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    Summary
    EudraCT Number:2009-011150-17
    Sponsor's Protocol Code Number:AMB112565
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-06-22
    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 ConcernedUK - MHRA
    A.2EudraCT number2009-011150-17
    A.3Full title of the trial
    AMBITION: A Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of two drugs used to treat pulmonary arterial hypertension (PAH)
    A.3.2Name or abbreviated title of the trial where available
    AMBITION
    A.4.1Sponsor's protocol code numberAMB112565
    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 R&D 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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameambrisentan 5 mg film-coated tablets
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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.3.10 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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Cialis
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nametadalafil 20 mg film-coated tablets
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNTADALAFIL
    D.3.9.1CAS number 171596-29-5
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    D.8 Placebo: 2
    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
    Pulmonary arterial hypotension
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    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 compare the two treatment strategies; first-line combination therapy (ambrisentan AND tadalafil) versus first-line monotherapy (ambrisentan OR tadalafil) in treatment naive subjects with PAH. This will be assessed by time to the first clinical failure event.
    E.2.2Secondary objectives of the trial
    To compare the change in other clinical measures of PAH after initiating first-line combination therapy or first-line monotherapy, in subjects with PAH.

    The safety and tolerability of first-line combination therapy will be compared to first-line monotherapy.

    In addition, the effect of ambrisentan on exercise capacity at both peak and trough plasma concentrations will be assessed in subjects with pulmonary arterial hypertension (PAH).
    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:
    Demographics
    1. Subject must be between 18 and 75 years of age, inclusive, at the Screening Visit
    2. Subject must weigh ≥40 kg at the Screening Visit PAH Diagnosis and Classification
    3. Subjects must have a diagnosis of PAH due to the following:a. idiopathic or heritable PAHb. PAH associated with:
    i. connective tissue disease (e.g., limited scleroderma, diffuse scleroderma,mixed CTD, systemic lupus erythematosus, or overlap syndrome)
    ii. drugs or toxins
    iii. HIV infectioniv. congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects, and patent ductus arteriosus) NB: subjects with portopulmonary hypertension and PVOD are NOT eligible for the study NB: Subjects must not have 3 or more of the following left ventriculardisease/dysfunction risk factors:
    i. Body Mass Index (BMI) ≥ 30
    ii. History of Essential Hypertension
    iii. Diabetes Mellitus – any type
    iv. Historical evidence of significant coronary disease established by any one of:
    • history of myocardial infarction
    • history of percutaneous intervention
    • angiographic evidence of CAD (>50% stenosis in at least one vessel), either by invasive angiography or by CT Angiography
    • positive stress test with imaging (either pharmacologic or with exercise)
    • previous coronary artery surgery
    • chronic stable angina
    4. Subject must have a current diagnosis of being in WHO Functional Class II or III.5. Subject with a diagnosis of HIV must have stable disease status. For this study, stable HIV status is defined as:
    i. No addition of medications for treatment of HIV for at least 8 weeks prior to screening
    ii. No active opportunistic infection during the Screening Period
    iii. No hospitalizations due to HIV for at least 4 weeks prior to screening
    6. Subject must meet all of the following haemodynamic criteria by means of a RHC prior to screening:
    i. mPAP of ≥25 mmHg
    ii. PVR ≥ 300 dynes/sec/cm5
    iii. PCWP or LVEDP of ≤12 mmHg if PVR ≥300 to <500 dyne⋅sec/cm5 , or PCWP/LVEDP ≤15 mmHg if PVR ≥500 dynes/sec/cm5(refer to section 4.2 for US specific text).
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria must not be enrolled in thestudy (please note that screening visit laboratory tests may be performed by local or central laboratory):
    PAH Treatments
    1. Subject received previous PAH therapy (PDE5i, ERA, chronic prostanoid*) within 4weeks prior to the screening visit *Chronic prostanoid use is considered >7 days of treatment
    2. Subject received ERA treatment (e.g., bosentan or sitaxentan) or PDE5i treatment(e.g. Sildenafil) at any time AND discontinued due to tolerance issues other than those associated with liver function abnormalities
    3. Subjects who have previously discontinued ambrisentan or tadalafil ineither another clinical study or commercial product (Volibris/Letairis or Adcirca) for safety or tolerability reasons.
    4. Subject has a known hypersensitivity to the Investigational Products, the metabolites, or formulation excipients.
    5. Subject receiving intravenous inotropes within 2 weeks prior to the Screening Visit(e.g. dopamine, dobutamine)
    6. Subject is receiving treatment with a potent inhibitor of CYP3A4 (e.g. proteaseinhibitors, systemic ketoconazole, or systemic itraconazole)
    7. Subject is receiving treatment with a potent inducer of CYP3A4 (e.g. rifampicin)8. Subject is receiving treatment with cyclosporine A (except ophthalmic formulation)
    9. 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)
    10. Subject has a history of angina pectoris that was treated with long or
    short-acting nitrates <12 weeks of screening or nitrate use for any other
    condition within 48 hours of screening
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the time to the first clinical failure event of PAH. Time to clinical failure is defined as the time from randomisation to the first occurrence of:
    • Death (all-cause)
    • Any Hospitalization for worsening PAH (adjudicated)
    i. Non-elective hospitalization for worsening PAH
    ii. Lung or heart/lung transplant
    iii. Atrial septostomy
    iv. Initiation of parenteral prostanoid therapy
    • Disease progression (adjudicated)
    i. >15% decrease from baseline in 6MWD combined with WHO class III or IV symptoms (at two consecutive post-baseline clinic visits separated by ≥14 days)
    • Unsatisfactory long-term clinical response (adjudicated, all criteria required)
    i. Receiving randomised treatment for at least 6 months
    ii. A decrease from baseline in 6MWD at two consecutive post-baseline clinic visits separated by ≥14 days
    iii. Sustained WHO class III or IV symptoms for ≥6 months (WHO class III symptoms assessed at two clinic visits separated by ≥6 months)

    Time to clinical worsening (death, hospitalization for worsening PAH, or disease progression) and long-term survival (time to death) will be examined as supportive analyses of the primary endpoint.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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 AMBITION study is an event driven study. When 105 adjudicated primary endpoint events are projected to have occurred, i.e. 105 mITT subjects with an event, all subjects will be notified to return for a Final Assessment Visit (FAV) within 28 days or their week 24 visit,
    whichever is later.
    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 days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    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.1.3Elderly (>=65 years) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-06-22. Yes
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 250
    F.4.2.2In the whole clinical trial 545
    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)
    Following the first database lock, subjects will be requested to return for an end of study visit where they will have their final assessment done and be unblinded.
    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 sponsor will no longer supply ambrisentan or tadalafil after the end of the study.
    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 Decision2010-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-08-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-07-31
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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