Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients
Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients
This was a non-confirmatory, randomized, placebo controlled, subject and investigator blinded
 study of QCC374 in PAH subjects. The study was planned to have 2 Parts: Part 1, an initial
 safety cohort with a 0.03 mg bid starting dose, and Part 2, a larger cohort with a 0.06 mg
 bid starting dose. However, due to early study termination following Part 1, Part 2 was not
 completed. Both study parts were comprised of four phases: a screening period for up to 28
 days, a titration period of 2 weeks, a stable dose period of 14 weeks and safety follow-up
 period for 28 days. At the end of the treatment period of 16 weeks, eligible patients were
 given the option to participate in a separate long-term extension study (CQCC374X2201E1
 (NCT02939599)), where all patients were treated with an individual optimal dose of QCC374.
The decision for early termination was based on changes in Novartis strategy, and was not
 based on any safety concerns regarding QCC374. Only Part 1 of the study was completed.
Inclusion Criteria:

 -  Male and female patients 18 years of age or older with symptomatic PAH.

 -  Subjects with PAH belonging to one of the following subgroups of the Updated Clinical
 Classification Group 1 (Nice, 2013):

 -  Idiopathic PAH

 -  familial PAH

 -  PAH associated with connective tissue disease, congenital heart disease (surgically
 repaired at least 12 months prior to screening) or drug or toxin induced (for example,
 anorexigen use).

 -  Subjects must have persistent symptoms due to PAH despite therapy with at least one of
 the following PAH medications: an endothelin receptor antagonist, asoluble guanylate
 cyclase stimulator or a phosphodiesterase inhibitor. The subjects' PAH medication
 regimen, with typical medications including calcium channel blockers, endothelin
 receptor antagonists, soluble guanylate cyclase stimulators and/or phosphodiesterase
 inhibitors, must have been used at a stable dose and frequency for at least 12 weeks
 before the screening visit and during the screening period.

 -  Diagnosis of PAH established according to the standard criteria before the screening
 visit:

 -  Resting mean pulmonary arterial pressure > 25 mmHg.

 -  PVR > 240 dynes s/cm5.

 -  Pulmonary capillary wedge pressure or left ventricular end diastolic pressure < 15
 mmHg

 -  PVR > 400 dynes s/cm5 at the time of the baseline right heart catheterization (RHC)
 (if a RHC was completed within one month of the screening visit, that result may be
 used for inclusion).

 -  6-minute walk distance greater than 150 meters at Screening. This distance must be
 confirmed by a second 6MWT prior to randomization. The value of the second 6MWD should
 be within ± 15% of the value obtained at Screening.

 Exclusion Criteria:

 -  Subjects with clinically unstable right heart failure within the last three months
 (New York Heart Association (NYHA) Class IV).

 -  Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus
 (HIV) infection or unrepaired congenital systemic to pulmonary shunts

 -  Subjects who have received or have been scheduled to receive long-term treatment with
 epoprostenol or any prostacyclin within the three months prior to the screening visit
 or during the screening period.

 -  Hypotensive subjects (systemic systolic blood pressure < 85 mmHg)

 -  Subjects with a history of left sided heart disease, chronic left sided heart failure,
 congenital or acquired valvular disease and/or pulmonary venous hypertension.

 -  Subjects with significant obstructive (forced expiratory volume in one second
 [FEV1]/forced vital capacity [FVC] < 70% predicted) or restrictive (total lung
 capacity < 70% predicted) lung disease at screening.