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    Summary
    EudraCT Number:2015-005131-40
    Sponsor's Protocol Code Number:MA29957
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-10-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2015-005131-40
    A.3Full title of the trial
    A PHASE IIb, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED
    STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF SILDENAFIL ADDED TO PIRFENIDONE IN PATIENTS
    WITH ADVANCED IDIOPATHIC PULMONARY FIBROSIS AND RISK OF GROUP 3 PULMONARY HYPERTENSION.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Efficacy, Safety, and Tolerability of Sildenafil Added
    to Pirfenidone in Patients with Advanced Idiopathic Pulmonary Fibrosis and
    Risk of Pulmonary Hypertension due to the lung disease.
    A.4.1Sponsor's protocol code numberMA29957
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF. Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF. Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Esbriet
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/04/241
    D.3 Description of the IMP
    D.3.1Product nameEsbriet
    D.3.2Product code RO0220912
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPIRFENIDONE
    D.3.9.1CAS number 53179-13-8
    D.3.9.2Current sponsor codeRO0220912
    D.3.9.4EV Substance CodeSUB09907MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number267
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Sildenafil
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharmaceuticals USA Inc
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSildenafil
    D.3.2Product code RO0280296
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSILDENAFIL
    D.3.9.1CAS number 139755-83-2
    D.3.9.4EV Substance CodeSUB10517MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary Hypertension in patients with Idiopathic pulmonary fibrosis (IPF)
    E.1.1.1Medical condition in easily understood language
    Idiopathic pulmonary fibrosis leads to formation of scars in lungs due to unknown reason causing breathing problems. Pulmonary Hypertension is a disease adversely affecting blood flow in lungs.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10021240
    E.1.2Term Idiopathic pulmonary fibrosis
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of adding sildenafil compared with placebo to
    pirfenidone treatment in patients with advanced IPF and risk of Group 3
    pulmonary hypertension (PH) on the basis of relevant decline in 6-
    minute walk distance (6MWD) of at least 15% from baseline,
    respiratory-related non-elective hospitalizations, or all-cause mortality
    E.2.2Secondary objectives of the trial
    •To evaluate the efficacy of adding sildenafil compared with placebo to pirfenidone treatment on the basis of
    Progression-free survival (PFS)
    Proportion of patients with decline in 6MWD of >=15% from baseline
    Time to all-cause and respiratory-related non-elective hospitalization
    Time to death from any cause and respiratory-related death
    Lung transplantation
    Change from baseline in transthoracic echocardiography (ECHO) parameters, pulmonary function tests (PFTs), and oxyhemoglobin saturation (SpO2) at rest and during the 6MWT
    World Health Organization (WHO) Functional Class
    Dyspnoea (assessed by the University of California San Diego Shortness of Breath questionnaire [UCSD SOBQ])
    Health-related quality of life (HRQoL) (assessed by the Saint George’s Respiratory Questionnaire [SGRQ])
    N-terminal pro-brain natriuretic peptide (NT-proBNP) level (assessed by a blood test)

    •To evaluate the safety of adding sildenafil compared with placebo to pirfenidone treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age 40-80 years (inclusive) at Screening
    - Diagnosis of IPF for at least 3 months prior to screening
    - Confirmation of IPF diagnosis by the Investigator, in accordance with
    the 2011 international consensus guidelines, at Screening
    - Advanced IPF as defined by a measurable carbon monoxide diffusing
    capacity/pulmonary diffusing capacity [DLCO] <= 40% of predicted
    value at Screening and risk of Grade 3 PH (as defined in the protocol)
    - Prior to the start of Screening, receiving pirfenidone for at least 12
    weeks, and on a dose in the range of 1602 to 2403 mg/day for at least 4
    weeks prior to the first Screening Visit.
    - WHO Functional Class II or III at Screening
    - 6MWD of 100 to 450 meters at Screening
    - For women of childbearing potential: agreement to remain abstinent
    or use a non-hormonal contraceptive method with a failure rate of <1%
    per year during the treatment period and for at least 58 days after the
    last dose of study treatment
    - For men who are not surgically sterile: agreement to remain
    abstinent or use contraceptive measures, and agreement to refrain from
    donating sperm for at least 118 days after the last dose of study
    treatment
    E.4Principal exclusion criteria
    - History of any of the following types of PH: Group 1 pulmonary arterial hypertension (PAH); Group 2 (left-heart disease); Group 3 (due to conditions other than interstitial lung disease; Group 4 (chronic thromboembolic pulmonary hypertension); Group 5 (other disorders)
    - History of clinically significant cardiac disease in the opinion of the Investigator
    - History of coexistent and clinically significant (in the opinion of the Investigator) COPD, bronchiectasis, asthma, inadequately treated sleep-disordered breathing, or any clinically significant pulmonary diseases or disorders other than IPF or PH secondary to IPF
    - Hypotension, autonomic dysfunction, or conditions in which vasodilation may cause an unsafe drop in blood pressure (BP)
    - History of use of drugs and toxins known to cause PAH
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be evaluated based on a comparison of the proportion of patients showing disease progression over 52 weeks of treatment period, as evidenced by reaching the following combined endpoint:
    •Relative decline in 6MWD of at least 15% from baseline (as defined in the protocol), respiratory related non elective hospitalization, or all cause mortality
    E.5.1.1Timepoint(s) of evaluation of this end point
    •The primary analysis of the study will be conducted when all patients completed the 52 weeks treatment phase and the mandatory 4 weeks follow-up visit.
    E.5.2Secondary end point(s)
    Efficacy:
    1.Progression-free survival (PFS)
    2.Proportion of patients with decline in 6MWD of >=15% from baseline
    3.Time to respiratory-related non-elective hospitalization
    4.Time to death from any cause
    5.Lung transplantation will be analysed descriptively
    6.Time to all-cause non-elective hospitalization
    7.Time to respiratory-related death
    8.Change from baseline in transthoracic ECHO parameters
    9.Change from baseline in PFTs (FVC, FEV1, FEV1/FVC, and DLCO)
    10.Oxyhemoglobin saturation (SpO2) at rest and during the 6MWT will be summarized descriptively over time
    11.Borg scale measurement of perceived exertion will be summarized descriptively over time
    12.WHO Functional Class II or III over time
    13.Dyspnea as assessed by UCSD SOBQ will be summarized descriptively over time
    14.HRQoL (assessed by SGRQ) will be summarized descriptively over time
    15.Changes from baseline in NT-proBNP levels
    Safety:
    16.Nature, frequency, severity, relationship and timing of treatment-emergent adverse events
    17.Changes in vital signs, physical examination, clinical laboratory test results, 12-lead electrocardiograms (ECGs)
    18.Proportion of patients with study discontinuation or study drug discontinuation
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-18. The primary analysis of the study will be conducted when all patients completed the 52 weeks treatment phase and the mandatory 4 weeks follow-up visit.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    TOLERABILITY
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Belgium
    Canada
    Czech Republic
    Egypt
    Germany
    Greece
    Hungary
    Israel
    Italy
    Netherlands
    South Africa
    Spain
    Turkey
    United Arab Emirates
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the clinical trial is defined as the date when the last patient completes the last visit (LPLV) or the date at which the last data point which is required for the statistical analysis is received, whichever is the later date.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 132
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 117
    F.4.2.2In the whole clinical trial 176
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The sponsor will offer the possibility to the patient to receive pirfenidone within the study protocol for 12 months safety FU after completing visit 10. Following this period, the Sponsor will offer post-trial access to pirfenidone free of charge to eligible patients in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product (please see protocol section 4.3.4).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-12-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-08
    P. End of Trial
    P.End of Trial StatusOngoing
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