| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypotension |
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| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary arterial hypertension (a narrowing of the arteries connecting the lungs to the heart that leads to an increase in blood pressure) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| 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 |
| The primary objective of this study is to compare the difference between two treatment strategies; first-line combination therapy (with ambrisentan 10mg once daily and tadalafil 40mg once daily) vs. monotherapy (with ambrisentan 10mg once daily or tadalafil 40mg once daily) in subjects with pulmonary arterial hypertension (PAH). This will be assessed by time to first clinical failure (TtCF) 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 |
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 PAH
b. 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 infection
iv. 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 ventricular disease/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 U.S. Specific Text: Subjects in the United States who have had previous RHC and have evidence to suggest the presence of PH but require an RHC during the Screening Period
to confirm the diagnosis of PH (as defined above) may be permitted to receive a RHC as a study procedure, provided approval from the medical monitor is obtained in advance.
Approval will be based upon the following criteria:
• The existing RHC data in the subject's medical record is deemed to be inadequate or non-interpretable per the investigator's judgment
• An adequate RHC record could not be obtained or was not accessible from the subject's medical record
• Subject has met all other screening requirements prior to undergoing RHC
• The site/subject are able to perform the RHC in advance and within the screening period Documentation of approval will be maintained in the source documents and by the Sponsor
7. Subject must meet all of the following pulmonary function tests completed no more than 24 weeks before the Screening visit:
i. Total lung capacity (TLC) ≥60% of predicted normal and
ii. Forced expiratory volume in one second (FEV1) ≥55% of predicted normal Subjects are required to have a documented negative V/Q scan or pulmonary arteriogram confirming the absence of CTEPH prior to screening.
8. Subject must walk a distance of ≥125m and ≤500m at the screening visit. In addition the screening and baseline 6MWD tests must not vary by greater than 10%
9. Subject, with or without supplemental oxygen, must have a resting arterial oxygen saturation (SaO2) ≥88% as measured by pulse oximetry at the Screening Visit.
10. Subject has not enrolled in an exercise training program for pulmonary 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 24 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 24 weeks of the
study.
11. Female subject of childbearing potential, if sexually active, 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 . Subjects who have had a Copper T 380A IUD or LNg 20 IUD inserted are not required to use additional methods of contraception
12. Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study
13. Subject must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF and must sign the form prior to the initiation of any study procedures. |
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| E.4 | Principal exclusion criteria |
1. Subject received previous PAH therapy continuously for 14 days or more (PDE5i, ERA, prostanoid) prior to the screening visit. Subjects who previously received PAH therapy for less than 14 days must not have received any PAH therapy within 7 days prior to Screening Visit.
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 in either 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
Other Therapies
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. protease inhibitors, 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)
• Hospitalization for worsening PAH (adjudicated)
i. Any 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 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.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 0, 4, 8, 16, 24 and then every 12 weeks until 105 events are reported for the study |
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| E.5.2 | Secondary end point(s) |
6 Minute Walk Distance and Borg Dyspnea Index: The 6MWD will be assessed at each clinic visit, and The Borg Dyspnea Index score will be collected at each clinic visit. It should be
performed immediately after the 6MWD test. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| 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 | No |
| 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 |
| Australia |
| Canada |
| Japan |
| United States |
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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
|
| 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 |
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