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    Summary
    EudraCT Number:2012-001646-18
    Sponsor's Protocol Code Number:AMB115811
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-05
    Trial results View 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 number2012-001646-18
    A.3Full title of the trial
    A randomised, multicentre, double-blind, placebo-controlled study
    of ambrisentan in subjects with inoperable chronic thromboembolic
    pulmonary hypertension (CTEPH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of a drug to treat chronic thromboembolic pulmonary hypertension (CTEPH)
    A.4.1Sponsor's protocol code numberAMB115811
    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 SponsorGlaxoSmithKline Research & Developement Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportGSK Pharma & R&D
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trials HelpDesk
    B.5.3 Address:
    B.5.3.1Street AddressIron Bridge Road
    B.5.3.2Town/ cityUxbridge
    B.5.3.3Post codeUB11 1BU
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 208990 4466
    B.5.5Fax number+44 208990 1234
    B.5.6E-mailGSKClinicalSupportHD@gsk.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 Volibris
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxo Group Ltd
    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/3/05/273
    D.3 Description of the IMP
    D.3.1Product nameGSK1325760
    D.3.2Product code GSK1325760
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNAmbrisentan
    D.3.9.1CAS number 177036-94-1
    D.3.9.2Current sponsor codeGSK1325760
    D.3.9.3Other descriptive nameambrisentan
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 placeboFilm-coated tablet
    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
    subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
    E.1.1.1Medical condition in easily understood language
    inoperable chronic thromboembolic pulmonary hypertension
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10068739
    E.1.2Term Chronic thromboembolic pulmonary hypertension
    E.1.2System Organ Class 100000004855
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to assess the efficacy of ambrisentan 5mg after treatment period of 16 weeks, in subjects with inoperable CTEPH.
    E.2.2Secondary objectives of the trial
    The secondary objectives are safety and tolerability of ambrisentan 5mg.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Demographics
    1. Subject must be between 18 and 75 years of age, inclusive, at the Screening Visit

    CTEPH Diagnosis and Classification
    2. Subjects must have a diagnosis of CTEPH at an expert centre* with a positive V/Q and CT angiogram and a pulmonary angiogram if available within 6 months prior to screening
    *Expert centre is an expert multidisciplinary team which must include at least one cardiology or respiratory consultant, and one consultant PEA surgeon
    3. Subject must meet all of the following haemodynamic criteria by means of a RHC within 3 months prior to screening:
    i. mPAP of >25 mmHg
    ii. PVR > 400 dynes.sec/cm5
    iii. PCWP or LVEDP of <15 mmHg
    4. Subjects must have previously been judged inoperable due to the obstruction being surgically inaccessible (i.e. distal disease) by an expert multidisciplinary team which must include at least one cardiology or respiratory consultant, and one consultant PEA surgeon. For countries with CTEPH expert centers (including at least a surgeon with sound experience performing PEAs) the expert team will be the local expert
    centre. For countries without a CTEPH surgical expert center a central adjudication committee will assess the operability of the subjects during the screening period. See Section 6.1.1 of the protocol.
    5. Subject must walk a distance of ≥150m and ≤475m at the screening visit. See Section 6.2.1.
    6. Subject must have a current diagnosis of being in WHO Functional Class II or III.
    7. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) =>92% as measured by pulse oximetry at the Screening Visit.
    8. Subjects must have received anticoagulation for a minimum of 3 months prior to Screening.

    General
    9. Female subject of childbearing potential must agree to use 2 reliable methods of contraception from the Screening Visit until study completion and for at least 30 days following the last dose of Investigational Product (reliable methods of contraception are described in Appendix 1 of the protocol.
    10. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study.
    11. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form (ICF)and must sign the form prior to the initiation of any study procedures.

    Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the investigational product that may impact subject eligibility is provided in the IB and product label.
    Deviations from inclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore,
    adherence to the criteria as specified in the protocol is essential.

    E.4Principal exclusion criteria
    CTEPH Treatments
    1. Subject received previous PAH therapy (PDE5i, ERA, chronic prostanoid use*) within 12 weeks prior to the screening visit
    *Chronic prostanoid use is considered >7 days of treatment
    2. Subject has previously discontinued other ERA in either another clinical study or commercial product for safety or tolerability reasons other than for liver function abnormalities.
    3. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients.

    Other Therapies
    4. Subject has previously undergone a pulmonary endartorectamy or a balloon pulmonary angioplasty.
    5. Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit (e.g. dopamine, dobutamine)
    6. Subjects receiving Calcium Channel Blockers or HMG-CoA reductase inhibitors (i.e., statins) on an unstable dose 4 weeks prior to the Screening Visit (to be eligible subjects must not have changed their dose <4 weeks prior to the screening visit)

    Exercise Programmes
    7. Subject has not enrolled in an exercise training program for cardiopulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 16 weeks of the study. Subjects enrolled in an exercise program for pulmonary rehabilitation 12 weeks prior to screening may enter the study if they agree to maintain their current level of rehabilitation for the first 16 weeks of the study.

    Laboratory Values at Screening
    8. ALT and/or AST ≥ 3xULN
    9. Bilirubin ≥ 1.5xULN (>35% direct bilirubin)
    10. Subject has severe renal impairment (estimated creatinine clearance <30 mL/min) at the Screening Visit
    NOTE: if serum bilirubin is elevated at screening it will need to be fractionated to exclude liver injury and determine if the patient is able to be included in the trial.

    Liver
    11. Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the Screening Visit

    Haematology and bleeding disorders
    12. Subject has clinically significant anaemia: Hb < 10g/dL
    13. Subjects with bleeding disorders or significant active peptic ulceration in the opinion of the investigator

    Cardiovascular
    14. Subject has uncontrolled hypertension (>180/110 mmHg) at screening
    15. Subject has severe hypotension (<90/50 mmHg) at screening
    16. Subject has had an acute myocardial infarction within the last 90 days prior to screening
    17. Subject has, in the opinion of the investigator, clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction (ejection fraction <50% of normal); left ventricular outflow obstruction; symptomatic coronary artery disease; autonomic
    hypotension; fluid depletion.

    General Medical Conditions
    18. Subject with significant pulmonary disease (FEV1<70% of predicted): COPD, Emphysema, evidence of fibrotic lung disease on imaging
    19. Subject has clinically significant fluid retention in the opinion of the investigator
    20. Subject with significant obesity (BMI ≥ 35), cardiovascular, musculoskeletal or any other condition that in the opinion of the investigator may involve an impairment of exercise capacity or the performance of the 6MWD test (e.g. previous history of hip/knee surgery, lower limb ulcers associated with autoimmune diseases)
    21. Subject with cardiovascular, liver, renal, haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the investigational product or severely limit the lifespan of the subject other than the condition being studied
    22. Subjects with a prior malignancy whose cancer is expected to require additional active treatment in the next 2 years and whose prior malignancy would prevent them from fully participating in the study

    General Criteria
    23. Female subject who is pregnant or breastfeeding
    24. Subject has demonstrated noncompliance with previous medical regimens
    25. Subject has a recent (within 1 year) history of abusing alcohol or illicit drugs
    26. Subject has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit
    Subjects who fail inclusion/exclusion criteria may be re-screened once provided the subject meets the inoperability criteria.

    Deviations from exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in 6MWD measured at week 16.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 16
    E.5.2Secondary end point(s)
    Secondary endpoints include change from baseline to week 16 in:
    • Pulmonary Vascular Resistance (PVR)
    • WHO Functional Class (FC)
    • Borg CR10 Scale (BCR10S) immediately following exercise
    • Clinical worsening of CTEPH, as defined by the time from randomization to the first occurrence of death, lung transplantation, hospitalization for CTEPH, atrial septostomy, addition of parenteral prostanoids, or study withdrawal due to two or more early escape criteria*

    *Early escape criteria to consider:
    1. A decrease from baseline of at least 20 percent in the distance walked during the six-minute walk test;
    2. An increase of one or more WHO Functional Class;
    3. Worsening right ventricular failure (e.g., as indicated by increased jugular venous pressure; new/worsening hepatomegaly, ascites, or peripheral edema; worsening echocardiographic parameters such as tricuspid annulus plane systolic excursion (TAPSE) and TDI of the tricuspid annulus);
    4. Rapidly progressing cardiogenic, hepatic, or renal failure;
    5. Refractory systolic hypotension (systolic blood pressure less than 85 mmHg).

    • Other haemodynamics: Right atrial pressure (mm Hg), pulmonary artery pressure (mm Hg) and cardiac index (L/min/m2)
    • N-terminal pro-B-type natriuretic peptide (NT-proBNP)

    Health outcomes endpoints include:
    • Change from baseline to week 16 in Quality of Life as measured by the Short Form 36 Health Survey (SF-36)

    Safety endpoints include:
    • Incidence of Adverse events and Serious Adverse events
    • Change from baseline in haemoglobin or haematocrit levels
    • Liver Testing abnormalities
    • Vital signs (i.e. supine blood pressure and heart rate)
    • Laboratory test: clinical chemistry, haematology, testicular function (males only)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline and week 16
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA23
    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
    Argentina
    Austria
    Brazil
    Canada
    China
    Czech Republic
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Russian Federation
    Spain
    Turkey
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    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: 80
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 160
    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)
    Eligible subjects may participate in the open-label extension study AMB116457. Otherwise, the Investigator should then treat the subjects according to best standard of care available to the investigator. Subjects will be followed for 30 days post their last dose of study medication.

    The investigator is responsible for ensuring that consideration has been given to the poststudy care of the patient’s medical condition whether or not GSK is providing specific post study treatment.
    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 Decision2013-07-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-03-30
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