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    Clinical Trial Results:
    A multi-center, double-blind, randomized, placebo-controlled, parallel group, exploratory Phase 2 study to assess efficacy and safety of selexipag in adult subjects with Raynaud's Phenomenon secondary to Systemic Sclerosis

    Summary
    EudraCT number
    		 2014-000865-34
    Trial protocol
    		 GB   DE  
    Global end of trial date
    07 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2016
    First version publication date
    19 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-065C202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02260557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland,
    Public contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
    Scientific contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.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
    18 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine the activity of selexipag on Raynaud attack frequency in subjects with Raynaud’s Phenomenon (RP) secondary to Systemic Sclerosis (SSc).
    Protection of trial subjects
    The clinical trial was designed and conducted in accordance with the ICH Good Clincal Practice (GCP) Guidelines, with applicable local regulations, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 The following commonly used therapies in the management of RP and SSc were allowed if they had been initiated at least one month prior to the Screening visit and their dose was to remain unchanged during study treatment up to end of treatment: Calcium channel blockers (CCBs), Nitrates or nitric oxide donors, Endothelin receptor antagonits (ERAs), Alpha-blockers, Antithrombotic agents, Non-steroidal anti-inflammatory drugs (occasional use), angiotensin-converting-enzyme inhibitors, Beta-blockers, Clonidine, Systemic corticosteroids, Fluoxetine
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    United Kingdom: 27
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    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)
    63
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 92 subjects at 16 sites in 3 countries (France, Germany, UK) were screened and 91 of them entered a single-blind placebo run-in period. Of the 90 subjects who completed the run-in period, 74 were randomized in the double-blind treatment period.

    Pre-assignment
    Screening details
    		 A single-blind placebo run-in period was performed prior to randomization, during which the number of RP attacks was collected. The last 7 days of the run-in period were used as baseline week for the assessments derived from eDiary data.

    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, Monitor, Data analyst, Carer
    Blinding implementation details
    The sponsor and all clinical trial team (CTT) members and CRO staff remained blinded to the treatment until study closure

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selexipag
    Arm description
    		 During the 3-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated every 3 days in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d.. This was followed by a 5-week maintenance phase, during which patients continued the treatment at their individual MTD. Dose reduction was allowed at any time in case of tolerability issues.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selexipag
    Investigational medicinal product code
    ACT-293987
    Other name
    NS304
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Each tablet contained 200 μg of selexipag

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo was administered following the same administration schedule as described for selexipag
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching selexipag tablets

    Number of subjects in period 1
    		Selexipag Placebo
    Started
    36
    38
    Completed
    29
    35
    Not completed
    7
    3
         Consent withdrawn by subject
    2
    -
         Physician decision
    -
    1
         Adverse event, non-serious
    4
    -
         Subject decision (no efficacy)
    -
    1
         Adverse event, serious non-fatal
    -
    1
         Subject decision (tolerability related)
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 During the 3-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated every 3 days in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d.. This was followed by a 5-week maintenance phase, during which patients continued the treatment at their individual MTD. Dose reduction was allowed at any time in case of tolerability issues.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered following the same administration schedule as described for selexipag

    Reporting group values
    		 Selexipag Placebo Total
    Number of subjects
    		 36 38 74
    Age categorical
    Units: Subjects
        18-64 years old
    		 30 33 63
        65-84 years old
    		 6 5 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.7 ± 12.2 52.6 ± 11.9 -
    Gender categorical
    Units:
        Female
    		 29 31 60
        Male
    		 7 7 14
    Systemic sclerosis (SSc) classification
    Number of subjects in each SSc subtypes at baseline
    Units: Subjects
        Limited cutaneous SSc
    		 22 22 44
        Diffuse cutaneous SSc
    		 12 14 26
        Other
    		 2 2 4
    Number of subjects with digital ulcers (DU) at baseline
    Units: Subjects
        DU present
    		 4 7 11
        DU absent
    		 32 31 63
    Number of Raynaud's Phenomenon (RP) attacks in the last 7 days prior to randomization
    Units: RP attacks
        arithmetic mean (standard deviation)
    		 22.1 ± 16.1 21.6 ± 14.7 -
    Time since first Raynaud's symptom
    Units: Years
        arithmetic mean (standard deviation)
    		 14.9 ± 10.7 13.4 ± 10.7 -

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 During the 3-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated every 3 days in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d.. This was followed by a 5-week maintenance phase, during which patients continued the treatment at their individual MTD. Dose reduction was allowed at any time in case of tolerability issues.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered following the same administration schedule as described for selexipag

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all randomized patients who had received at least one dose of study drug during the double-blind period and were evaluated according to the study drug to which they were randomized. The FAS was used for demographics and baseline characteristics.

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PPS comprised data from all subjects included in the FAS who: - had at least 7 RP attacks on at least 5 different days in the week prior to the randomization visit; - did not receive any of the forbidden concomitant medications from run-in treatment start date up to date of last study drug intake; - did not prematurely discontinue study treatment before Day 30; - had a rate of RP assessment ≥ 70% during the maintenance period. The PPS was used for the efficacy endpoint and quality of life

    Subject analysis set title
    DB Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The DB-SS Included all subjects who had received at least one dose of study treatment during the double-blind period and were evaluated based on the actual treatment received. This set was used for the report of adverse events during the double-blind treatment period.

    Primary: Average number of Raynaud's phenomenon (RP) attacks per week during the maintenance treatment period

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    End point title
    		 Average number of Raynaud's phenomenon (RP) attacks per week during the maintenance treatment period
    End point description
    The number of RP attacks was determined from daily entries in an eDiary during the baseline week (last 7 days prior to randomization) and the maintenance period. An RP attack is defined as an episode of at least a 2-phase color change in fingers, in response to cold exposure or emotion, consisting of pallor and/or cyanosis and reactive hyperemia associated with finger discomfort (i.e., pain or tingling, or numbness). The main analysis was performed on the per-protocol set using a Bayesian approach.
    End point type
    Primary
    End point timeframe
    Every day during the maintenance period, i.e., for 5 weeks starting from Day 26
    End point values
    		 Selexipag Placebo
    Number of subjects analysed
    27
    32
    Units: Average number of RP attacks
    arithmetic mean (standard deviation)
        RP attacks during baseline week
    22.38 ± 15.93
    21.53 ± 13.46
        RP attacks per week during maintenance period
    18.02 ± 14.13
    14.16 ± 10.27
    Statistical analysis title
    		 Negative-binomial [NB] regression Bayesian model
    Statistical analysis description
    Bayesian criterion of efficacy and criterion of significance based on posterior probability distributions were used. The analysis was adjusted for the mean-centered number of RP attacks during the baseline week and the treatment group [selexipag or placebo] were included as covariate.
    Comparison groups
    Placebo v Selexipag
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0 [2]
    Method
    		 Posterior probability for efficacy
    Parameter type
    		 Mean difference (posterior distribution)
    Point estimate
    3.43
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 6.6
    Variability estimate
    Standard deviation
    Dispersion value
    1.9
    Notes
    [1] - A difference (selexipag minus placebo) < −4, with probability ≥ 0.50 , in the average number of RP attacks per week during the maintenance period was targeted as a proof of efficacy. A difference (selexipag minus placebo) < 0 with probability ≥ 0.95 was targeted as criteria of significance
    [2] - Posterior probability to observe a treatment difference (selexipag minus placebo) <-4 (efficacy criteria). P-value for significance (diff. selexipag minus placebo < 0) was 0.03

    Other pre-specified: Change from baseline in quality of life as assessed by the Scleroderma Health Assessment Questionnaire (SHAQ) at end of treatment (EOT)

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    End point title
    		 Change from baseline in quality of life as assessed by the Scleroderma Health Assessment Questionnaire (SHAQ) at end of treatment (EOT)
    End point description
    The SHAQ is a validated self-administered questionnaire used to evaluate change over time of physical disability in subjects with SSc. An overall SHAQ score was calculated and can range from 0 (no disability) to 3 (severe disability). The analyses were performed using the per protocol set.
    End point type
    Other pre-specified
    End point timeframe
    At baseline and Week 8
    End point values
    		 Selexipag Placebo
    Number of subjects analysed
    27
    31
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Overall SHAQ score at baseline
    0.63 ± 0.6
    0.58 ± 0.42
        Overall SHAQ score at EOT
    0.62 ± 0.61
    0.6 ± 0.55
        Change from baseline to EOT in overall SHAQ score
    -0.01 ± 0.17
    0.02 ± 0.22
    Statistical analysis title
    		 Treatment difference in the overall SHAQ score
    Statistical analysis description
    Scores were analyzed using non-parametric ANCOVA, considering the score at baseline as covariate
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - p-value based on Mann-Whitney test

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 (start of the double-blind period to end of study (30 days after last study drug intake)
    Adverse event reporting additional description
    Double-blind (DB) treatment-emergent adverse events (AEs), defined as AEs with onset on or after the DB treatment start date and up to the end of treatment / study treatment discontinuation plus 30 days, were considered here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo, double-blind period
    Reporting group description
    		 Subjects were exposed to placebo for a median duration of 55.5 days (range: 21.0 to 63.0 days).

    Reporting group title
    Selexipag, double-blind period
    Reporting group description
    		 Subjects were exposed to selexipag for a median duration of 55.5 days (range: 3.0 to 62.5 days). The median individual maintenance dose (i.e., dose to which each subject was exposed for the longest duration during the maintenance period) was 600 µg.

    Serious adverse events
    		 Placebo, double-blind period Selexipag, double-blind period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Raynaud’s phenomenon
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo, double-blind period Selexipag, double-blind period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 38 (78.95%)
    35 / 36 (97.22%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 36 (11.11%)
         occurrences all number
    1
    4
    Raynaud’s phenomenon
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 38 (36.84%)
    23 / 36 (63.89%)
         occurrences all number
    20
    78
    Dizziness
         subjects affected / exposed
    2 / 38 (5.26%)
    8 / 36 (22.22%)
         occurrences all number
    3
    14
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 36 (16.67%)
         occurrences all number
    3
    7
    Chest pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 38 (10.53%)
    13 / 36 (36.11%)
         occurrences all number
    5
    18
    Diarrhoea
         subjects affected / exposed
    5 / 38 (13.16%)
    10 / 36 (27.78%)
         occurrences all number
    7
    15
    Dry mouth
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    4
    Abdominal pain upper
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    4
    1
    Frequent bowel movements
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Constipation
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    5
    Oropharyngeal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 38 (5.26%)
    8 / 36 (22.22%)
         occurrences all number
    2
    14
    Pain in jaw
         subjects affected / exposed
    0 / 38 (0.00%)
    8 / 36 (22.22%)
         occurrences all number
    0
    12
    Myalgia
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
         occurrences all number
    3
    6
    Arthralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 36 (13.89%)
         occurrences all number
    1
    9
    Back pain
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    4
    Muscle spasms
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
         occurrences all number
    2
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 36 (11.11%)
         occurrences all number
    6
    9
    Influenza
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2

    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
    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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