E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypotension |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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). |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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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.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |