Clinical Trial Results:
The main objective was to assess the safety and tolerability of the combined treatment with nintedanib and pirfenidone in patients with idiopathic pulmonary fibrosis (IPF).
Summary
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EudraCT number |
2015-000640-42 |
Trial protocol |
FR NL DE IT |
Global end of trial date |
31 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Dec 2017
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First version publication date |
27 Dec 2017
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
1199.222
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Boehringer Ingelheim
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Sponsor organisation address |
Binger Strasse, 173, Ingelheim am Rhein, Germany, 55216
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Public contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Scientific contact |
QRPE Processes and Systems Coordination
Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Mar 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Jan 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective was to assess the safety and tolerability of the combined treatment with nintedanib and pirfenidone in patients with idiopathic pulmonary fibrosis (IPF).
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Protection of trial subjects |
Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 25
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Country: Number of subjects enrolled |
Canada: 17
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Country: Number of subjects enrolled |
France: 48
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Country: Number of subjects enrolled |
Germany: 7
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Country: Number of subjects enrolled |
Italy: 11
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Country: Number of subjects enrolled |
Netherlands: 28
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Worldwide total number of subjects |
136
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EEA total number of subjects |
94
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
29
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From 65 to 84 years |
107
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85 years and over |
0
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Recruitment
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Recruitment details |
4 weeks of run-in treatment on 150 mg nintedanib twice daily, followed by 12 weeks of randomised treatment with either Nintedanib alone or with the combined treatment of Nintedanib and Pirfenidone.In this study,105 subjects were enrolled & randomized. | ||||||||||||||||||
Pre-assignment
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Screening details |
All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated. | ||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
Blinding implementation details |
This is a Randomised, open-label and parallel-group trial
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Nintedanib | ||||||||||||||||||
Arm 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). One subject randomised to Nintedanib was not treated. Although actual number of subjects started is 52, 51 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Nintedanib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
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).
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Arm title
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Nintedanib + Pirfenidone | ||||||||||||||||||
Arm 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. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Pirfenidone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Patients were administered Pirfenidone in combination with Nintedanib. 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.
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Investigational medicinal product name |
Nintedanib
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule, soft
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Routes of administration |
Oral use
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Dosage and administration details |
Patients were 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 dose.
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication. |
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Baseline characteristics reporting groups
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Reporting group title |
Nintedanib
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Reporting 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). One subject randomised to Nintedanib was not treated. Although actual number of subjects started is 52, 51 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib + Pirfenidone
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Reporting 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Nintedanib
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Reporting 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). One subject randomised to Nintedanib was not treated. Although actual number of subjects started is 52, 51 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects. | ||
Reporting group title |
Nintedanib + Pirfenidone
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Reporting 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. |
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End point title |
Percentage of patients with on-treatment gastrointestinal (GI) AEs (SOC GI disorders) from baseline to week 12 [1] | ||||||||||||
End point 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).
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End point type |
Primary
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End point timeframe |
Baseline and week 12
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothiesis test were tested. |
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Notes [2] - Treated set [3] - Treated set |
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No statistical analyses for this end point |
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End point title |
Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline, weeks 2 and 4 | |||||||||||||||||||||
End point description |
Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline (Visit 3), Week 2 (Visit 4) and Week 4 (Visit 5).
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.
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End point type |
Secondary
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End point timeframe |
baseline, prior to intake of study medication on week 2 and week 4
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Notes [4] - PKS [5] - PKS |
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No statistical analyses for this end point |
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End point title |
Predose plasma concentrations at steady state (Cpre,ss) of Pirfenidone [6] | ||||||||||||
End point description |
Predose plasma concentrations at steady state (Cpre,ss) of Pirfenidone at Week 2 (Visit 4) and Week 4 (Visit 5)
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End point type |
Secondary
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End point timeframe |
Prior to intake of study medication on week 2 and week 4
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported. |
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Notes [7] - PKS |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From first dose administration of the study medication to 28 days after last drug administration; up to 124 days
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
Nintedanib + Pirfenidone
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Reporting 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Nintedanib
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Reporting 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). One subject randomised to Nintedanib was not treated. Although actual number of subjects started is 52, 51 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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19 Feb 2016 |
The following main changes in the conduct of the trial were introduced by the amendment: 1) The trial clinical monitor responsibility changed. 2) Clarification that all treated patients needed to attend the end-of-treatment and follow-up visits. 3) Clarification that the collection of the vital status was only required for randomised patients. 4) The Exclusion Criterion no. 8 was updated (i.e. inclusion of severe renal impairment
based on Cockroft-Gault) to match the summary of product characteristics of pirfenidone. 5) Patients developing signs or symptoms of angioedema were to permanently discontinue
pirfenidone; this specification was added to match the summary of product characteristics of pirfenidone. 6) Exclusion Criterion no. 20 was added based on advice from regulatory agencies: patients
with underlying chronic liver disease (Child Pugh A, B, or C hepatic impairment) |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |