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    Summary
    EudraCT Number:2012-001642-17
    Sponsor's Protocol Code Number:AMB116457
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-08-01
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2012-001642-17
    A.3Full title of the trial
    An open-label extension study of the long-term safety, tolerability and efficacy of ambrisentan in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH)
    Otevřené hodnocení dlouhodobé bezpečnosti, snášenlivosti a účinnosti ambrisentanu u pacientů s inoperabilní chronickou tromboembolickou plicní hypertenzí (CTEPH) – pokračování studie AMB115811
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An extension study of a drug to treat Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
    A.4.1Sponsor's protocol code numberAMB116457
    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 and 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+44208990 4466
    B.5.5Fax number+442081234
    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.3.9.4EV Substance CodeSUB25424
    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
    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 14.1
    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 is the long-term safety and tolerability of ambrisentan in the CTEPH population (see Safety).

    Safety assessments
     Adverse Events;
     Serious Adverse Events;
     Clinical laboratory parameters (including liver safety and haematological parameters);
     Physical examination (including jugular venous pressure, liver size, peripheral oedema, ascites and signs of deep vein thrombosis);
     Vital Signs (including body mass index at the entry visit only);
     The time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to tolerability issues (e.g. adverse events).
    E.2.2Secondary objectives of the trial
    Efficacy assessments
     6 minute walking distance (6MWD) test evaluated every three months;
     WHO functional class every three months;
     Borg CR10 Scale (BCR10S) immediately following exercise, every three months;
     Clinical worsening of CTEPH as defined by the time from randomization to the first occurrence of
     Death
     lung transplantation
     hospitalization for worsening CTEPH
     atrial septostomy
     addition parenteral prostanois
     appearance of two or more CTEPH worsening events*] (TTCW);

    For further information please view section 2.2.1 of the protocol
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects eligible for enrolment in the study must meet all of the following criteria:
    Have been randomized to the protocol for AMB115811 and have met one of the following:
    a) Completed the Week 16 visit in AMB115811;
    b) Prematurely withdrew from AMB115811 for whatever reason*
    *where IP has been stopped due to safety or efficacy reasons, the subject may still
    enter into the open label study regardless of what treatment they are receiving (other treatments will not be supplied by the sponsor) but will not be permitted to receive IP.
    Subject is able and willing to give written informed consent. As part of the consent, female subjects of childbearing potential will be informed of the risk of teratogenicity and will need to be counselled in a developmentally appropriate manner on the importance of pregnancy prevention; and male subjects will need to be informed of potential risk of testicular tubular atrophy and aspermia.
    Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study
    treatment that may impact subject eligibility is provided in the Investigators Brochure and product label for PAH indication.
    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.

    French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
    E.4Principal exclusion criteria
    Exclusion from IP
    Subjects meeting any of the following criteria must not receive ambrisentan, however may still be followed-up as part of the study and be treated according to best clinical practice as decided by the investigator:
    1. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients
    2. Female subjects who are pregnant or breastfeeding or no-longer agree to comply with using effective contraception as defined in Appendix 2
    3. Subjects with ALT and/or AST ≥ 3xULN
    4. Subjects with bilirubin ≥ 2xULN (>35% direct bilirubin)
    5. Subjects with severe renal impairment (estimated creatinine clearance <30 mL/min assessed within the previous 45 days) at the point of transition from Study AMB115811
    6. Subject has moderate - severe hepatic impairment (Child-Pugh class B-C with or without cirrhosis) at the point of transition from study AMB115811
    7. Subject with clinically significant fluid retention in the opinion of the investigator
    8. Subject with clinically significant anemia in the opinion of the investigator
    9. Subjects who are to enter another clinical trial or be treated with another investigational product after exiting Study AMB115811.

    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)
    The primary objective is the long-term safety and tolerability of ambrisentan in the CTEPH population.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Entry in the study, monthly, every 3 months, every 6 months and follow-up visits
    E.5.2Secondary end point(s)
    Efficacy

    • The change from Study AMB115811 baseline and week 16 visits in the 6 minute walking distance (6MWD) test evaluated every three months;
    • The change from Study AMB115811 baseline and week 16 visits in WHO functional class every three months;
    • The change from Study AMB115811 baseline and week 16 visits in Borg CR10 Scale (BCR10S) immediately following exercise, every three months;
    • Clinical worsening of CTEPH as defined by the time from randomization to the first occurrence of
    • Death
    • lung transplantation
    • hospitalization for worsening CTEPH
    • atrial septostomy
    • addition of parenteral prostanoids
    • appearance of two or more CTEPH worsening events*;
    *Worsening events 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);
    4. Rapidly progressing cardiogenic, hepatic, or renal failure;
    5. Refractory systolic hypotension (systolic blood pressure less than 85 mmHg).
    Clinical Worsening events will be independently adjudicated.

    • The time to addition of another targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to the following reasons:
    ­ - Deterioration of clinical condition;
    ­ - Lack of beneficial effect with previous therapy (not reaching set treatment goals);
    • The time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition;
    • The change from Study AMB115811 baseline and week 16 visits in Subject Global Assessment every three months using the Short Form 36 Health
    Survey (SF-36)
    • Change from Study AMB115811 baseline and week 16 visits in N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration every three months.
    Other
    • The change from Study AMB115811 baseline and week 16 visits cardiopulmonary hemodynamic assessments data in subjects in whom hemodynamic data is considered part of the standard of care
    E.5.2.1Timepoint(s) of evaluation of this end point
    Monthly, every 3 months, every 6 months and follow-up visits
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA31
    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
    France
    Germany
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    Russian Federation
    Spain
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days10
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days10
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 76
    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)
    Subjects can remain in this study until one of the following conditions is met:
     The product is approved locally and reimbursed for use in inoperable CTEPH patients;
     Development for use in the CTEPH population is discontinued or product is not approved locally;
     The investigator decides to discontinue the subject or subject decides to discontinue from the study.
    Please view section 5.7 of the protocol for further information.

    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 Decision2013-09-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-08-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-11-18
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