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    Clinical Trial Results:
    An Exploratory Multicenter, Open-label, Single Arm Study of the Safety and Tolerability of Pirfenidone (Esbriet®) in Combination with Nintedanib (Ofev®) in Patients with Idiopathic Pulmonary Fibrosis

    Summary
    EudraCT number
    2015-003280-11
    Trial protocol
    DE   ES   DK   NL   IT  
    Global end of trial date
    16 May 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2018
    First version publication date
    30 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MA29895
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02598193
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    16 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This 1-arm study is to investigate the safety and tolerability of adding nintedanib to treatment with pirfenidone in subjects with idiopathic pulmonary fibrosis.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Jan 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    89
    EEA total number of subjects
    40
    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)
    23
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects with idiopathic pulmonary fibrosis were recruited for this study.

    Pre-assignment
    Screening details
    At the start of Screening, subjects will have been on pirfenidone for at least 16 weeks and on a stable dose (1602–2403 mg/d) for at least 28 days. A total of 109 subjects were screened, 20 subjects were screen failures and 89 were enrolled at 36 study centers in 8 countries.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Experimental: Pirfenidone+Nintedanib
    Arm description
    Subjects with idiopathic pulmonary fibrosis (IPF) received pirfenidone at 1602-2403 milligrams per day (mg/day) dose and nintedanib at the 200-300 mg/day dose up to 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Esbriet
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Three 267 milligrams (mg) capsules orally administered three times a day for 24 weeks (total dose, 2403 mg/day)

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Ofev
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 150 mg orally administered as capsule twice daily for 24 weeks

    Number of subjects in period 1
    Experimental: Pirfenidone+Nintedanib
    Started
    89
    Completed
    73
    Not completed
    16
         Adverse event
    13
         Listen in active lung transplant list
    1
         Does not want to take nintedanib
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: Pirfenidone+Nintedanib
    Reporting group description
    Subjects with idiopathic pulmonary fibrosis (IPF) received pirfenidone at 1602-2403 milligrams per day (mg/day) dose and nintedanib at the 200-300 mg/day dose up to 24 weeks.

    Reporting group values
    Experimental: Pirfenidone+Nintedanib Total
    Number of subjects
    89 89
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    68.2 ± 6.82 -
    Gender Categorical
    Units: Subjects
        Female
    18 18
        Male
    71 71
    Race
    Units: Subjects
        White
    84 84
        Black or African American
    3 3
        Asian
    1 1
        Asian/White
    1 1
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    9 9
        Not Hispanic or Latino
    74 74
        Missing
    6 6

    End points

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    End points reporting groups
    Reporting group title
    Experimental: Pirfenidone+Nintedanib
    Reporting group description
    Subjects with idiopathic pulmonary fibrosis (IPF) received pirfenidone at 1602-2403 milligrams per day (mg/day) dose and nintedanib at the 200-300 mg/day dose up to 24 weeks.

    Primary: Percentage of Subjects Who Complete 24 Weeks of Combination Treatment on Pirfenidone at a Dose of 1602-2403 mg/day and Nintedanib at a Dose of 200-300 mg/day

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    End point title
    Percentage of Subjects Who Complete 24 Weeks of Combination Treatment on Pirfenidone at a Dose of 1602-2403 mg/day and Nintedanib at a Dose of 200-300 mg/day [1]
    End point description
    Safety population included all subjects who had received at least one dose of investigational medicinal product on or after Day 1.
    End point type
    Primary
    End point timeframe
    Week 24
    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: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    Experimental: Pirfenidone+Nintedanib
    Number of subjects analysed
    89
    Units: percentage of subjects
        number (confidence interval 95%)
    77.5 (67.4 to 85.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events and Serious Adverse Events

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    End point title
    Percentage of Subjects with Adverse Events and Serious Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Safety population included all subjects who had received at least one dose of investigational medicinal product on or after Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 28
    End point values
    Experimental: Pirfenidone+Nintedanib
    Number of subjects analysed
    89
    Units: percentage of subjects
    number (not applicable)
        Adverse Event
    98.9
        Serious Adverse Event
    18.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Discontinue Pirfenidone, Nintedanib, or Both Study Treatments Because of Adverse Events Before the Week 24 Visit

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    End point title
    Percentage of Subjects Who Discontinue Pirfenidone, Nintedanib, or Both Study Treatments Because of Adverse Events Before the Week 24 Visit
    End point description
    Safety population included all subjects who had received at least one dose of investigational medicinal product on or after Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    Experimental: Pirfenidone+Nintedanib
    Number of subjects analysed
    13
    Units: percentage of subjects
        number (confidence interval 95%)
    14.6 (8.0 to 23.7)
    No statistical analyses for this end point

    Secondary: Total Number of Subject Days of Combination Treatment With Pirfenidone and Nintedanib

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    End point title
    Total Number of Subject Days of Combination Treatment With Pirfenidone and Nintedanib
    End point description
    Safety population included all subjects who had received at least one dose of investigational medicinal product on or after Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    Experimental: Pirfenidone+Nintedanib
    Number of subjects analysed
    89
    Units: subject days
    13330
    No statistical analyses for this end point

    Secondary: Total Number of Days From the Initiation of Combination Treatment to Discontinuation of Pirfenidone, Nintedanib, or Both Study Treatments

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    End point title
    Total Number of Days From the Initiation of Combination Treatment to Discontinuation of Pirfenidone, Nintedanib, or Both Study Treatments
    End point description
    Safety population included all participants who had received at least one dose of investigational medicinal product on or after Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    Experimental: Pirfenidone+Nintedanib
    Number of subjects analysed
    89
    Units: Number of Days
        arithmetic mean (standard deviation)
    149.8 ± 43.93
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 28
    Adverse event reporting additional description
    Safety population included all subjects who received at least one dose of investigational medicinal product on or after Day 1.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Experimental: Pirfenidone+Nintedanib
    Reporting group description
    Subjects with IPF will receive pirfenidone at 1602-2403 milligrams per day (mg/day) dose and nintedanib at the 200-300 mg/day dose up to 24 weeks.

    Serious adverse events
    Experimental: Pirfenidone+Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 89 (17.98%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    3 / 89 (3.37%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    2 / 89 (2.25%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Experimental: Pirfenidone+Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 89 (93.26%)
    Investigations
    Weight decreased
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 89 (22.47%)
         occurrences all number
    22
    Dyspnoea
         subjects affected / exposed
    10 / 89 (11.24%)
         occurrences all number
    10
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 89 (14.61%)
         occurrences all number
    22
    Dizziness
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 89 (15.73%)
         occurrences all number
    16
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 89 (5.62%)
         occurrences all number
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    52 / 89 (58.43%)
         occurrences all number
    184
    Nausea
         subjects affected / exposed
    44 / 89 (49.44%)
         occurrences all number
    70
    Vomiting
         subjects affected / exposed
    29 / 89 (32.58%)
         occurrences all number
    57
    Dyspepsia
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 89 (7.87%)
         occurrences all number
    7
    Abdominal pain upper
         subjects affected / exposed
    6 / 89 (6.74%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 89 (15.73%)
         occurrences all number
    14
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 89 (10.11%)
         occurrences all number
    13
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 89 (8.99%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2015
    1) Study assessments have been changed to decrease the number of 12-lead electrocardiograms (ECGs) because no abnormalities in the ECGs potentially caused by pirfenidone were detected. 2) Clarification has been added on subjects to sign informed consent form prior to washout or discontinuation of prohibited medication. 3) Screening period has been changed to clarify that subjects stop commercial Esbriet and switch to pirfenidone provided as study drug based on feedback received during feasibility testing that there is an obligation in some countries to supply subjects with study medication once eligibility is confirmed. 4) Changes have been made to reflect that collection of unused pirfenidone need to be done, and dosing adherence, AEs and concomitant medications need to be reviewed, which is necessary as subject receives study drug from Screening Day to Day 21. 5) Relevant sections have been changed to clarify the allowance of down-titration for both study medication used in this trial.
    21 Jun 2016
    1) Excluded subjects with clinical evidence of active infection only if, according to the investigator, the infection would interfere with the study conduct, measurement of pulmonary function, or impact the course of IPF. 2) Excluded all subjects with any degree of hepatic impairment, based on an updated United States Package Insert (USPI) for nintedanib. 3) Excluded all subjects with hypersensitivity to peanuts or soy, and added soy products and soy lecithin-containing products as prohibited foods. 4) The requirement for a urine pregnancy test at Baseline was removed, as a serum pregnancy test was already required at Baseline. 5) Revised the Schedule of Assessments to include collection of Forced expiratory volume at 1 second (FEV1) at Screening and Baseline and to include the King’s Brief Interstitial Lung Disease (KBILD) questionnaire at the Early Discontinuation Visit. 6) Schedule of Assessment was revised to include monthly urine pregnancy testing for women of childbearing potential, based on a request by the Health Authorities in Germany. 7) The option for blood samples for laboratory tests to be drawn by a home nursing agency was added. 8) Clarified the timing for providing informed consent prior to entering the Washout Period, and clarified the procedure for tapering (down titration) of prohibited medications during the Washout Period. 9) Revised the assessment of laboratory parameters to specify c-reactive protein (CRP) as a separate measurement, and to remove hemoglobin A1c. 10) Added a third independent data monitoring committee (iDMC) meeting when approximately 75% of the total subject group had either completed 24 weeks of combination treatment or had permanently discontinued study treatments.
    21 Jun 2016
    11) Added a Biomarker Study to the protocol for the purpose of assessing the pharmacodynamic effect of nintedanib on pirfenidone- or IPC-related biomarkers. 12) Revised the Safety Population definition. 13) Corrected the confidence intervals (CIs) from 80% to 95% for reporting the number and proportion of subjects who completed 24 weeks on pirfenidone at a dose of 1602 to 2403 mg/day and nintedanib at a dose of 200 to 300 mg/day, and the number and proportion of subjects who discontinued combination treatment because of an AE. 14) Updated the embryo-fetal toxicity of nintedanib and updated the pirfenidone pregnancy wording. 15) Updated the impact on pirfenidone treatment due to a photosensitivity reaction or rash and gastrointestinal side effects. 16) Added hepatic side effects as a safety measure to be analyzed. 17) Revised contraception requirements after the final Follow-up Visit and updated reporting requirements related to hospitalizations, pregnancy, and post-study AEs. 18) Clarified that all adverse event of special interests (AESIs) needed to be reported within 24 hours after learning of the event.

    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
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