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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-001412-38
    Trial protocol
    		 DE  
    Global end of trial date
    11 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2019
    First version publication date
    19 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQCC374X2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02927366
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the efficacy of 16 weeks of QCC374 administration in adult subjects with pulmonary arterial hypertension (PAH). Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    8
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    7
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 5 centers in 4 countries: Germany (2), Korea (1), UK (1) and USA (1).

    Pre-assignment
    Screening 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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QCC374
    Arm description
    		 Adult patients with pulmonary arterial hypertension (PAH) on QCC374
    Arm type
    		 Experimental

    Investigational medicinal product name
    QCC374
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule, Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    QCC374 capsules for inhalation were supplied to the investigators at dose strengths of 0.015 mg and 0.06 mg.

    Arm title
    		 Placebo
    Arm description
    		 Adult patients with pulmonary arterial hypertension (PAH) on matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder, hard capsule, Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo to match QCC374 capsules for inhalation.

    Number of subjects in period 1
    		QCC374 Placebo
    Started
    6
    2
    Pharmacodynamic (PD) analysis set
    6
    2
    Pharmacokinetic (PK) analysis set
    4
    0 [1]
    Completed
    4
    2
    Not completed
    2
    0
         Adverse event, non-fatal
    1
    -
         Patient schedule
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All randomized patients were included in the Safety Analysis Set (SAS) and Pharmacodynamic (PD) analysis set. The PK analysis set (PAS) included 4 subjects with available PK data and no protocol deviations with relevant impact on PK data in the QCC374 treatment arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QCC374
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on QCC374

    Reporting group title
    Placebo
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on matching placebo

    Reporting group values
    		 QCC374 Placebo Total
    Number of subjects
    		 6 2 8
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 2 7
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 41.0 ( 14.62 ) 57.5 ( 9.19 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 5 2 7
        Male
    		 1 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 1 0 1
        White
    		 5 2 7
    Ethiology of Pulmonary Arterial Hypertension (PAH)
    Units: Subjects
        Family PAH
    		 1 0 1
        Idiopathic PAH
    		 4 1 5
        PAH associated with Connective Tissue Disease
    		 1 0 1
        PAH induced by Drug/Toxin
    		 0 1 1
    Time from Pulmonary Arterial Hypertension (PAH) diagnosis
    Units: Years
        median (full range (min-max))
    		 2.985 (0.56 to 7.77) 9.201 (6.04 to 12.36) -

    End points

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    End points reporting groups
    Reporting group title
    QCC374
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on QCC374

    Reporting group title
    Placebo
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on matching placebo

    Primary: Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111)

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    End point title
    		 Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 16 (Day 111) [1]
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16 (Day 111)
    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
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: dyn*s/cm5
    arithmetic mean (standard deviation)
        PVR at Screening-Ratio to Baseline (n=6,2)
    1.00 ( 0.000 )
    1.00 ( 0.000 )
        PVR at Day 111-Ratio to Baseline (n=4,2)
    1.07 ( 0.274 )
    1.05 ( 0.073 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Six Minute Walk Distance (6MWD) over time

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    End point title
    		 Change from Baseline in Six Minute Walk Distance (6MWD) over time
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28, Day 56, Day 84 and Day 111
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: Meter
    arithmetic mean (standard deviation)
        Baseline (n=6,2)
    443.83 ( 47.942 )
    458.50 ( 111.723 )
        Chge from BL at Day 28 (n=6,2)
    -7.17 ( 20.651 )
    9.75 ( 13.789 )
        Chge from BL at Day 56 (n=5,2)
    -11.60 ( 19.562 )
    14.50 ( 19.799 )
        Chge from BL at Day 84 (n=4,2)
    -4.25 ( 21.956 )
    12.50 ( 16.971 )
        Chge from BL at Day 111 (n=4,2)
    13.25 ( 25.002 )
    14.00 ( 9.192 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cardiac Output (CO) at Week 16 (Day 111)

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    End point title
    		 Change from Baseline in Cardiac Output (CO) at Week 16 (Day 111)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: L/min
    arithmetic mean (standard deviation)
        Average Cardiac Output at Baseline (n=6,2)
    4.33 ( 1.527 )
    3.61 ( 0.085 )
        Average Cardiac Output at Day 111 (n=4,2)
    4.46 ( 0.937 )
    3.79 ( 0.191 )
        Cardiac Output 1 at Baseline (n=6,2)
    4.38 ( 1.491 )
    3.61 ( 0.127 )
        Cardiac Output 1 at Day 111 (n=4,2)
    4.58 ( 1.002 )
    3.69 ( 0.311 )
        Cardiac Output 2 at Baseline (n=5,2)
    3.96 ( 1.588 )
    3.60 ( 0.000 )
        Cardiac Output 2 at Day 111 (n=3,2)
    4.33 ( 0.993 )
    3.89 ( 0.233 )
        Cardiac Output 3 at Baseline (n=5,2)
    3.98 ( 1.340 )
    3.61 ( 0.127 )
        Cardiac Output 3 at Day 111 (n=3,2)
    4.40 ( 1.238 )
    3.79 ( 0.028 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Cardiac Index at Week 16 (Day 111)

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    End point title
    		 Change from Baseline in Cardiac Index at Week 16 (Day 111)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: L/min/m2
    arithmetic mean (standard deviation)
        Cardiac Index at Baseline (n=6,2)
    2.45 ( 0.794 )
    2.15 ( 0.070 )
        Cardiac Index at Day 111 (n=1,0)
    2.54 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16 (Day 111)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: mmHg
    arithmetic mean (standard deviation)
        PCWP at Baseline (n=6,2)
    8.67 ( 1.366 )
    9.50 ( 0.707 )
        PCWP at Day 111 (n=4,2)
    11.75 ( 5.188 )
    9.50 ( 0.707 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111)

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    End point title
    		 Change from Baseline in Systemic Vascular Resistance (SVR) at Week 16 (Day 111)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    6
    2
    Units: dynes*Sec*cm5
    arithmetic mean (standard deviation)
        SVR at Baseline (n=5,2)
    1133.31 ( 410.336 )
    1425.89 ( 633.723 )
        SVR at Day 111 (n=2,2)
    1285.50 ( 465.983 )
    1240.00 ( 274.357 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in RV fractional area change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) using Echocardiography

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    End point title
    		 Change from Baseline in RV fractional area change and RV Free Wall Average Peak Long Strain at Week 16 (Day 111) using Echocardiography
    End point description
    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. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    5
    2
    Units: Percent
    arithmetic mean (standard deviation)
        RV FAC at Baseline (n=4,2)
    20.17 ( 8.717 )
    30.05 ( 7.050 )
        RV FAC at Day 111 (n=2,1)
    20.70 ( 5.091 )
    26.20 ( 999 )
        RV FWPLS at Baseline (n=5,1)
    12.68 ( 3.534 )
    16.30 ( 999 )
        RV FWPLS at Day 111 (n=2,0)
    7.85 ( 2.758 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in RV Tei Index at Week 16 (Day 111) using Echocardiography

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    End point title
    		 Change from Baseline in RV Tei Index at Week 16 (Day 111) using Echocardiography
    End point description
    Key Right Ventricular (RV) function endpoints such as RV myocardial performance index or Tei Index were assessed with echocardiography. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    5
    2
    Units: Index
    arithmetic mean (standard deviation)
        RV Tei Index at Baseline (n=4,2)
    0.92 ( 0.260 )
    0.88 ( 0.361 )
        RV Tei Index at Day 111 (n=2,2)
    0.89 ( 0.099 )
    0.89 ( 0.078 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) using Echocardiography

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    End point title
    		 Change from Baseline in Tricuspid Annular Peak Systolic Velocity (TA S') at Week 16 (Day 111) using Echocardiography
    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.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    5
    2
    Units: cm/s
    arithmetic mean (standard deviation)
        TA S' at Baseline (n=4,2)
    11.23 ( 1.723 )
    9.50 ( 0.990 )
        TA S' at Day 111 (n=3,1)
    9.73 ( 1.069 )
    13.20 ( 999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) using Echocardiography

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    End point title
    		 Change from Baseline in Tricuspid Annular Plane Sys Excursion (TAPSE) at Week 16 (Day 111) using Echocardiography
    End point description
    Key Right Ventricular (RV) function endpoints such as Tricuspid Annular Plane Sys Excursion (TAPSE) were assessed with echocardiography. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16 (Day 111)
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    5
    2
    Units: cm
    arithmetic mean (standard deviation)
        TAPSE at Baseline (n=4,2)
    1.88 ( 0.313 )
    1.27 ( 0.170 )
        TAPSE at Day 111 (n=3,1)
    1.79 ( 0.511 )
    1.76 ( 999 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) for QCC374 and its metabolite QCM441

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) for QCC374 and its metabolite QCM441
    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.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 112
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    4
    0 [2]
    Units: pg/mL
    geometric mean (geometric coefficient of variation)
        QCC374: Day 1, Dose Level 0.03 mg (n=4,0)
    101 ( 15.7 )
    ( )
        QCC374: Day 112, Dose Level 0.06 mg (n=1,0)
    461 ( 999 )
    ( )
        QCC374: Day 112, Dose Level 0.12 mg (n=1,0)
    406 ( 999 )
    ( )
        QCM441: Day 1, Dose Level 0.03 mg (n=4,0)
    346 ( 32.4 )
    ( )
        QCM441: Day 112, Dose Level 0.06 mg (n=1,0)
    2350 ( 999 )
    ( )
        QCM441: Day 112, Dose Level 0.12 mg (n=1,0)
    3610 ( 999 )
    ( )
    Notes
    [2] - PK sampling only performed in the QCC374 treatment arm
    No statistical analyses for this end point

    Secondary: Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and its metabolite QCM441

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    End point title
    		 Time to Reach the Maximum Plasma Concentration (Tmax) for QCC374 and its metabolite QCM441
    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.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 112
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    4
    0 [3]
    Units: hour
    median (full range (min-max))
        QCC374: Day 1, Dose Level 0.03 mg( n=4,0)
    0.159 (0.0830 to 0.267)
    ( to )
        QCC374: Day 112, Dose Level 0.06 mg (n=1,0)
    0.00 (0.00 to 0.00)
    ( to )
        QCC374: Day 112, Dose Level 0.12 mg (n=1,0)
    0.517 (0.517 to 0.517)
    ( to )
        QCM441: Day 1, Dose Level 0.03 mg (n=4,0)
    3.99 (3.85 to 8.00)
    ( to )
        QCM441: Day 112, Dose Level 0.06 mg (n=1,0)
    1.00 (1.00 to 1.00)
    ( to )
        QCM441: Day 112, Dose Level 0.12 mg (n=1,0)
    4.02 (4.02 to 4.02)
    ( to )
    Notes
    [3] - PK sampling only performed in the QCC374 treatment arm
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and its metabolite QCM441

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    End point title
    		 Area Under the Plasma Concentration-time Curve From 0 to the Last Measurable Concentration (AUClast) for QCC374 and its metabolite QCM441
    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.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 112
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    4
    0 [4]
    Units: h*pg/mL
    geometric mean (geometric coefficient of variation)
        QCC374: Day 1, Dose Level 0.03 mg (n=4,0)
    128 ( 14.3 )
    ( )
        QCC374: Day 112, Dose Level 0.06 mg (n=1,0)
    638 ( 999 )
    ( )
        QCC374: Day 112, Dose Level 0.12 mg (n=1,0)
    883 ( 999 )
    ( )
        QCM441: Day 1, Dose Level 0.03 mg (n=4,0)
    2590 ( 22.8 )
    ( )
        QCM441: Day 112, Dose Level 0.06 mg (n=1,0)
    17700 ( 999 )
    ( )
        QCM441: Day 112, Dose Level 0.12 mg (n=1,0)
    33800 ( 999 )
    ( )
    Notes
    [4] - PK sampling only performed in the QCC374 treatment arm
    No statistical analyses for this end point

    Secondary: Area Under the plasma Concentration time Curve From 0 to the end of a dosing interval (AUCtau) for QCC374 and its metabolite QCM441

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    End point title
    		 Area Under the plasma Concentration time Curve From 0 to the end of a dosing interval (AUCtau) for QCC374 and its metabolite QCM441
    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.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 112
    End point values
    		 QCC374 Placebo
    Number of subjects analysed
    4
    0 [5]
    Units: h*pg/mL
    geometric mean (geometric coefficient of variation)
        QCC374: Day 1, Dose Level 0.03 mg (n=4,0)
    148 ( 15.5 )
    ( )
        QCC374: Day 112, Dose Level 0.06 mg (n=1,0)
    638 ( 999 )
    ( )
        QCC374: Day 112, Dose Level 0.12 mg (n=1,0)
    910 ( 999 )
    ( )
        QCM441: Day 1, Dose Level 0.03 mg (n=4,0)
    2600 ( 40.6 )
    ( )
        QCM441: Day 112, Dose Level 0.06 mg (n=1,0)
    17700 ( 999 )
    ( )
        QCM441: Day 112, Dose Level 0.12 mg (n=1,0)
    33800 ( 999 )
    ( )
    Notes
    [5] - PK sampling only performed in the QCC374 treatment arm
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 5 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on matching placebo

    Reporting group title
    QCC374
    Reporting group description
    		 Adult patients with pulmonary arterial hypertension (PAH) on QCC374

    Serious adverse events
    		 Placebo QCC374
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo QCC374
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 2 (50.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    3
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Head Discomfort
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    5 / 6 (83.33%)
         occurrences all number
    0
    8
    General disorders and administration site conditions
    Hangover
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Dental Caries
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    Dyspepsia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Gastrointestinal Disorder
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    4
    Vomiting
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Pain In Jaw
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    3
    Otitis Media
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2017
    Amendment 1: The primary purpose of this amendment was to clarify inclusion/exclusion criteria, and study design (including the addition of a study design figure), based on investigator and health authority feedback. In addition, minor changes were made to align this protocol with an amendment to the companion QCC374X2201E1 protocol. The completion of this amendment was prior to enrolling any subjects in the study.
    07 May 2018
    Amendment 2: As the study was terminated early and part 2 was not completed, this amendment was written and distributed, but was not implemented.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the limited number of subjects with the available data at Week 16 (Day 111), for the primary and secondary efficacy endpoints, it is not possible to draw any meaningful treatment comparisons.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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