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Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

Primary Purpose

Pulmonary Arterial Hypertension

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

QCC374

Placebo Matching

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

QCC374

Placebo

Arm Description

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).

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)).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

The Six Minute Walk Test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway. Only descriptive analysis performed.

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

The Right Heart Catheterization (RHC) assessment was performed to assess several hemodynamic variables in pulmonary hypertension, including Cardiac Output (CO). All hemodynamic parameters were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive CO measurements within 10% of each other) while the patient was breathing ambient air or oxygen. CO was measured in triplicate using the thermodilution technique. Direct Fick could be used only after discussion and approval by the Sponsor. In all cases, the same technique was to be used at baseline and week 16. . A higher positive number in Cardiac Output indicates improvement. Only descriptive analysis performed.

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

The Right Heart Catheterization (RHC) assessment was performed to assess several hemodynamic variables in pulmonary hypertension, including Cardiac Index. All hemodynamic parameters were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive CO measurements within 10% of each other) while the patient was breathing ambient air or oxygen. A higher negative number in Cardiac Index indicates improvement. Only descriptive analysis performed.

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

The Right Heart Catheterization (RHC) assessment was performed to assess several hemodynamic variables in pulmonary hypertension, including mean Pulmonary Capillary Wedge Pressure (PCWP). All hemodynamic parameters were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive CO measurements within 10% of each other) while the patient was breathing ambient air or oxygen. Pressure measurements were made in the PA, PA wedge, right ventricle (RV) and right atrium (RA) and determined at the end of normal expiration. The PCWP was recorded as the mean of three measurements. Only descriptive analysis performed.

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

The Right Heart Catheterization (RHC) assessment was performed to assess several hemodynamic variables in pulmonary hypertension, including Systemic Vascular Resistance (SVR). All hemodynamic parameters were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive CO measurements within 10% of each other) while the patient was breathing ambient air or oxygen. SVR is derived from the CO measurement in dyn·s/cm5 and can be calculated as 80 multiplied by (Mean Arterial Pressure - Mean Venous Pressure or CVP)) divided by Cardiac Output. A higher negative number in Mean Systemic Vascular Resistance indicates improvement. Only descriptive analysis performed.

Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography

Key Right Ventricular (RV) function endpoints such as RV fractional area change (RV FAC) and RV Free Wall Average Peak Long Strain (RV FWPLS) were assessed with echocardiography. A higher number in RV FAC and a lower number in RV FWPLS indicate an improvement. Only descriptive analysis performed.

Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography

Key Right Ventricular (RV) function endpoints such as Tei Index were assessed with echocardiography. The RV Tei index is using both systolic and diastolic time intervals to evaluate the overall global dysfunction of the right ventricle in PAH patients. A lower number in RV Tei Index indicates an improvement. Only descriptive analysis performed.

Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography

Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Peak Systolic Velocity (TA S') were assessed with echocardiography. Only descriptive analysis performed.

Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography

Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Plane Sys Excursion (TAPSE) were assessed with echocardiography. A higher number in TAPSE indicates an improvement. Only descriptive analysis performed.

Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441

Cmax is the maximum (peak) observed plasma drug concentration after single dose administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.

Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441

Tmax is the time to reach maximum plasma concentration after single dose administration. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.

Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441

AUClast is the area under the plasma concentration-time curve from time zero to the last measurable concentration sampling time. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.

Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441

AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval. PK parameters were calculated from plasma concentration-time data using non-compartmental methods. Only descriptive analysis performed.

Full Information

NCT ID

NCT02927366

First Posted

October 5, 2016

Last Updated

December 9, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT02927366

Brief Title

Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2020

Overall Recruitment Status

Terminated

Why Stopped

Study was terminated early for strategic reasons. Only Part I of the study was completed.

Study Start Date

September 19, 2017 (Actual)

Primary Completion Date

June 7, 2018 (Actual)

Study Completion Date

June 7, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

QCC374

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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)).

Intervention Type

Drug

Intervention Name(s)

QCC374

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

Intervention Type

Drug

Intervention Name(s)

Placebo Matching

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Week 16 (Day 111)

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

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

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

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

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

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

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography

Description

Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Peak Systolic Velocity (TA S') were assessed with echocardiography. Only descriptive analysis performed.

Time Frame

Baseline, Week 16 (Day 111)

Title

Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography

Description

Time Frame

Baseline, Week 16 (Day 111)

Title

Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441

Description

Time Frame

Day 1 and 112 (0.00, 0.05, 0.15, 0.30, 1.00, 2.00, 4.00, 8.00 and 12.00 hours post-dose))

Title

Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441

Description

Time Frame

Day 1 and 112 (0.00, 0.05, 0.15, 0.30, 1.00, 2.00, 4.00, 8.00 and 12.00 hours post-dose))

Title

Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441

Description

Time Frame

Day 1 and 112 (0.00, 0.05, 0.15, 0.30, 1.00, 2.00, 4.00, 8.00 and 12.00 hours post-dose))

Title

Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441

Description

Time Frame

Day 1 and 112 (0.00, 0.05, 0.15, 0.30, 1.00, 2.00, 4.00, 8.00 and 12.00 hours post-dose))

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15261

Country

United States

Facility Name

Novartis Investigative Site

City

Dresden

ZIP/Postal Code

01307

Country

Germany

Facility Name

Novartis Investigative Site

City

Heidelberg

ZIP/Postal Code

69120

Country

Germany

Facility Name

Novartis Investigative Site

City

Seoul

ZIP/Postal Code

03722

Country

Korea, Republic of

Facility Name

Novartis Investigative Site

City

Cambridge

State/Province

Cambridgeshire

ZIP/Postal Code

CB23 3RE

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

IPD Sharing URL

https://www.clinicalstudydatarequest.com

Links:

URL

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=403

Description

A Plain Language Trial Summary is available on novartisclinicatrials.com

Learn more about this trial

Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

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