A Multicenter, Single-arm, Open-label, Phase 3b Study to Assess the Effects of Switching From Flolan® to ACT-385781A in Patients with Pulmonary Arterial Hypertension

1.1 Pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial
vasoconstriction and vascular remodeling resulting in a progressive increase in
pulmonary arterial pressure and pulmonary vascular resistance, ultimately
leading to right ventricular failure and death. PAH is defined as a resting
mean pulmonary arterial pressure (mPAP) > 25 mm Hg and pulmonary capillary
wedge pressure (PCWP) * 15
mm Hg [Badesch 2009]. If left untreated, the prognosis for PAH patients is
poor; untreated patients have a median life expectancy of 2.8 years from
diagnosis [D*Alonzo 1991]. Currently approved treatments include prostanoids,
endothelin receptor antagonists (ERAs), and phosphodiesterase-5 inhibitors
(PDE-5). The pathophysiology of PAH involves multiple pathways, which are
influenced by many
overlapping secondary messenger systems. Vasoconstriction, obstructive
remodeling of the pulmonary vessel wall, inflammation, and thrombosis within
the pulmonary arteries are promoted by activation of these pathways, and lead
to elevated PAP and PVR, and
eventually right ventricular failure.

1.2 Prostacyclin pathway
Patients with PAH have been shown to have a deficiency of prostacyclin (PGI2;
IP) and PGI2 synthase, which led to the hypothesis that targeting the PGI2
pathway with IP receptor agonists could be beneficial. PGI2, a metabolite of
arachidonic acid, is produced by both endothelial and smooth muscle cells in
the vasculature and is a potent endogenous vasodilator and inhibitor of
platelet aggregation and smooth muscle cell
proliferation through its activity at the IP receptor [O*Grady 1980]. Several
drugs acting on the IP receptor have already been approved for the treatment of
PAH. The first was epoprostenol, approved in 1995 for modified New York Heart
Association (NYHA) Functional Class III -IV idiopathic PAH (IPAH) and PAH
associated with scleroderma, and shown to improve exercise tolerance and
survival in IPAH [Barst 1996]. Approved prostacyclin analogs include:
intravenous prostacyclin (epoprostenol sodium or Flolan), subcutaneous,
intravenous or inhaled treprostinil sodium (Remodulin®), and inhaled iloprost
(Ventavis®).

1.3 ACT-385781A (Epoprostenol for injection, EFI)
ACT-385781A (Epoprostenol for injection, EFI) is a new formulation containing
the same active ingredient as Flolan. The new formulation includes the omission
of sodium chloride, the substitution of mannitol by sucrose, the substitution
of L-glycine by L-arginine, and a higher pH.

- To evaluate the change in cardiac hemodynamics from baseline to 3-month
following switch from Flolan to EFI in patients with PAH.
- To evaluate the safety and tolerability of switching from Flolan to EFI in
patients with PAH.
- To evaluate the change from baseline to 3-month following switch from Flolan
to EFI on exercise capacity, NT-proBNP level, Borg dyspnea score and NYHA
functional class.
- To evaluate treatment satisfaction and quality of life before and after
switch from Flolan to EFI.

Multicenter, single-arm, open-label, phase 3b study

This is a prospective, multicenter, single-arm, open-label, phase 3b study to
assess the effects of switching from Flolan to EFI in patients with pulmonary
arterial hypertension. Between 25 and 35 patients will be evaluated for 90 days
treatment.
The study includes the following consecutive periods which total up to
approximately 104 days of study participation:
- Screening period: up to 14 days prior to this study.
- Treatment period: from the switching from Flolan to EFI (Day 1) to the end of
study treatment (Day 90 or premature discontinuation).

Study drug risks: There is the chance of experiencing side effectsadverse
events to the study drug. The adverse events side effects are unknown and have
not been studied. However, Epoprostenol for injection (EFI) is expected to have
similar risks as Flolan®. For Flolan® the most common adverse events side
effects reported to date are flushing, headache, nausea, vomiting, hypotension
(low blood pressure), anxiety (nervousness), chest pain, dizziness, bradycardia
(slow heartbeat), abdominal pain, musculoskeletal pain, jaw pain, diarrhea,
nausea, vomiting, and flu-like symptoms. These adverse events side effects may
occur at the medically recommended dose, which is used in this study. It is
possible that complications and adverse events side effects of EFI, which are
still unknown at this time, may occur.
The transition to EFI will occur simultaneously with the termination of
Flolan®. EFI will directly replace Flolan® in the infusion pump and
cathetersyringe or cassette in the infusion pump at a time designated by the
investigator. The dose of EFI will be the same dose (+-10%) as the most recent
one of Flolan®. Patients will be carefully monitored during the transition for
signs and symptoms of PAH and vital signs. The patient will remain hospitalized
for approximately 48 hours. The patient is discharged after the investigator
determines that she/he is clinically stable and appropriately trained on the
preparation and administration of EFI.

The dose and infusion rate of EFI may be adjusted throughout the study in order
to balance tolerability and maximum clinical benefit. Dose adjustment is
dependent on the investigator*s judgment. Patients are evaluated during phone
and clinic visits, according to schedule, at which time it assessed whether a
dose adjustment is appropriate. The investigator will provide instruction to
the patient on when to up- or down-titrate the study medication.

Blood Draw Risks: During the study, patient blood will be drawn twice to
perform a variety of tests. The risks of drawing blood include temporary
discomfort from the I.V. in patient arm, bruising, swelling at the I.V. site,
and in rare instances, infection. Standard care will be taken to avoid these
complications.

Right heart catheterization involves placing a thin, flexible tube into the
patient vein in their arm, neck or groin which then follows the blood stream
inside the heart into their main lung artery, where it can be used to measure
their lung artery pressures. X-ray may be used to follow the tube. The
procedure is typically more uncomfortable than painful and will usually be done
while they are awake, because their doctor needs their cooperation. Right heart
catheterization may be associated with side effectsadverse events. Minor local
adverse events side effects include bruising or hematoma, swelling and
infection. Sometimes patients may have an irritating sensation in the chest,
less frequently this is felt as pain and is usually not harmful. Side effects
that are seen rarely include heart rhythm abnormalities, low blood pressure,
bleeding, general infection, collapsed lung, or clotting of the blood,
sometimes followed by an obstruction of an artery. As with any procedure
involving the heart, complications can sometimes, although rarely, be fatal.

Other medicines and EFI: patients are asked to tell their study doctor before
starting treatment about any medicines they are taking or have recently taken.
This includes medicines they have bought without prescription as some of these
could interact with EFI. Patients are reminded that it is especially important
to tell their study doctor if they are taking: diuretics, antihypertensives or
other vasodilators such as calcium channel blockers or converting enzyme
inhibitors (to treat high blood pressure), platelet aggregation inhibitors,
anticoagulants, or non steroidal anti-inflammatory drugs.