E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with modified NYHA functional Class II PAH have mild symptoms, but their pulmonary artery pressures are elevated which leads to increased wall stress and silent heart damage progression. Therefore Class I-II patients have a better survival rate than Class III-IV patients (Odds ratio = 1.9) but will eventually deteriorate if untreated.
|
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
|
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 is to demonstrate that bosentan improves exercise capacity and/or cardiac hemodynamics in mildly symptomatic PAH patients. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to demonstrate that bosentan delays time to clinical worsening, and improves dyspnea, modified NYHA functional class, and quality of life, and to demonstrate that bosentan is safe and well tolerated in this patient population. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a)Men or women aged 12 years of age and over (except for countries where this age limit is contrary to specific regulatory requirements). Women of childbearing potential must have a negative pre-treatment pregnancy test and use a reliable method of contraception during study treatment and for at least 3 months after study treatment termination. – Reliable method of contraception are: Barrier type devices (e.g., female condom, diaphragm, contraceptive sponge) only in combination with a spermicide. Intra-uterine devices. Oral, injectable or implantable contraceptives only in combination with a barrier method. – Hormone-based contraceptives alone, regardless of the route of administration, are not considered as reliable methods of contraception. – Abstention, rhythm method, and contraception by the partner alone are not acceptable methods of contraception. Women not of childbearing potential are defined as prepubescent, postmenopausal (i.e., amenorrhea for at least 1 year), or surgically or naturally sterile.
b) PAH in modified NYHA functional class II due to: 1. PAH idiopathic (Primary Pulmonary Hypertension) 2. PAH secondary to human immunodeficiency virus (HIV) 3. PAH secondary to anorexigens 4. PAH secondary to atrial septum defect (ASD) < 2 cm, ventricular septum defect (VSD) < 1 cm or patent ductus arteriosus (PAD) 5. PAH secondary to connective tissue or auto-immune diseases
c) 6-minute walk test (6MWT) distance < 80% of normal predicted value (see Appendix 3 in protocol)
d) Mean pulmonary arterial pressure (mPAP) 25 mmHg and over, pulmonary capillary wedge pressure (PCWP) < 15 mmHg, and pulmonary vascular resistance (PVR) at rest 500 dyn.sec.cm-5 and over
e) Signed informed consent prior to initiation of any study-mandated procedure.
|
|
E.4 | Principal exclusion criteria |
1) PAH associated with conditions other than those mentioned above, e.g., PAH secondary to portal hypertension, complex congenital heart disease or reverse shunt 2) Severe obstructive lung disease: FEV1/FVC < 0.5 3) Total lung capacity (TLC) < 80% of normal predicted value (see Appendix 4 in protocol) 4) Significant vasoreactivity during right heart catheterization: i.e., a fall in mPAP to < 40 mmHg with a decrease of 10 mmHg and over and with a normal cardiac index ( 2.5 l/min.m2 and over) 5) Acute or chronic impairment (other than dyspnea) limiting the ability to comply with study requirements (in particular with 6MWT) 6) Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements 7) Symptomatic lower limb vascular disease 8) HIV patient with opportunistic infection 9) Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C 10) Aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 times the upper limit of the normal (ULN) range 11) Hemoglobin concentration < 75% of the lower limit of the normal range 12) Systolic blood pressure (BP) < 85 mmHg 13) Pregnancy or breast-feeding 14) Recently started (< 8 weeks prior to randomization) or planned cardio-pulmonary rehabilitation program based on exercise 15) Treatment or planned treatment with another investigational drug within 3 months of randomization. 16) Treatment with an endothelin receptor antagonist or with prostanoids (excluding acute administration during a catheterization procedure to test vascular reactivity) within 3 months of randomization. 17) Treatment for PAH within one month of randomization, excluding calcium channel blockers (if present for at least 1 month before randomization) and anticoagulants. 18) Treatment with calcineurin-inhibitors (e.g., cyclosporine A, tacrolimus), fluconazole, glibenclamide (glyburide) within 1 week of randomization. 19) Known hypersensitivity to bosentan or any of the excipients
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
There are two primary efficacy endpoints to be tested independently to assess the superiority of bosentan over placebo on exercise capacity or cardiac hemodynamics in mildly symptomatic PAH patients, namely:
Change from baseline to Month 6 in 6MWT distance Change from baseline to Month 6 in PVR at rest.
The main analysis of the primary efficacy endpoints is performed on the All-Randomized set for this superiority study. The All-Treated and Per-Protocol sets are used for the supplementary analysis of the primary efficacy endpoints meant to test the robustness of the main results.
|
|
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 | No |
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 | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |