NCT02927366

Safety, Pharmacokinetics and Efficacy Study of QCC374 in PAH Patients

Terminated Phase 2 Results posted Last updated 5 January 2021

What this trial tests

Phase 2 trial testing QCC374 in Pulmonary Arterial Hypertension in 8 participants. Terminated before completion.

Timeline

19 September 2017

Primary endpoint
7 June 2018

7 June 2018

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	8
Start date	19 September 2017
Primary completion	7 June 2018
Estimated completion	7 June 2018
Sites	5 locations across United Kingdom, United States, Germany, South Korea

Drugs / interventions tested

• QCC374 — full drug profile →
• Placebo Matching

Conditions studied

• Pulmonary Arterial Hypertension — all drugs for Pulmonary Arterial Hypertension →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Pulmonary Arterial Hypertension. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

PVR at Screening-Ratio to Baseline

Group	Value	95% CI
QCC374	1.00	± 0.000
Placebo	1.00	± 0.000

PVR at Day 111-Ratio to Baseline

Group	Value	95% CI
QCC374	1.07	± 0.274
Placebo	1.05	± 0.073

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

Baseline

Group	Value	95% CI
QCC374	443.83	± 47.942
Placebo	458.50	± 111.723

Chge from BL at Day 28

Group	Value	95% CI
QCC374	-7.17	± 20.651
Placebo	9.75	± 13.789

Chge from BL at Day 56

Group	Value	95% CI
QCC374	-11.60	± 19.562
Placebo	14.50	± 19.799

Chge from BL at Day 84

Group	Value	95% CI
QCC374	-4.25	± 21.956
Placebo	12.50	± 16.971

Chge from BL at Day 111

Group	Value	95% CI
QCC374	13.25	± 25.002
Placebo	14.00	± 9.192

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

Average Cardiac Output at Baseline

Group	Value	95% CI
QCC374	4.33	± 1.527
Placebo	3.61	± 0.085

Average Cardiac Output at Day 111

Group	Value	95% CI
QCC374	4.46	± 0.937
Placebo	3.79	± 0.191

Cardiac Output 1 at Baseline

Group	Value	95% CI
QCC374	4.38	± 1.491
Placebo	3.61	± 0.127

Cardiac Output 1 at Day 111

Group	Value	95% CI
QCC374	4.58	± 1.002
Placebo	3.69	± 0.311

Cardiac Output 2 at Baseline

Group	Value	95% CI
QCC374	3.96	± 1.588
Placebo	3.60	± 0.000

Cardiac Output 2 at Day 111

Group	Value	95% CI
QCC374	4.33	± 0.993
Placebo	3.89	± 0.233

Cardiac Output 3 at Baseline

Group	Value	95% CI
QCC374	3.98	± 1.340
Placebo	3.61	± 0.127

Cardiac Output 3 at Day 111

Group	Value	95% CI
QCC374	4.40	± 1.238
Placebo	3.79	± 0.028

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

Cardiac Index at Baseline

Group	Value	95% CI
QCC374	2.45	± 0.794
Placebo	2.15	± 0.070

Cardiac Index at Day 111

Group	Value	95% CI
QCC374	2.54	± NA

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

PCWP at Baseline

Group	Value	95% CI
QCC374	8.67	± 1.366
Placebo	9.50	± 0.707

PCWP at Day 111

Group	Value	95% CI
QCC374	11.75	± 5.188
Placebo	9.50	± 0.707

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

SVR at Baseline

Group	Value	95% CI
QCC374	1133.31	± 410.336
Placebo	1425.89	± 633.723

SVR at Day 111

Group	Value	95% CI
QCC374	1285.50	± 465.983
Placebo	1240.00	± 274.357

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

RV FAC at Baseline

Group	Value	95% CI
QCC374	20.17	± 8.717
Placebo	30.05	± 7.050

RV FAC at Day 111

Group	Value	95% CI
QCC374	20.70	± 5.091
Placebo	26.20	± NA

RV FWPLS at Baseline

Group	Value	95% CI
QCC374	12.68	± 3.534
Placebo	16.30	± NA

RV FWPLS at Day 111

Group	Value	95% CI
QCC374	7.85	± 2.758

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

RV Tei Index at Baseline

Group	Value	95% CI
QCC374	0.92	± 0.260
Placebo	0.88	± 0.361

RV Tei Index at Day 111

Group	Value	95% CI
QCC374	0.89	± 0.099
Placebo	0.89	± 0.078

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

TA S' at Baseline

Group	Value	95% CI
QCC374	11.23	± 1.723
Placebo	9.50	± 0.990

TA S' at Day 111

Group	Value	95% CI
QCC374	9.73	± 1.069
Placebo	13.20	± NA

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

TAPSE at Baseline

Group	Value	95% CI
QCC374	1.88	± 0.313
Placebo	1.27	± 0.170

TAPSE at Day 111

Group	Value	95% CI
QCC374	1.79	± 0.511
Placebo	1.76	± NA

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

QCC374: Day 1, Dose Level 0.03 mg

Group	Value	95% CI
QCC374	101	± 15.7

QCC374: Day 112, Dose Level 0.06 mg

Group	Value	95% CI
QCC374	461	± NA

QCC374: Day 112, Dose Level 0.12 mg

Group	Value	95% CI
QCC374	406	± NA

QCM441: Day 1, Dose Level 0.03 mg

Group	Value	95% CI
QCC374	346	± 32.4

QCM441: Day 112, Dose Level 0.06 mg

Group	Value	95% CI
QCC374	2350	± NA

QCM441: Day 112, Dose Level 0.12 mg

Group	Value	95% CI
QCC374	3610	± NA

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

QCC374: Day 1, Dose Level 0.03 mg

Group	Value	95% CI
QCC374	0.159	0.0830 – 0.267

QCC374: Day 112, Dose Level 0.06 mg

Group	Value	95% CI
QCC374	0.00	0.00 – 0.00

QCC374: Day 112, Dose Level 0.12 mg

Group	Value	95% CI
QCC374	0.517	0.517 – 0.517

QCM441: Day 1, Dose Level 0.03 mg

Group	Value	95% CI
QCC374	3.99	3.85 – 8.00

QCM441: Day 112, Dose Level 0.06 mg

Group	Value	95% CI
QCC374	1.00	1.00 – 1.00

QCM441: Day 112, Dose Level 0.12 mg

Group	Value	95% CI
QCC374	4.02	4.02 – 4.02

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse Events and Serious Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 5 months.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

QCC374

Serious: 1/6 (17%)

Deaths: 0/6

Placebo

Serious: 0/2 (0%)

Deaths: 0/2

Serious adverse events (1 terms)

Reaction	System	QCC374	Placebo
Syncope	Nervous system disorders	—	—

Other adverse events (18 terms — click to expand)

Reaction	System	QCC374	Placebo
Headache	Nervous system disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Flushing	Vascular disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Pain In Jaw	Musculoskeletal and connective tissue disorders	—	—
Dental Caries	Gastrointestinal disorders	—	—
Dyspepsia	Gastrointestinal disorders	—	—
Gastrointestinal Disorder	Gastrointestinal disorders	—	—
Gastrooesophageal Reflux Disease	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Hangover	General disorders	—	—
Gastroenteritis	Infections and infestations	—	—
Otitis Media	Infections and infestations	—	—
Pain In Extremity	Musculoskeletal and connective tissue disorders	—	—
Dysgeusia	Nervous system disorders	—	—
Head Discomfort	Nervous system disorders	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—

Most-reported serious reactions: Syncope.

Data from ClinicalTrials.gov NCT02927366 adverse events section.

Sponsor's own description

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.

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. Exploring Functional Differences between the Right and Left Ventricles to Better Understand Right Ventricular Dysfunction.
   Bernal-Ramirez J, Díaz-Vesga MC, Talamilla M, Méndez A, et al · · 2021 · cited 20× · PMID 34497685 · DOI 10.1155/2021/9993060
2. Repurposing of medications for pulmonary arterial hypertension.
   Toshner M, Spiekerkoetter E, Bogaard H, Hansmann G, et al · · 2020 · cited 11× · PMID 33282182 · DOI 10.1177/2045894020941494
3. The Changing Landscape of Pulmonary Arterial Hypertension in the Adult with Congenital Heart Disease.
   van Dissel AC, Mulder BJ, Bouma BJ. · · 2017 · cited 11× · PMID 28358329 · DOI 10.3390/jcm6040040