Endothelin antagonist trial in mildly symptomatic PAH patients. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and tolerability of bosentan in patients with mildly symptomatic pulmonary arterial hypertension. - EARLY

• Register: EUCTR
• Last refreshed on: 7 September 2021
• Main ID: EUCTR2004-000478-30-ES
• Date of registration: 03/11/2004
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd.
• Public title: Endothelin antagonist trial in mildly symptomatic PAH patients. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and tolerability of bosentan in patients with mildly symptomatic pulmonary arterial hypertension. - EARLY
• Scientific title: Endothelin antagonist trial in mildly symptomatic PAH patients. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and tolerability of bosentan in patients with mildly symptomatic pulmonary arterial hypertension. - EARLY
• Date of first enrolment: 10/02/2005
• Target sample size: 170
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2004-000478-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Czech Republic, Denmark, Italy, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

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.

Are the trial subjects under 18? yes
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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. There are no approved drug therapies for Class II PAH and the EARLY study is the first trial designed to enroll exclusively class II patients.

Intervention(s)

Trade Name: Tracleer
Product Name: bosentan
Product Code: Ro 47-0203
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: bosentan monohydrate
CAS Number: 147536-97-8
Current Sponsor code: Ro47-0203/029
Other descriptive name: ------------
Concentration unit: % percent
Concentration type: range
Concentration number: 98.0-102.0
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The primary objective is to demonstrate that bosentan improves exercise capacity and/or cardiac hemodynamics in mildly symptomatic PAH patients.

Secondary Objective: 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.

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.

Secondary ID(s)

2004-000478-30-SE

AC-052-364

Ethics review

Status: Approved
Approval date: 10/12/2004
Contact:

Results

• Results available: Yes
• Date Posted: 23/10/2016
• Date Completed: 09/11/2006
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-000478-30/results