Clinical Trial Results:
Long-term, open label, multicenter, extension study to evaluate the safety and tolerability of QCC374 in patients with PAH
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Summary
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EudraCT number |
2016-001411-20 |
Trial protocol |
GB DE |
Global end of trial date |
06 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Nov 2019
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First version publication date |
20 Nov 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CQCC374X2201E1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02939599 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 Nov 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Nov 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the safety and tolerability of QCC374 in patients with PAH over a two year period
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Feb 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
United States: 1
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Worldwide total number of subjects |
5
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EEA total number of subjects |
4
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
5
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
The screening period (Day-8 to Day-1, max 8 days, min 1 day) began no earlier than Day 111 of the companion QCC374X2201 study. The goal is for patients to continue to receive QCC374 without interruption between the QCC374X2201 study and the extension study. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm 1 | ||||||||||||||||||
Arm description |
Subjects randomized in the QCC374X2201 core study continued on QCC374 at their highest stable dose, in this extension study | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
QCC374
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Investigational medicinal product code |
QCC374
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Other name |
QCC374
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
0.015 mg and 0.06mg
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Arm title
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Arm 2 | ||||||||||||||||||
Arm description |
Subjects randomized to placebo in the QCC374X2201 core study completed a titration scheme similar to that of the active arm in QCC374X2201 core study protocol | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
QCC374
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Investigational medicinal product code |
QCC374
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Other name |
QCC374
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
0.015 mg and 0.06 mg.
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Baseline characteristics reporting groups
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Reporting group title |
Arm 1
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Reporting group description |
Subjects randomized in the QCC374X2201 core study continued on QCC374 at their highest stable dose, in this extension study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm 2
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Reporting group description |
Subjects randomized to placebo in the QCC374X2201 core study completed a titration scheme similar to that of the active arm in QCC374X2201 core study protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Arm2
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects randomized to placebo in the QCC374X2201 core study completed a titration scheme similar to that of the active arm in QCC374X2201 core study protocol
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Subject analysis set title |
Arm 1
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
placebo patients from QCC374X2201 rolled into extension study will start at 0.03mg b.i.d. or 0.06mg b.i.d. and have the opportunity to up-titrate 0.12mg
-active patients will continue at the dose they finished on the QCC374X2201 study
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End points reporting groups
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Reporting group title |
Arm 1
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Reporting group description |
Subjects randomized in the QCC374X2201 core study continued on QCC374 at their highest stable dose, in this extension study | ||
Reporting group title |
Arm 2
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Reporting group description |
Subjects randomized to placebo in the QCC374X2201 core study completed a titration scheme similar to that of the active arm in QCC374X2201 core study protocol | ||
Subject analysis set title |
Arm2
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects randomized to placebo in the QCC374X2201 core study completed a titration scheme similar to that of the active arm in QCC374X2201 core study protocol
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Subject analysis set title |
Arm 1
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
placebo patients from QCC374X2201 rolled into extension study will start at 0.03mg b.i.d. or 0.06mg b.i.d. and have the opportunity to up-titrate 0.12mg
-active patients will continue at the dose they finished on the QCC374X2201 study
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End point title |
Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events (SAEs) in patients with PAH over a two year period [1] | |||||||||||||||
End point description |
Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported, Only descriptive analysis performed
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End point type |
Primary
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End point timeframe |
Two years
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis performed. |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Maximum Observed Plasma Concentration (Cmax) | ||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
16 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Reach the Maximum Plasma Concentration (Tmax) | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
16 Weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) | ||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
16 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Area Under the plasma Concentration time Curve From 0 to the end of a dosing interval (AUCtau) | ||||||||||||
End point description |
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
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End point type |
Secondary
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End point timeframe |
16 Weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change from Baseline in Six Minute Walk Distance (6MWD) [2] | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
16 weeks
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive analysis performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 112) using Echocardiography [3] | ||||||||
End point description |
Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Peak Systolic Velocity (TA S') were assessed with echocardiography. Only descriptive analysis performed.
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End point type |
Secondary
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End point timeframe |
Two Years
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| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive analysis performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in RV Tei Index at Week 16 (Day 112) using Echocardiography [4] | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
16 weeks
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive analysis performed. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change from Baseline in RV fractional area change at Week 16 (Day 112) using Echocardiography [5] | ||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
16 weeks
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive analysis performed. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Treatment-emergent adverse events
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
QCC374 Arm 2
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Reporting group description |
QCC374 Arm 2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
QCC374 Arm 1
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Reporting group description |
QCC374 Arm 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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27 Feb 2017 |
The primary purpose of this amendment was to clarify language around the
study design (including the addition of a study design figure) based on
health authority feedback. Specifically, the starting dose for subjects enrolling in the QCC374X2201E1 study who were randomized to placebo in the companion QCC374X2201 study was further clarified throughout the protocol. |
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07 May 2018 |
The purpose of this amendment is to: (1) lower the dose of QCC374 based on emerging data from the companion QCC374X2201 study, (2) to clarify the transition from the companion QCC374X2201 study to this extension study based on investigator feedback, and (3) to remove 12 hours post-dose PK samples on Day 1 and D112.
In the companion QCC374X2201 study, a planned safety review occurred at the end of Part 1, to review the tolerability of the selected QCC374 titration regimen. No clinically significant findings were identified during the review of vital signs, ECG, spirometry and laboratory data.
The majority of AEs were mild and consistent with expected prostacyclin adverse events (headache, jaw pain, flushing, nausea). Considering the incidence of expected prostacyclin
adverse events, and after receiving feedback from site Investigators, the companion QCC374X2201 study and this study are being amended to make two changes to the dosing
regimen: (1) the starting dose will be maintained at 0.03 mg bid for all subjects and (2) the maximum dose with titration will be 0.06 mg bid.
In regards to the transition from the QCC374X2201 study to the extension study, the text has been modified to clarify the alignment of the extension study screening period with the
companion QCC374X2201 study, as well as further clarify the screening period duration and what assessments need to be completed during screening.
To reduce patient burden, the 12 hours post-dose PK collections on Day 1 and Day 112 have been removed with this amendment, and the steady state AUCtau,ss will be calculated using predose values at steady state |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
