Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: QCC374; Placebo Matching
Intervention description: 0.03 mg (2 capsules of 0.015 mg) BID 0.06 mg (1 capsule of 0.06 mg) BID 0.12 mg (2 capsules of 0.06 mg) BID; Placebo matching to QCC374:
0.03 mg BID, 0.06 mg BID and 0.12 mg BID
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pulmonary hypertension (PH),; Increase blood pressure in the pulmonary artery; Increased blood pressure in the pulmonary vein; Increased blood pressure in the lung vasculature; Shortness of breath; Dizziness; Fainting; Leg swelling; Cough; QCC374

Summary:

      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.
    

Eligibility criteria:

        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.