted: February 13, 2018
Last Update Posted: February 13, 2018