A multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome.

Eisenmenger syndrome (ES) belongs to the group 1.4.4 of the Dana Point clinical
classification of pulmonary hypertension (PH) [Simonneau 2009] [see Appendix
5.2]. ES represents the most advanced form of congenital heart defect
(CHD)-induced pulmonary arterial hypertension (PAH) [Beghetti 2009]. It is
characterized by elevated pulmonary vascular resistance (PVR) and right-to-left
shunting through a systemic-to-pulmonary circulation connection. The disease is
a progressive, multi-organ disorder, the symptoms and complications of which
include dyspnea, cyanosis, syncope, fatigue, hemoptysis, erythrocytosis,
cerebrovascular accidents, brain abscesses, arrhythmias and eventually right
heart failure [Baumgartner 2010, Diller 2007].
Due to advances in surgery and pediatric cardiology, the prevalence of ES in
the Western world has been reduced by an estimated 50% in the past 50 years. It
is now estimated that more than 50% of patients with ES reach their fifth
decade [Moons 2009]. Nevertheless, it remains a devastating condition with high
mortality and considerable impact on patients* lives [Diller 2005, Diller
2006].
Available treatment options for patients with ES have been limited to empirical
palliative measures including oxygen, warfarin, diuretics, high-dose calcium
channel blockers, and long-term continuous intravenous epoprostenol [Galie
2008a], until the BREATHE-5 placebo-controlled trial and the following
open-label (OL) study revealed beneficial effects of bosentan-mediated dual
endothelin receptor blockade in this patient population [Galie 2006, Gatzoulis
2008].
Currently, patients with ES are usually treated with the endothelin receptor
antagonist (ERA) bosentan or other PAH-specific therapies (e.g.
phosphodiesterase-5 [PDE-5] inhibitors, prostanoids), but only bosentan has
demonstrated efficacy in a controlled, multi-center trial. Lung transplant with
repair of the cardiac defect or heart-lung transplantation is the final
treatment option for patients with markers of poor prognosis, but has offered
limited survival benefit [Baumgartner 2010, Moons 2009, Trulock 2001].
Macitentan / ACT 064992 is an orally active, non-peptide, potent dual ETA and
ETB receptor antagonist selected for clinical development in PAH and other
indications associated with an activated ET system. Macitentan shows
dose-dependent efficacy similar to that observed with bosentan (Tracleer®, the
first ERA registered for the treatment of patients with PAH) in preclinical
models of hypertension and PAH, but macitentan is approximately 10 times more
potent than bosentan.
The ERA bosentan was the first drug showing efficacy in patients with ES in a
controlled clinical trial, demonstrating improvement in cardiac hemodynamics
and exercise capacity. Endothelin receptor antagonism has thus emerged as an
important therapeutic strategy in pulmonary vasculopathy associated with ES. In
the recently completed AC 055-302 / SERAPHIN study, macitentan demonstrated
efficacy in PAH patients by improving clinical outcomes, functional status and
exercise capacity.
The present study aims at demonstrating that macitentan improves exercise
capacity in subjects with ES

To demonstrate that macitentan improves exercise capacity in comparison with
placebo in subjects with Eisenmenger Syndrome (ES).

This is a prospective, multi-center, double-blind, randomized,
placebo-controlled, parallel-group Phase 3 study.
The trial is designed to demonstrate the efficacy of macitentan versus placebo
in improving exercise capacity (6MWD) in subjects with ES. Approximately 220
subjects will be randomized in a 1:1 ratio into 2 treatment groups (macitentan,
placebo), i.e., approximately 110 subjects per group.
The study is planned to be conducted in approximately 90 centers in 30
countries, approximately half of which will participate in the hemodynamic
sub-study.
The hemodynamic sub-study will be conducted in approximately 80 evaluable
subjects at specialized sites, in which hemodynamic exploratory endpoints will
be assessed by cardiac catheterization at baseline and at Visit 6 (i.e., at
Week 16 or earlier in case of premature discontinuation of study drug). All
eligible adult subjects at these sites will be included in the sub-study until
the required number of subjects has been recruited. Thereafter, subjects from
these sites may be enrolled into the main study.
Protocol-mandated procedures will be performed according to the table of
assessments [Table 1] and are described in Section 3.9 of the protocol.

Study drugs include macitentan in the dosage of 10mg or placebo .

Assessments performed at screening are:
physical examination (including vital parameters, SpO2 length and weight),
echocardiography (if not performed within 1 year prior to screening),
pulmonary function test,
12-lead ECG,
6 minutes walk test,
determination of the WHO functional class,
cardiac catheterization (for subjects participating in the hemodynamic substudy
this is to take place in the screening period. For subjects that do not
participate in the hemodynamic substudy procedure must have been performed
within 5 years prior to randomization)
SF-36 questionnaire
Laboratory tests (for which blood is drawn from the patient)

Physical examinations are repeated at each visit, 12-lead ECG at visit 6, 6mwt
at visit 2, 4, 5 and 6, determination of the WHO class at visit 2,3,4,5 and 6,
cardiac catheterization at visit 6 if the subject participates in the substudy,
SF-36 questionnaire at visit 2, 4 and 6, and laboratory tests at visit 2, 3, 4,
5, 6 and 7.

Adverse events of macitentan are listed in the Investigator*s Brochure. For
possible complications regarding the heart catheterization please refer to E9
of this ABR-form.

The conduct of this trial can be justified as Eisenmenger is a serious disease
which cannot be cured and might lead to death. A good insight in the effects of
macitentan is very important to come to optimal treatment options.