Pulmonary Arterial Hypertension
Conditions
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
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.
Interventions
DRUGQCC374
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
DRUGPlacebo Matching
Placebo matching to QCC374: 0.03 mg BID, 0.06 mg BID and 0.12 mg BID
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) | Baseline, 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Baseline, 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) | Baseline, 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) | Baseline, 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) | Baseline, 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 | Baseline, Week 16 (Day 111) | 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 | Baseline, Week 16 (Day 111) | 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 Six Minute Walk Distance (6MWD) Over Time | Baseline, Day 28, Day 56, Day 84 and Day 111 | 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 Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography | Baseline, Week 16 (Day 111) | 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 | 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)) | 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 | 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)) | 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 | 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)) | 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 | 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)) | 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. |
| Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography | Baseline, Week 16 (Day 111) | Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Peak Systolic Velocity (TA S') were assessed with echocardiography. Only descriptive analysis performed. |
Countries
Germany, South Korea, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted in 5 centers in 4 countries: Germany (2), Korea (1), UK (1) and USA (1).
Pre-assignment details
Part 1 consisted of 8 subjects, randomized in a 6:2 ratio to QCC374 or placebo. The planned bid dose levels in Part 1 were 0.03 mg, 0.06 mg and 0.12 mg. Subjects began dosing at 0.03 mg bid.
Participants by arm
| Arm | Count |
|---|---|
| QCC374 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). | 6 |
| Placebo 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)). | 2 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Patient schedule | 1 | 0 |
Baseline characteristics
| Characteristic | QCC374 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 41.0 Years STANDARD_DEVIATION 14.62 | 57.5 Years STANDARD_DEVIATION 9.19 | 45.1 Years STANDARD_DEVIATION 14.93 |
| Ethiology of Pulmonary Arterial Hypertension (PAH) Family PAH | 1 Participants | 0 Participants | 1 Participants |
| Ethiology of Pulmonary Arterial Hypertension (PAH) Idiopathic PAH | 4 Participants | 1 Participants | 5 Participants |
| Ethiology of Pulmonary Arterial Hypertension (PAH) PAH associated with Connective Tissue Disease | 1 Participants | 0 Participants | 1 Participants |
| Ethiology of Pulmonary Arterial Hypertension (PAH) PAH induced by Drug/Toxin | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 1 Participants |
| Time from Pulmonary Arterial Hypertension (PAH) diagnosis | 2.985 Years | 9.201 Years | 4.966 Years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 6 / 6 | 1 / 2 |
| serious Total, serious adverse events | 1 / 6 | 0 / 2 |
Outcome results
Primary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) | PVR at Screening-Ratio to Baseline | 1.00 dyn*s/cm5 | Standard Deviation 0 |
| QCC374 | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) | PVR at Day 111-Ratio to Baseline | 1.07 dyn*s/cm5 | Standard Deviation 0.274 |
| Placebo | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) | PVR at Screening-Ratio to Baseline | 1.00 dyn*s/cm5 | Standard Deviation 0 |
| Placebo | Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) | PVR at Day 111-Ratio to Baseline | 1.05 dyn*s/cm5 | Standard Deviation 0.073 |
Secondary
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.
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))
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCC374: Day 1, Dose Level 0.03 mg | 148 h*pg/mL | Geometric Coefficient of Variation 15.5 |
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.06 mg | 638 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.12 mg | 910 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCM441: Day 1, Dose Level 0.03 mg | 2600 h*pg/mL | Geometric Coefficient of Variation 40.6 |
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.06 mg | 17700 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration Time Curve From 0 to the End of a Dosing Interval (AUCtau) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.12 mg | 33800 h*pg/mL | — |
Secondary
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.
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))
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.06 mg | 638 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCM441: Day 1, Dose Level 0.03 mg | 2590 h*pg/mL | Geometric Coefficient of Variation 22.8 |
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.06 mg | 17700 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.12 mg | 33800 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.12 mg | 883 h*pg/mL | — |
| QCC374 | Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and Its Metabolite QCM441 | QCC374: Day 1, Dose Level 0.03 mg | 128 h*pg/mL | Geometric Coefficient of Variation 14.3 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Cardiac Index at Week 16 (Day 111) | Cardiac Index at Baseline | 2.45 L/min/m2 | Standard Deviation 0.794 |
| QCC374 | Change From Baseline in Cardiac Index at Week 16 (Day 111) | Cardiac Index at Day 111 | 2.54 L/min/m2 | — |
| Placebo | Change From Baseline in Cardiac Index at Week 16 (Day 111) | Cardiac Index at Baseline | 2.15 L/min/m2 | Standard Deviation 0.07 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Average Cardiac Output at Baseline | 4.33 L/min | Standard Deviation 1.527 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 2 at Baseline | 3.96 L/min | Standard Deviation 1.588 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 1 at Baseline | 4.38 L/min | Standard Deviation 1.491 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 2 at Day 111 | 4.33 L/min | Standard Deviation 0.993 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Average Cardiac Output at Day 111 | 4.46 L/min | Standard Deviation 0.937 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 3 at Baseline | 3.98 L/min | Standard Deviation 1.34 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 3 at Day 111 | 4.40 L/min | Standard Deviation 1.238 |
| QCC374 | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 1 at Day 111 | 4.58 L/min | Standard Deviation 1.002 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 3 at Day 111 | 3.79 L/min | Standard Deviation 0.028 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Average Cardiac Output at Baseline | 3.61 L/min | Standard Deviation 0.085 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Average Cardiac Output at Day 111 | 3.79 L/min | Standard Deviation 0.191 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 1 at Baseline | 3.61 L/min | Standard Deviation 0.127 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 1 at Day 111 | 3.69 L/min | Standard Deviation 0.311 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 2 at Baseline | 3.60 L/min | Standard Deviation 0 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 2 at Day 111 | 3.89 L/min | Standard Deviation 0.233 |
| Placebo | Change From Baseline in Cardiac Output (CO) at Week 16 (Day 111) | Cardiac Output 3 at Baseline | 3.61 L/min | Standard Deviation 0.127 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111) | PCWP at Baseline | 8.67 mmHg | Standard Deviation 1.366 |
| QCC374 | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111) | PCWP at Day 111 | 11.75 mmHg | Standard Deviation 5.188 |
| Placebo | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111) | PCWP at Baseline | 9.50 mmHg | Standard Deviation 0.707 |
| Placebo | Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111) | PCWP at Day 111 | 9.50 mmHg | Standard Deviation 0.707 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FWPLS at Baseline | 12.68 Percentage | Standard Deviation 3.534 |
| QCC374 | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FAC at Day 111 | 20.70 Percentage | Standard Deviation 5.091 |
| QCC374 | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FAC at Baseline | 20.17 Percentage | Standard Deviation 8.717 |
| QCC374 | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FWPLS at Day 111 | 7.85 Percentage | Standard Deviation 2.758 |
| Placebo | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FWPLS at Baseline | 16.30 Percentage | — |
| Placebo | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FAC at Day 111 | 26.20 Percentage | — |
| Placebo | Change From Baseline in RV Fractional Area Change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) Using Echocardiography | RV FAC at Baseline | 30.05 Percentage | Standard Deviation 7.05 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography | RV Tei Index at Baseline | 0.92 Index | Standard Deviation 0.26 |
| QCC374 | Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography | RV Tei Index at Day 111 | 0.89 Index | Standard Deviation 0.099 |
| Placebo | Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography | RV Tei Index at Baseline | 0.88 Index | Standard Deviation 0.361 |
| Placebo | Change From Baseline in RV Tei Index at Week 16 (Day 111) Using Echocardiography | RV Tei Index at Day 111 | 0.89 Index | Standard Deviation 0.078 |
Secondary
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.
Time frame: Baseline, Day 28, Day 56, Day 84 and Day 111
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 28 | -7.17 Meter | Standard Deviation 20.651 |
| QCC374 | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 84 | -4.25 Meter | Standard Deviation 21.956 |
| QCC374 | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 56 | -11.60 Meter | Standard Deviation 19.562 |
| QCC374 | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 111 | 13.25 Meter | Standard Deviation 25.002 |
| QCC374 | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Baseline | 443.83 Meter | Standard Deviation 47.942 |
| Placebo | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 111 | 14.00 Meter | Standard Deviation 9.192 |
| Placebo | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Baseline | 458.50 Meter | Standard Deviation 111.723 |
| Placebo | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 28 | 9.75 Meter | Standard Deviation 13.789 |
| Placebo | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 56 | 14.50 Meter | Standard Deviation 19.799 |
| Placebo | Change From Baseline in Six Minute Walk Distance (6MWD) Over Time | Chge from BL at Day 84 | 12.50 Meter | Standard Deviation 16.971 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111) | SVR at Baseline | 1133.31 dynes*Sec*cm5 | Standard Deviation 410.336 |
| QCC374 | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111) | SVR at Day 111 | 1285.50 dynes*Sec*cm5 | Standard Deviation 465.983 |
| Placebo | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111) | SVR at Baseline | 1425.89 dynes*Sec*cm5 | Standard Deviation 633.723 |
| Placebo | Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111) | SVR at Day 111 | 1240.00 dynes*Sec*cm5 | Standard Deviation 274.357 |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography | TA S' at Baseline | 11.23 cm/s | Standard Deviation 1.723 |
| QCC374 | Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography | TA S' at Day 111 | 9.73 cm/s | Standard Deviation 1.069 |
| Placebo | Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography | TA S' at Baseline | 9.50 cm/s | Standard Deviation 0.99 |
| Placebo | Change From Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) Using Echocardiography | TA S' at Day 111 | 13.20 cm/s | — |
Secondary
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.
Time frame: Baseline, Week 16 (Day 111)
Population: Participants from the Pharmacodynamic (PD) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PD assessment, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography | TAPSE at Baseline | 1.88 cm | Standard Deviation 0.313 |
| QCC374 | Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography | TAPSE at Day 111 | 1.79 cm | Standard Deviation 0.511 |
| Placebo | Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography | TAPSE at Baseline | 1.27 cm | Standard Deviation 0.17 |
| Placebo | Change From Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) Using Echocardiography | TAPSE at Day 111 | 1.76 cm | — |
Secondary
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 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))
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 1, Dose Level 0.03 mg | 101 pg/mL | Geometric Coefficient of Variation 15.7 |
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.06 mg | 461 pg/mL | — |
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.12 mg | 406 pg/mL | — |
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 1, Dose Level 0.03 mg | 346 pg/mL | Geometric Coefficient of Variation 32.4 |
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.06 mg | 2350 pg/mL | — |
| QCC374 | Maximum Observed Plasma Concentration (Cmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.12 mg | 3610 pg/mL | — |
Secondary
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.
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))
Population: Participants from the Pharmacokinetic (PK) analysis set, defined as all randomized participants who received at least one dose of study drug and one evaluable PK concentration measurement, with data available for analysis were considered.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.12 mg | 4.02 hour |
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 1, Dose Level 0.03 mg | 0.159 hour |
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.06 mg | 0.00 hour |
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCC374: Day 112, Dose Level 0.12 mg | 0.517 hour |
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 1, Dose Level 0.03 mg | 3.99 hour |
| QCC374 | Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and Its Metabolite QCM441 | QCM441: Day 112, Dose Level 0.06 mg | 1.00 hour |