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    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
    EudraCT number
    		 2015-000640-42
    Trial protocol
    		 FR   NL   DE   IT  
    Global end of trial date
    31 Jan 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2017
    First version publication date
    27 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.222
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse, 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    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).
    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
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Netherlands: 28
    Worldwide total number of subjects
    136
    EEA total number of subjects
    94
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    29
    From 65 to 84 years
    107
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This is a Randomised, open-label and parallel-group trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    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).

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    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.

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    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.

    Number of subjects in period 1 [1]
    		Nintedanib Nintedanib + Pirfenidone
    Started
    51
    53
    Completed
    48
    51
    Not completed
    3
    2
         Adverse event, non-fatal
    2
    2
         Other than stated
    1
    -
    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.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib
    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
    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 values
    		 Nintedanib Nintedanib + Pirfenidone Total
    Number of subjects
    		 51 53 104
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age Continuous
    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.
    Units: years
        arithmetic mean (standard deviation)
    		 68.9 ± 6.8 68.9 ± 6.6 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 7 11 18
        Male
    		 44 42 86

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib
    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
    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.

    Primary: Percentage of patients with on-treatment gastrointestinal (GI) AEs (SOC GI disorders) from baseline to week 12

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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).
    End point type
    Primary
    End point timeframe
    Baseline and week 12
    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.
    End point values
    		 Nintedanib Nintedanib + Pirfenidone
    Number of subjects analysed
    51 [2]
    53 [3]
    Units: percentage of participants
        number (not applicable)
    52.9
    69.8
    Notes
    [2] - Treated set
    [3] - Treated set
    No statistical analyses for this end point

    Secondary: Predose plasma concentrations at steady state (Cpre,ss) of nintedanib at baseline, weeks 2 and 4

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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.
    End point type
    Secondary
    End point timeframe
    baseline, prior to intake of study medication on week 2 and week 4
    End point values
    		 Nintedanib Nintedanib + Pirfenidone
    Number of subjects analysed
    51 [4]
    53 [5]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        baseline (# of participants analysed= 46; 46)
    7.08 ± 56.0
    7.65 ± 72.5
        Week 2 (# of participants analysed= 41; 35)
    7.25 ± 52.7
    8.17 ± 69.8
        Week 4 (# of participants analysed= 44; 30)
    5.92 ± 73.5
    7.13 ± 63.9
    Notes
    [4] - PKS
    [5] - PKS
    No statistical analyses for this end point

    Secondary: Predose plasma concentrations at steady state (Cpre,ss) of Pirfenidone

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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)
    End point type
    Secondary
    End point timeframe
    Prior to intake of study medication on week 2 and week 4
    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.
    End point values
    		 Nintedanib + Pirfenidone
    Number of subjects analysed
    53 [7]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Week 2 (# of participants analysed= 32)
    1120 ± 122
        Week 4 (# of participants analysed= 28)
    1220 ± 90.7
    Notes
    [7] - PKS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose administration of the study medication to 28 days after last drug administration; up to 124 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Nintedanib + Pirfenidone
    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
    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.

    Serious adverse events
    		 Nintedanib + Pirfenidone Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 51 (9.80%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nintedanib + Pirfenidone Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 53 (86.79%)
    36 / 51 (70.59%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Weight decreased
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Dysgeusia
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Headache
         subjects affected / exposed
    7 / 53 (13.21%)
    1 / 51 (1.96%)
         occurrences all number
    7
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Fatigue
         subjects affected / exposed
    10 / 53 (18.87%)
    6 / 51 (11.76%)
         occurrences all number
    13
    6
    Pyrexia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 53 (7.55%)
    0 / 51 (0.00%)
         occurrences all number
    5
    0
    Abdominal pain
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Abdominal pain upper
         subjects affected / exposed
    7 / 53 (13.21%)
    4 / 51 (7.84%)
         occurrences all number
    8
    4
    Constipation
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Diarrhoea
         subjects affected / exposed
    20 / 53 (37.74%)
    16 / 51 (31.37%)
         occurrences all number
    34
    28
    Nausea
         subjects affected / exposed
    22 / 53 (41.51%)
    6 / 51 (11.76%)
         occurrences all number
    27
    7
    Vomiting
         subjects affected / exposed
    15 / 53 (28.30%)
    6 / 51 (11.76%)
         occurrences all number
    25
    7
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 53 (7.55%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Dyspnoea
         subjects affected / exposed
    2 / 53 (3.77%)
    8 / 51 (15.69%)
         occurrences all number
    2
    8
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 53 (9.43%)
    2 / 51 (3.92%)
         occurrences all number
    5
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 53 (7.55%)
    2 / 51 (3.92%)
         occurrences all number
    4
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 53 (11.32%)
    5 / 51 (9.80%)
         occurrences all number
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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