Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

NCT02927366 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: CQCC374X22012016-001412-38
• Study Type: interventional
• Target: 8
• Locations: 4 countries
• Sites: 5

Brief 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.

Conditions

Pulmonary Arterial Hypertension

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

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111)

  The efficacy of 16 weeks of QCC374 administration in subjects with Pulmonary Arterial Hypertension (PAH) was assessed by measuring changes from baseline in Pulmonary Vascular Resistance (PVR). PVR is derived from the CO measurement in dyn·s/cm5 and can be calculated as 80 multiplied by (Mean Arterial Pressure - Mean Pulmonary Artery Wedge Pressure) divided by Cardiac Output. A higher negative number in Pulmonary Vascular Resistance indicates improvement. Only descriptive analysis performed.

  Baseline, Week 16 (Day 111)

Secondary Outcomes (13)

• Change From Baseline in Six Minute Walk Distance (6MWD) Over Time

  Baseline, Day 28, Day 56, Day 84 and Day 111

• Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111)

  Baseline, Week 16 (Day 111)

• Change From Baseline in Cardiac Index at Week 16 (Day 111)

  Baseline, Week 16 (Day 111)

• Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111)

  Baseline, Week 16 (Day 111)

• Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111)

  Baseline, Week 16 (Day 111)

Study Arms (2)

QCC374

EXPERIMENTAL

Adult patients with pulmonary arterial hypertension (PAH) on QCC374. All patients were initiated at 0.03 mg BID (Day 1-3), and were up-titrated to next higher dose 0.06 mg BID (Day 4) and increased to 0.12 mg BID (Day 7-14).

Drug: QCC374

Placebo

PLACEBO COMPARATOR

Adult patients with pulmonary arterial hypertension (PAH) on placebo matching to QCC374 doses (0.03 mg BID (Day 1-3), 0.06 mg BID (Day 4) and 0.12 mg BID (Day 7-14)).

Drug: Placebo Matching

Interventions

QCC374 DRUG

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

QCC374

Placebo Matching DRUG

Placebo matching to QCC374: 0.03 mg BID, 0.06 mg BID and 0.12 mg BID

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (5)

Novartis Investigative Site

Pittsburgh, Pennsylvania, 15261, United States

Location

Novartis Investigative Site

Dresden, 01307, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Seoul, 03722, South Korea

Location

Novartis Investigative Site

Cambridge, Cambridgeshire, CB23 3RE, United Kingdom

Location

Related Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Dyspnea; Dizziness; Syncope; Cough

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Sensation Disorders; Neurologic Manifestations; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Nervous System Diseases

Limitations and Caveats

Due to the limited number of subjects with the available data at Week 16 (Day 111), for the primary and secondary efficacy endpoints, it is not possible to draw any meaningful treatment comparisons.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2016
• First Posted: October 7, 2016
• Study Start: September 19, 2017
• Primary Completion: June 7, 2018
• Study Completion: June 7, 2018
• Last Updated: January 5, 2021
• Results First Posted: August 7, 2019

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share

Locations

US (1); KR (1); GB (1); DE (2)