A prospective, multicenter, open-label extension of FUTURE 3 to assess the safety, tolerability and efficacy of the pediatric formulation of bosentan two versus three times a day in children with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare and progressive disease
associated with high morbidity and mortality.
PAH is a disease of the pulmonary arteries characterized by vasoconstriction,
vascular proliferation and remodelling,
and thrombosis in situ. It results in a progressive increase of pulmonary
artery pressure, pulmonary vascular
resistance, and ultimately right ventricular failure and death. The definition
of PAH in adults and children is the same: a
mean pulmonary artery pressure > 25 mmHg at rest or > 30 mmHg during exercise,
with normal pulmonary artery
wedge pressure smaller or equal to 15 mmHg and pulmonary vascular resistance >3
Wood units.m2. Despite recent
major improvements in symptomatic treatments, no current pharmacological
treatment cures PAH. However, during the
past 20 years, several drugs with potent vasodilatory effects on the pulmonary
vasculature have been approved for the
treatment of PAH in adults. In adults and adolescents, epoprostenol, sildenafil
and bosentan have been shown to
improve quality of life, exercise capacity, hemodynamics, and clinical outcomes
in
patients with PAH.

In patients younger than 12 years, the efficacy, tolerability, and safety of
these drugs are less well documented.
Although the approved drugs in adults are being used in younger patients, only
bosentan has been formally approved
for the treatment of PAH in children: the European Commission has approved
dispersible 32 mg tablets for use in children above 2 years of age.

To evaluate the long-term safety, tolerability and efficacy of the pediatric
formulation of bosentan two versus three times a day in children with pulmonary
arterial hypertension (PAH).

This is a prospective, multicenter, multinational, open-label, double-arm
exploratory Phase 3 extension study enrolling those patients who completed the
FUTURE 3 core study (AC 052-373). It is designed to evaluate the long-term
tolerability and safety of bosentan using the pediatric formulation in children
with idiopathic or heritable PAH or PAH persisting after complete repair of a
congenital heart defect.

Patients will receive the bosentan pediatric formulation. The bosentan dosage
will be adjusted to the patient*s body weight during the study to achieve a
maintenance dose of 2 mg/kg either b.i.d. or t.i.d. Patients will receive the
maintenance dose (2 mg/kg either b.i.d. or t.i.d.) of bosentan using the
pediatric formulation for the entire duration of the study.

The maximum number of participants corresponds to the number of patients
treated in the FUTURE 3 core study (AC-052-373).
The study will be conducted at expert pediatric PAH centers in Europe, US,
Latin America, Australia and Asia.

The study will consist of a treatment period and a post-treatment follow-up
period of 60 days.
The treatment period in FUTURE 3 Study Extension will last for 12 months or
until:
• The investigator or the patient decides to discontinue the study treatment
permanently
• the sponsor decides not to pursue the development of the pediatric
formulation of bosentan.

No interim analysis is planned.

Bosentan dispersible tablet (32 mg) in the dosage of 2 mg/kg b.i.d. or 2 mg/kg
t.i.d.

At screening standard physical examination (including vital parameters, length
and weight) and laboratory assessments. Physical examinations are repeated at
each visit; laboratory assessements will be done monthly.

Adverse events of bosentan are listed in the Investigator Brochure version 13
(30Aug2010; see also E9).

The conduction of this trial can be justified because PAH is a serious disease
which cannot be cured and might lead to
death. A good insight in the long-term safety, tolerability and safety of
bosentan in children is very important to come to optimal treatment
options for children affected with this disease.