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    Clinical Trial Results:
    A Phase II, randomised, multi-centre placebo-controlled, double-blind study to investigate the safety of GS-248, and efficacy on Raynaud’s phenomenon (RP) and peripheral vascular blood flow, in subjects with systemic sclerosis (SSc)

    Summary
    EudraCT number
    		 2020-002081-13
    Trial protocol
    		 GB   NL   BE   PL  
    Global end of trial date
    15 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2023
    First version publication date
    05 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04744207
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gesynta Pharma AB
    Sponsor organisation address
    Wallingatan-24, Stockholm, Sweden, SE-111 24
    Public contact
    Clinical Information Point, Gesynta Pharma AB, ClinicalInformation@gesynta.se
    Scientific contact
    Clinical Information Point, Gesynta Pharma AB, ClinicalInformation@gesynta.se
    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
    28 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and efficacy of GS-248 versus placebo on RP in subjects with SSc.
    Protection of trial subjects
    The first IMP administration was taken at the study site, under the supervision of the study staff. Patients were closely followed with regular safety blood samples taken, patients were asked about any adverse events at each visit and IMP accountability was checked at each visit.
    Background therapy
    		 Subjects were permitted the following background vasodilatory treatment; Ca-blockers or PDE-5 inhibitors.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    29 Dec 2020
    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
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    Belgium: 5
    Worldwide total number of subjects
    94
    EEA total number of subjects
    57
    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)
    83
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In addition to fulfilling all eligibility criteria, subjects must fulfil the following criteria to be randomised: • ≥7 RP attacks during the last week of the run-in period as captured in the eDiary, with no more than 2 days without RP attacks. • Compliance with the eDiary during the 7 most recent days prior to baseline (Visit 2), excluding the vi

    Pre-assignment
    Screening details
    		 The run-in period was 14-21 days prior to Day 1, Baseline visit (the first dose of IMP).

    Pre-assignment period milestones
    Number of subjects started
    		 94
    Number of subjects completed
    		 69

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Reason: Number of subjects
    		 Violated inclusion/exclusion: 23
    Period 1
    Period 1 title
    Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GS-248
    Arm description
    		 Allocated to receive active treatment, GS-248
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-248
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    GS-248, supplied as 40mg capsules. Each single dose consisted of 3 capsules constituting a total of 120mg. The initial dose of IMP (120 mg once daily) was taken at the study site at Visit 2 under supervision of the investigator or qualified staff. Subsequent doses of IMP were self-administered by the subject, taken orally, once daily. The final dose of IMP was taken at the study site (Visit 4). The IMP was administered with water, in the morning with food.

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, supplied as capsules identical to GS-248. The initial dose of placebo (3 capsules) was taken at the study site at Visit 2 under supervision of the investigator or qualified staff. Subsequent doses of placebo were self-administered by the subject, taken orally, once daily. The final dose of placebo was taken at the study site (Visit 4). The placebo was administered with water, in the morning with food.

    Number of subjects in period 1 [1]
    		GS-248 Placebo
    Started
    33
    36
    Completed
    30
    34
    Not completed
    3
    2
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of patients enrolled worldwide is all patients who signed the ICF but the number of subjects in the baseline period is those who completed the pre-assignment period and were randomised.
    Period 2
    Period 2 title
    Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GS-248
    Arm description
    		 Follow-up of those allocated to receive active treatment, GS-248
    Arm type
    		 Experimental

    Investigational medicinal product name
    GS-248
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Not applicable, no treatment was received during follow-up period

    Arm title
    		 Placebo
    Arm description
    		 Follow-up of those randomised to placebo arm
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Not applicable as no treatment received during follow-up period.

    Number of subjects in period 2
    		GS-248 Placebo
    Started
    30
    34
    Completed
    30
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GS-248
    Reporting group description
    		 Allocated to receive active treatment, GS-248

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm

    Reporting group values
    		 GS-248 Placebo Total
    Number of subjects
    		 33 36 69
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 30 32 62
        From 65-84 years
    		 3 4 7
    Age continuous
    Patients were aged between 18 and 75 years
    Units: years
        arithmetic mean (standard deviation)
    		 49.0 ( 10.6 ) 50.6 ( 10.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 33 60
        Male
    		 6 3 9
    Subjects per stratum (background vasodilatory treatment)
    Subjects were stratified for background vasodilatory treatment (Ca- blockers, PDE-5 inhibitors or no vasodilatory treatment.
    Units: Subjects
        Ca-blockers
    		 18 19 37
        PDE-5 inhibitors
    		 9 10 19
        No vasodilatory treatment
    		 6 7 13
    Subject analysis sets

    Subject analysis set title
    FAS - GS-248
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) consisted of all subjects that were randomised to receive GS-248 and received at least one dose

    Subject analysis set title
    PPS - GS-248
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) encompassed all subjects randomized to receive GS-248 of the FAS who had no major protocol deviations that affected the evaluation of the effect of GS-248 on the primary endpoint as determined during the blinded data review meeting (BDRM).

    Subject analysis set title
    SAS - GS-248
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) consisted of all subjects who were randomised to receive GS-248 and administered GS-248 at least once

    Subject analysis set title
    FAS - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) consisted of all subjects that were randomised to receive placebo and received at least one dose.

    Subject analysis set title
    PPS - placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) encompassed all subjects randomized to receive placebo of the FAS who had no major protocol deviations that affected the evaluation of the effect of placebo on the primary endpoint as determined during the blinded data review meeting (BDRM).

    Subject analysis set title
    SAS - placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) consisted of all subjects who were randomised to receive placebo and administered the placebo at least once

    Subject analysis sets values
    		 FAS - GS-248 PPS - GS-248 SAS - GS-248 FAS - placebo PPS - placebo SAS - placebo
    Number of subjects
    33
    29
    33
    36
    32
    36
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age continuous
    Patients were aged between 18 and 75 years
    Units: years
        arithmetic mean (standard deviation)
    49.0 ( 10.6 )
    48.9 ( 10.6 )
    49.0 ( 10.6 )
    50.6 ( 10.6 )
    50.1 ( 10.6 )
    50.6 ( 10.6 )
    Gender categorical
    Units: Subjects
        Female
    27
    24
    27
    33
    29
    33
        Male
    6
    5
    6
    3
    3
    3
    Subjects per stratum (background vasodilatory treatment)
    Subjects were stratified for background vasodilatory treatment (Ca- blockers, PDE-5 inhibitors or no vasodilatory treatment.
    Units: Subjects
        Ca-blockers
    18
    16
    18
    19
    18
    19
        PDE-5 inhibitors
    9
    7
    9
    10
    8
    10
        No vasodilatory treatment
    6
    6
    6
    7
    6
    7

    End points

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    End points reporting groups
    Reporting group title
    GS-248
    Reporting group description
    		 Allocated to receive active treatment, GS-248

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm
    Reporting group title
    GS-248
    Reporting group description
    		 Follow-up of those allocated to receive active treatment, GS-248

    Reporting group title
    Placebo
    Reporting group description
    		 Follow-up of those randomised to placebo arm

    Subject analysis set title
    FAS - GS-248
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) consisted of all subjects that were randomised to receive GS-248 and received at least one dose

    Subject analysis set title
    PPS - GS-248
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) encompassed all subjects randomized to receive GS-248 of the FAS who had no major protocol deviations that affected the evaluation of the effect of GS-248 on the primary endpoint as determined during the blinded data review meeting (BDRM).

    Subject analysis set title
    SAS - GS-248
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) consisted of all subjects who were randomised to receive GS-248 and administered GS-248 at least once

    Subject analysis set title
    FAS - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) consisted of all subjects that were randomised to receive placebo and received at least one dose.

    Subject analysis set title
    PPS - placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) encompassed all subjects randomized to receive placebo of the FAS who had no major protocol deviations that affected the evaluation of the effect of placebo on the primary endpoint as determined during the blinded data review meeting (BDRM).

    Subject analysis set title
    SAS - placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) consisted of all subjects who were randomised to receive placebo and administered the placebo at least once

    Primary: Mean change from baseline to week 4 in the number of RP attacks per week.

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    End point title
    		 Mean change from baseline to week 4 in the number of RP attacks per week.
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively.
    End point values
    		 FAS - GS-248 PPS - GS-248 FAS - placebo PPS - placebo
    Number of subjects analysed
    30
    29
    33
    30
    Units: number of attacks
        arithmetic mean (standard deviation)
    -3.3 ( 4.7 )
    -3.1 ( 4.6 )
    -4.4 ( 7.4 )
    -4.5 ( 7.8 )
    Statistical analysis title
    		 Primary endpoint analysis
    Statistical analysis description
    ANCOVA model for change from baseline to visit 4 (week 4) including the stratification factor (vasodilatory treatment) and treatment as fixed factors and baseline levels as a covariate. The placebo multiple imputation (pMI) method was used for replacement of missing data.
    Comparison groups
    FAS - GS-248 v FAS - placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Parameter type
    		 Least square means estimate
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.48
         upper limit
    		 4.1
    Variability estimate
    Standard deviation
    Dispersion value
    0.628
    Notes
    [1] - The primary objective was to be met if there was a p-value <0.05 with a numerical superior efficacy of the active group versus placebo with regard to the primary endpoint, i.e., the mean change (reduction) in RP attacks that is greater in the active group.

    Secondary: Mean change from baseline to week 4 in the Raynaud’s Condition Score

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    End point title
    		 Mean change from baseline to week 4 in the Raynaud’s Condition Score
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively.
    End point values
    		 FAS - GS-248 FAS - placebo
    Number of subjects analysed
    29
    33
    Units: score
        arithmetic mean (standard deviation)
    -0.9 ( 1.3 )
    -1.0 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline to week 4 in the cumulative duration of RP attacks.

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    End point title
    		 Mean change from baseline to week 4 in the cumulative duration of RP attacks.
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively.
    End point values
    		 FAS - GS-248 FAS - placebo
    Number of subjects analysed
    30
    33
    Units: minutes
        arithmetic mean (standard deviation)
    -84.9 ( 437.2 )
    -148.5 ( 249.0 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline to week 4 in pain experienced during RP attacks.

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    End point title
    		 Mean change from baseline to week 4 in pain experienced during RP attacks.
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively.
    End point values
    		 FAS - GS-248 FAS - placebo
    Number of subjects analysed
    29
    32
    Units: numeric rating scale
        arithmetic mean (standard deviation)
    -0.62 ( 1.0 )
    -0.66 ( 1.6 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline to week 4 in the mean duration of RP attacks

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    End point title
    		 Mean change from baseline to week 4 in the mean duration of RP attacks
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to week 4, i.e. the 7 most recent days prior to Visit 2 and Visit 4 respectively.
    End point values
    		 FAS - GS-248 FAS - placebo
    Number of subjects analysed
    30
    33
    Units: minutes
        arithmetic mean (standard deviation)
    4.5 ( 37.6 )
    -3.5 ( 11.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All SAEs and AEs were to be collected from the signing of the ICF until the follow-up visit (Visit 5)
    Adverse event reporting additional description
    An AE that occurs from first IMP dose until 7 days after last IMP dose was considered a Treatment Emergent AE regardless of the assessed relationship to the IMP. All other AEs reported after signed ICF but outside of the period specified above were considered non-treatment emergent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    GS-248
    Reporting group description
    		 Actually received GS-248 during the study

    Reporting group title
    Placebo
    Reporting group description
    		 Actually received placebo during study

    Serious adverse events
    		 GS-248 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    0 / 33 (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
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 33 (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 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GS-248 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 33 (30.30%)
    9 / 36 (25.00%)
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 36 (11.11%)
         occurrences all number
    18
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2020
    The protocol has been updated to reflect following changes and for some minor administrative and clarification changes, including to the exclusion criteria. Secondary efficacy endpoints were updated: - Mean change from baseline to week 4 in peripheral blood flow prior to cold challenge and IMP administration. - Mean change in peripheral blood flow from pre-IMP to post-IMP administration at Visit 2. - Mean change from baseline to week 4 in recovery of peripheral blood flow after cold challenge - Number of countries was updated for the conduct of the study. - Study assessment was updated to include PK sampling - Removed the inclusion criteria related to finger temperature - Exclusion Criterion for Cold Challenge was added - Definition of Prolonged QTcF interval was updated
    01 Sep 2020
    The protocol has been updated following requests from the MHRA and for some minor administrative changes WOCBP and Highly Effective Contraception was updated based on the request from MHRA WOCBP given home pregnancy test to be used 35-40 days after their last dose of IMP (Visit 4).
    25 Mar 2021
    The protocol has been updated to reflect following changes and for some minor administrative and clarification changes, including to the exclusion criteria. - Visit 4, End of Treatment Visit, occurred on Day 28 (-2/+1 days), which was the day subjects took their final dose of IMP, to be administered at the study site - Mean change in recovery of peripheral blood flow after cold challenge from pre-IMP to post-IMP administration at Visit 2. - A COVID-19 vaccination considered a permitted concomitant medication and is therefore not contraindicated for use with GS-248.
    10 Dec 2021
    The protocol has been updated to reflect emerging data on GS-248 interaction with moderate and strong CYP3A4 inhibitors resulting in an additional exclusion criterion and addition of prohibited concomitant medications. Changes in the descriptions of analyses populations as well as some minor administrative updates have also been made. A safety measure added relating to results from a drug-drug interaction (DDI) clinical study with GS-248.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Apr 2021
    Subject recruitment was temporarily interrupted during summer months to protect data integrity and minimize influence of warmer weather on the efficacy outcome variables. No subjects were enrolled in the study between 20-April-2021 and 22-September-2021.
    22 Sep 2021

    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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