| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients to be included must have PAH belonging to WHO Group I, in agreement with the approved indications for sildenafil in PAH by the US FDA:
a.Idiopathic (IPAH)
b.Familial (FPAH)
c.Associated with (APAH):
i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
iii.Drugs and toxins |
|
| 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 | 10064908 |
| E.1.2 | Term | Associated with (APAH) |
|
| 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 | 10064909 |
| E.1.2 | Term | Idiopathic (IPAH) |
|
| 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 | 10064910 |
| E.1.2 | Term | Familial (FPAH) |
|
| 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 demonstrate that the combination of bosentan and sildenafil prolongs the time to the first adjudicated morbidity/mortality event compared with sildenafil monotherapy in symptomatic patients with pulmonary arterial hypertension (PAH) |
|
| E.2.2 | Secondary objectives of the trial |
To assess:
- the effects of the combination of bosentan and sildenafil compared with sildenafil monotherapy:
·on the 6-minute walk test (6MWT)
·on the modified WHO functional class in the patient population investigated,
·on the Borg dyspnea index in the patient population investigated,
·on the change in Patient Global Self Assessment in the patient population investigated
·on the time to event for the first occurrence of hospitalization for worsening or complication of PAH (including initiation of i.v. prostanoids), atrial septostomy, lung transplantation or death in the patient population investigated
·on the time to death of all causes in the patient population investigated
·on the quality of life in the patient population investigated
and to assess the safety and tolerability of the combination of bosentan and sildenafil in the patient population investigated |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1)Signed informed consent prior to initiation of any study-mandated procedure
2)Males or females => 18 years of age
•Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception.
•Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
3)Patients with symptomatic PAH
4)Patients with the following types of PAH belonging to WHO Group I:
a.Idiopathic (IPAH)
b.Familial (FPAH)
c.Associated with (APAH):
i.Collagen vascular disease with normal left ventricular function (ejection fraction (EF) > 50%)
ii.Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair
iii.Drugs and toxins
5)PAH diagnosed by right heart catheter showing:
a.Mean pulmonary arterial pressure
(mPAP) => 25 mmHg
AND
b.Pulmonary capillary wedge pressure
(PCWP) =< 15 mmHg or left ventricular end diastolic pressure (LVEDP) 15 mmHg
If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion
6)Treatment with a stable dose of sildenafil equal to or greater than 20 mg t.i.d. for at least 12 weeks prior to randomization (no sildenafil dosage adjustment should occur in this period)
7)150 m =< 6MWT =< 480 m
|
|
| E.4 | Principal exclusion criteria |
1)PAH belonging to WHO group II-V
2)PAH associated with portal hypertension and HIV infection
3)PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy
4)PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg): pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
5)Persistent pulmonary hypertension of the newborn
6)Significant valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included)
7)Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value
8)Obstructive lung disease: forced expiratory volume/ forced vital capacity (FEV1/FVC) < 0.5
9)Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
10)Known HIV infection
11)Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements or that may interfere with the safety or the evaluation of the study, such as chronic infection, chronic renal failure etc.
12)Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
13)Pregnancy or breast-feeding
14)Condition that prevents compliance with the protocol or adherence to therapy
15)Systolic blood pressure < 85 mmHg
16)Body weight < 40 kg
17)Hemoglobin < 75% of the lower limit of the normal range
18)Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges
19)Known hypersensitivity or history of drug-related adverse events with bosentan (e.g., increase in liver function test results [LFTs]), or any of the excipients of its formulation
20)Receipt of an investigational product other than sildenafil within 3 months prior to randomization
21)Treatment with endothelin receptor antagonists (ERAs), prostanoids or phosphodiesterase (PDE) 5 inhibitors other than sildenafil within 3 months prior to randomization
22) Concomitant systemic treatment within 1 week prior to randomization with
• calcineurin inhibitors (e.g., cyclosporine A and tacrolimus), sirolimus and everolimus
• glibenclamide (glyburide)
• inhibitors of both CYP2C9 and CYP3A4 (e.g., fluconazole, amiodarone, voriconazole)
• combination of drugs that inhibit CYP2C9 and CYP3A4
23)Treatment with nitrates and alpha-blockers at time of randomization
24) In the opinion of the investigator – patients in need for treatment with any prostanoid up to Visit 4
25)Significant left ventricular dysfunction |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•Time from baseline to first adjudicated morbidity/mortality event, defined as follows:
a.Death
b.Hospitalization for worsening or complications of PAH or initiation of i.v. prostanoids
c.Atrial septostomy
d.Lung transplantation
e.Worsening PAH defined by fulfillment of both of the following criteria:
1)The recognition that the patient’s symptoms are worse using a 7-item Patient Global Self Assessment Scale:
•If the Patient Global Self Assessment is “moderately worse” or “markedly worse,” confirmatory examinations of worsening PAH may be performed if deemed necessary by the investigator. These examinations include (but are not limited to): right heart catheterization (RHC), 6MWT. However, none of these examinations are mandatory and the investigator can choose the method of evaluation.
•If the Patient Global Self Assessment is “no change” or “mildly worse,” but in the opinion of the investigator the patient’s condition is bad enough to initiate additional therapy (e.g., for patients in denial), then a 6MWT is mandatory to demonstrate either a decrease by more than 20% from the previous evaluation or a decrease by more than 30% from baseline in order to confirm disease progression.
The 6MWT should be performed in the absence of any factor, e.g. pneumonia, that may cause a temporary deterioration in 6MWT
AND
2)The initiation of s.c. or inhaled prostanoids or the “Disease Progression Package”
The observation period for all patients will start with the treatment start of the first patient and end when the overall target number of adjudicated morbidity/mortality events is achieved (EOS); the length of the observation period is independent of the duration of treatment. Censoring before EOS will be applied only to patients who are lost to follow-up and is expected to be 5.7%/year.
The risk of a morbidity/mortality event in one group relative to the other is not expected to change with time, and the risk in the placebo group is expected to be 20%/year. The anticipated treatment effect to be detected is a risk reduction of 40% that corresponds to a Hazard Ratio for bosentan/placebo of 0.5729 i.e., 12% in the bosentan group. Patients' enrollment is expected to be 75 patients per year.
|
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Information not present in EudraCT |
| 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) | 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.8.4.1 | 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 | 16 |
| 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 | 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
|
| End-of-Study (EOS) is defined as the point in time when the overall target number of adjudicated morbidity/mortality events has been reached. All patients, including those who had an EOT visit, will have an EOS visit once the target number of adjudicated morbidity/mortality events is reached. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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