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    Clinical Trial Results:
    AC-055-310/ORCHESTRA: A pulmOnary aRterial hypertension study with maCitentan to validate tHE PAH-SYMPACT® in FRAnce, Italy, and Spain A multi-center, open-label, single-arm, Phase 3b study of macitentan in patients with pulmonary arterial hypertension to psychometrically validate the French, Italian, and Spanish versions of the PAH-SYMPACT®

    Summary
    EudraCT number
    		 2013-003462-14
    Trial protocol
    		 IT   ES  
    Global end of trial date
    09 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 May 2017
    First version publication date
    07 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055-310
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02081690
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACTELION Pharmaceuticals Ltd.
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Laurie Bertrand, ACTELION Pharmaceuticals Ltd., 41 61 565 83 36,
    Scientific contact
    Laurie Bertrand, ACTELION Pharmaceuticals Ltd., 41 61 565 83 36,
    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
    09 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the psychometric characteristics of reliability and construct validity of the French, Italian, and Spanish versions of the PAH-SYMPACT®
    Protection of trial subjects
    The protocol and any material provided to the patient (such as a patient information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety and well-being of the study subjects. Actelion and investigators ensured that the study was conducted in full compliance with the principles of the ʽDeclaration of Helsinkiʼ and with the laws and regulations of the country in which the research was conducted. GCP training was provided to investigators and investigational site staff. Both Actelion and the investigator had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. Written informed consent was obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each patient that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason.
    Background therapy
    		 Concomitant treatment with oral diuretics was allowed if patients had been on a stable dose for at least 1 week prior to Baseline period and up to the Treatment Initiation visit. The following treatments for PAH were allowed if patients had been on a stable dose for at least 3 months before the Treatment Initiation visit: • Oral PDE-5 inhibitors; • Inhaled prostacyclin analogs; • Calcium channel blockers. Forbidden concomitant therapy included: • ERAs, i.v. or s.c. prostanoids, and soluble guanylate cyclase stimulator unless initiated for clinical worsening of PAH; • Strong CYP3A4 inducers; • Any investigational drug.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Spain: 29
    Worldwide total number of subjects
    88
    EEA total number of subjects
    88
    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)
    59
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 3 countries (France, Italy, and Spain), with patients enrolled in 37 centers.

    Pre-assignment
    Screening details
    		 The screening period lasted from Day −28 to Day −15 and included the Screening Visit (Visit 1).

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Baseline period
    Arm description
    		 Baseline period
    Arm type
    		 No IMP

    Investigational medicinal product name
    No IMP
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Anticoagulant and preservative solution for blood
    Routes of administration
    Other use
    Dosage and administration details
    No IMP

    Number of subjects in period 1
    		Baseline period
    Started
    88
    Completed
    88
    Period 2
    Period 2 title
    Macitentan treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Macitentan
    Arm description
    		 Macitentan 10 mg o.d.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg o.d. for 16 weeks

    Number of subjects in period 2
    		Macitentan
    Started
    88
    Completed
    81
    Not completed
    7
         Adverse event, serious fatal
    3
         Consent withdrawn by subject
    1
         Physician decision
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 Baseline period

    Reporting group values
    		 Baseline period Total
    Number of subjects
    		 88 88
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 59 59
        From 65-84 years
    		 29 29
    Age continuous
    Units: years
        median (full range (min-max))
    		 57.5 (21 to 79) -
    Gender categorical
    Units:
        Male
    		 30 30
        Female
    		 58 58
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all enrolled patients.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set (SS) included all patients who received at least one dose of study treatment, based on the actual treatment received

    Subject analysis set title
    Validation Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Validation Analysis Set (VAS) comprised data from all patients included in the FAS who had no protocol deviation(s) that could affect the analysis.

    Subject analysis set title
    Per-protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-protocol Set (PPS) comprised data from all patients included in the FAS who did not have any of the following protocol deviations: • Patients who did not receive study treatment • Patients who violated selected inclusion/exclusion criteria • Patients who received a prohibited concomitant PAH medication

    Subject analysis sets values
    		 Full Analysis Set Safety Set Validation Analysis Set Per-protocol Set
    Number of subjects
    88
    88
    87
    81
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    59
        From 65-84 years
    29
    Age continuous
    Units: years
        median (full range (min-max))
    57.5 (21 to 79)
    57.5 (21 to 79)
    Gender categorical
    Units:
        Male
    30
    30
        Female
    58
    58

    End points

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    End points reporting groups
    Reporting group title
    Baseline period
    Reporting group description
    		 Baseline period
    Reporting group title
    Macitentan
    Reporting group description
    		 Macitentan 10 mg o.d.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) included all enrolled patients.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set (SS) included all patients who received at least one dose of study treatment, based on the actual treatment received

    Subject analysis set title
    Validation Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Validation Analysis Set (VAS) comprised data from all patients included in the FAS who had no protocol deviation(s) that could affect the analysis.

    Subject analysis set title
    Per-protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per-protocol Set (PPS) comprised data from all patients included in the FAS who did not have any of the following protocol deviations: • Patients who did not receive study treatment • Patients who violated selected inclusion/exclusion criteria • Patients who received a prohibited concomitant PAH medication

    Primary: Psychometric validation of the French, Italian and Spanish versions of the PAH-SYMPACT™ patient-reported outcome tool

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    End point title
    		 Psychometric validation of the French, Italian and Spanish versions of the PAH-SYMPACT™ patient-reported outcome tool [1]
    End point description
    Evaluation of the psychometric characteristics of reliability and construct validity of the PAH-SYMPACT, and the ability of the PAH-SYMPACT to detect change.
    End point type
    Primary
    End point timeframe
    From Screening Visit (Visit 1) to End of Treatment (EOT) Visit (Visit 4, Week 16)
    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: Not applicable due to specific study design
    End point values
    		 Macitentan Validation Analysis Set
    Number of subjects analysed
    87
    87
    Units: Not applicable (Score)
    arithmetic mean (standard deviation)
        MLFQ total score at Baseline
    35 ± 20.8
    35 ± 20.8
        MLFQ total score at Week 16
    33.4 ± 23
    33.4 ± 23
        Physical Dimension score at Baseline
    16.9 ± 10
    16.9 ± 10
        Physical Dimension score at Week 16
    15.7 ± 10
    15.7 ± 10
        Emotional Dimension score at Baseline
    7.7 ± 6.6
    7.7 ± 6.6
        Emotional Dimension score at Week 16
    7.5 ± 7.2
    7.5 ± 7.2
    No statistical analyses for this end point

    Primary: Change in the PAH-SYMPACT symptom and impact scores assessed by Clinician Global Impression of Change (CGI-C)

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    End point title
    		 Change in the PAH-SYMPACT symptom and impact scores assessed by Clinician Global Impression of Change (CGI-C)
    End point description
    Change in the PAH-SYMPACT symptom and impact scores assessed by the PAH-SYMPACT questionnaire - Clinician Global Impression of Change (CGI-C)
    End point type
    Primary
    End point timeframe
    From Baseline Visit (Visit 2, Day 1) to Week 16
    End point values
    		 Macitentan Per-protocol Set
    Number of subjects analysed
    87
    87
    Units: Not applicable (Score)
    least squares mean (standard error)
        Cardiopulmonary symptoms_Responders
    -0.08 ± 0.04
    -0.08 ± 0.04
        Cardiopulmonary symptoms_No change
    0.13 ± 0.1
    0.13 ± 0.1
        Cardiopulmonary symptoms_Non-Responders
    0.6 ± 0.16
    0.6 ± 0.16
        Cardiovascular symptoms_Responders
    -0.04 ± 0.05
    -0.04 ± 0.05
        Cardiovascular symptoms_No change
    0.02 ± 0.1
    0.02 ± 0.1
        Cardiovascular symptoms_Non-Responders
    0.16 ± 0.16
    0.16 ± 0.16
        Physical impacts_Responders
    -0.04 ± 0.05
    -0.04 ± 0.05
        Physical impacts_No change
    0.19 ± 0.19
    0.19 ± 0.05
        Physical impacts_Non-Responders
    0.83 ± 0.25
    0.83 ± 0.25
        Cognitive/Emotional impacts_Responders
    0.08 ± 0.09
    0.08 ± 0.09
        Cognitive/Emotional impacts_No change
    -0.28 ± 0.19
    -0.28 ± 0.19
        Cognitive/Emotional impacts_Non-Responders
    0.3 ± 0.26
    0.3 ± 0.26
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Not applicable
    Comparison groups
    Macitentan v Per-protocol Set
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0 [3]
    Method
    		 Not applicable
    Confidence interval
    Notes
    [2] - Not applicable
    [3] - Not applicable

    Primary: Change in the PAH-SYMPACT symptom and impact scores assessed by Patient Global Assessment of Disease Severity (PGA-S)

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    End point title
    		 Change in the PAH-SYMPACT symptom and impact scores assessed by Patient Global Assessment of Disease Severity (PGA-S) [4]
    End point description
    Mean change in the PAH-SYMPACT symptom and impact scores assessed by the PAH-SYMPACT questionnaire - Patient Global Assessment of Disease Severity (PGA-S)
    End point type
    Primary
    End point timeframe
    From Baseline Visit (Visit 2, Day 1) to Week 16
    Notes
    [4] - 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: Not applicable due to specific study design
    End point values
    		 Macitentan Per-protocol Set
    Number of subjects analysed
    75
    75
    Units: Not applicable (Score)
    least squares mean (standard error)
        Cardiopulmonary symptoms_Decline (>=1)
    0.08 ± 0.12
    0.08 ± 0.12
        Cardiopulmonary symptoms_Stable (0)
    0.02 ± 0.06
    0.02 ± 0.06
        Cardiopulmonary symptoms_Improvement (= -1)
    -0.17 ± 0.11
    -0.17 ± 0.11
        Cardiopulmonary symptoms_Better Improvement (< -1)
    -0.08 ± 0.15
    -0.08 ± 0.15
        Cardiovascular symptoms_Decline (>=1)
    0.03 ± 0.1
    0.03 ± 0.1
        Cardiovascular symptoms_Stable (0)
    -0.06 ± 0.05
    -0.06 ± 0.05
        Cardiovascular symptoms_Improvement (= -1)
    -0.01 ± 0.1
    -0.01 ± 0.1
        Cardiovascular symptoms_Better Improvement (< -1)
    -0.07 ± 0.13
    -0.07 ± 0.13
        Physical impacts_Decline (>=1)
    -0.06 ± 0.19
    -0.06 ± 0.19
        Physical impacts_Stable (0)
    0.02 ± 0.09
    0.02 ± 0.09
        Physical impacts_Improvement (= -1)
    -0.23 ± 0.18
    -0.23 ± 0.18
        Physical impacts_Better Improvement (< -1)
    -0.06 ± 0.26
    -0.06 ± 0.26
        Cognitive/Emotional impacts_Decline (>=1)
    0.11 ± 0.18
    0.11 ± 0.18
        Cognitive/Emotional impacts_Stable (0)
    -0.06 ± 0.09
    -0.06 ± 0.09
        Cognitive/Emotional impacts_Improvement (= -1)
    0.08 ± 0.17
    0.08 ± 0.17
        Cognitive/Emot. impacts_Better Improvement (< -1)
    -0.25 ± 0.24
    -0.25 ± 0.24
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study treatment initiation up to 30 days after study treatment discontinuation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    		 Macitentan

    Serious adverse events
    		 Macitentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 88 (14.77%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Investigation
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Coronary artery stenosis
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    4 / 88 (4.55%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Surgical and medical procedures
    Sympathectomy
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 88 (3.41%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 88 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Macitentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 88 (23.86%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 88 (5.68%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 88 (12.50%)
         occurrences all number
    12
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    8 / 88 (9.09%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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    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
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