Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

A Randomized, Parallel-group, Placebo-controlled Subject and Investigator Blinded Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of QCC374 in the Treatment of Pulmonary Arterial Hypertension

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.