| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | low |
| E.1.2 | Classification code | 10037400 |
|
| 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 determine the effect of ambrisentan on excercise capacity in subjects with PAH |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the effects of ambrisentan on other clinical measures of PAH, as well as the safety and tolerability of the study drug |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
In order to be considered eligible, a subject must meet all of the following criteria:
1. Subject must be at least 18 years of age;
2. Subject must have a current diagnosis of either PPH or PAH secondary to the scleroderma spectrum of disease (e.g., mixed connective tissue disease, CREST syndrome, systemic sclerosis, or overlap syndrome), systemic lupus erythematosus, anorexigen use, or HIV infection at the Screening Visit;
3. By means of a right heart catheterization, completed prior to Screening Visit, the subject must meet all of the following hemodynamic criteria:·
Mean PAP of ≥ 25 mmHg;·
PVR >3 mmHg/L/min;·
PCWP or LVEDP of <15 mmHg;
4. Subject must walk a distance of at least 150 meters but no more than 450 meters during two consecutive six-minute walk tests. These tests must be completed during the Screening Period and cannot vary by more than 15%;
5. Subject receiving calcium channel blockers must be on stable therapy for at least one month prior to the Screening Visit;
6. Subject receiving HMG-CoA reductase inhibitors (i.e. statins) must be on stable therapy for at least 12 weeks prior to the Screening Visit;
7. Subject with a diagnosis of HIV must have stable disease status during the Screening Period. Stable HIV status is defined as:·
No addition of medications for treatment of HIV in the last two months;·
No active opportunistic infection during the Screening Period;·
No hospitalizations due to HIV within the past four weeks;
8. Female subject of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit. Female subject who is surgically sterile or post-menopausal for at least two years is not considered to be of childbearing potential;
9. Female subject of childbearing potential must agree to use a reliable double barrier method of contraception until study completion and for at least four weeks following their final study visit. A reliable double barrier method of contraception is considered to be a combination of TWO of the following: birth control pills/implants/injections, intrauterine devices (IUDs), spermicide, diaphragms, or condoms;
10. Male subject must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking this study drug and queried regarding his understanding of the potential risks as described in the Informed Consent Form;
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 and must sign the form prior to the initiation of any study procedures. |
|
| E.4 | Principal exclusion criteria |
A subject who meets any one of the following criteria is ineligible for participation in the study:
1. Subject with PAH due to or associated with congenital heart disease, coronary artery disease, left heart disease, interstitial lung disease, chronic obstructive pulmonary disease, veno-occlusive disease, chronic thrombotic and/or embolic disease, or sleep apnea;
2. Subject with portopulmonary hypertension;
3. Subject receiving bosentan within four weeks prior to the Screening Visit;
4. Subject receiving a phosphodiesterase type V inhibitor (sildenafil, vardenafil, tadalafil, etc.) within four weeks prior to the Screening Visit;
5. Subject receiving chronic prostanoid therapy (epoprostenol, treprostinil, iloprost, beraprost, or any other investigational prostacyclin derivative) within four weeks prior to the Screening Visit;
6. Subject receiving iv inotropes within two weeks prior to the Screening Visit;
7. Subject who has a serum ALT or AST lab value that is greater than 1.5 times the upper limit of normal at the Screening Visit;
8. Subject who has, as measured by a historical pulmonary function test:
· Total lung capacity (TLC) <70% of predicted normal or;
· Forced expiratory volume in one second (FEV1) <65% of predicted normal;
9. Subject who has:
· A hemoglobin concentration <10 g/dL at the Screening Visit or;
· A hematocrit <30% at the Screening Visit;
10. Subject, with or without supplemental oxygen, who has a resting arterial oxygen saturation (SaO2) <90% as measured by pulse oximetry at the Screening Visit;
11. Subject who has a contraindication to treatment with an ETRA. The contraindications include, but are not limited to, evidence of elevated LFTs or an event defined as a SAE attributed to previous treatment with an ETRA;
12. Subject who has a history of malignancies within the past five years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix;
13. Subject with cardiovascular, liver, renal, hematologic, 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 study drug or severely limit the lifespan of the subject;
14. Female subject who is pregnant or breastfeeding;
15. Subject who has demonstrated noncompliance with previous medical regimens;
16. Subject who has a recent history of abusing alcohol or illicit drugs;
17. Subject who has participated in a clinical study involving another investigational drug or device within four weeks before the Screening Visit.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change from baseline in the six-minute walk distance evaluated after 12 weeks of therapy compared to placebo.
This study will have approximately 90% power to detect a placebo-corrected treatment effect of 35 meters. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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