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    Clinical Trial Results:
    A Phase 2, single-center, randomised, double-blind, placebo-controlled, cross-over, cold challenge study investigating the effect of C21 on cold-induced vasoconstriction in subjects with Raynaud’s Phenomenon (RP) secondary to systemic sclerosis (SSc)

    Summary
    EudraCT number
    		 2019-003203-35
    Trial protocol
    		 GB  
    Global end of trial date
    14 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VP-C21-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04388176
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vicore Pharma AB
    Sponsor organisation address
    Kronhusgatan 11, Göteborg, Sweden, SE-411 05
    Public contact
    Anne Katrine Cohrt, Vicore Pharma AB, +45 20111391, anne-katrine.cohrt@vicorepharma.com
    Scientific contact
    Carl-Johan Dalsgaard, Vicore Pharma AB, +46 709759863, carl-johan.dalsgaard@vicorepharma.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
    30 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the effect of a single dose C21 200 mg o.d. on cold-induced vasoconstriction in subjects with Raynaud’s Phenomenon (RP) secondary to systemic sclerosis (SSc).
    Protection of trial subjects
    None
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Nov 2019
    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
    United Kingdom: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    0
    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)
    15
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial planned to include 16 subjects, however as recruitment was challenging during the COVID-19 pandemic, enrolment was stopped prematurely when 12 subjects were randomised. This ensured that trial results could be available in a timely manner.

    Pre-assignment
    Screening details
    		 A total of 20 unique subjects provided informed consent and were enrolled in the trial. Seven of these were screening failures. In addition, 2 subjects were not randomised; 1 subject due to the COVID-19 pandemic and 1 subject due technical issues with the Holter ECG. The latter subject was re-screened. A total of 12 subjects were randomised.

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 12

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Physician decision: 1
    Reason: Number of subjects
    		 Sponsor decision: 1
    Reason: Number of subjects
    		 Did not fulfill eligibility criteria: 4
    Reason: Number of subjects
    		 Not randomised due to COVID-19 pandemic: 1
    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PLA-C21
    Arm description
    		 Placebo followed by C21
    Arm type
    		 Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose of 200 mg

    Investigational medicinal product name
    Reference treatment (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose

    Arm title
    		 C21-PLA
    Arm description
    		 C21 followed by placebo
    Arm type
    		 Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose of 200 mg

    Investigational medicinal product name
    Reference treatment (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose

    Number of subjects in period 1 [1]
    		PLA-C21 C21-PLA
    Started
    6
    6
    Completed
    6
    6
    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: A total of 20 subjects provided informed consent and were enrolled in the trial. 12 of these subjects completed the pre-assignment period, were included in the baseline period and were randomised to treatment.
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 C21 200 mg
    Arm description
    		 200 mg C21
    Arm type
    		 Experimental

    Investigational medicinal product name
    C21
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose of 200 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Reference treatment (placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose

    Number of subjects in period 2
    		C21 200 mg Placebo
    Started
    12
    12
    Completed
    12
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PLA-C21
    Reporting group description
    		 Placebo followed by C21

    Reporting group title
    C21-PLA
    Reporting group description
    		 C21 followed by placebo

    Reporting group values
    		 PLA-C21 C21-PLA Total
    Number of subjects
    		 6 6 12
    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 4 9
        From 65-84 years
    		 1 2 3
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 51.5 (35 to 67) 59.5 (46 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6 12
        Male
    		 0 0 0
    Race
    Units: Subjects
        White
    		 6 6 12
    Ethnicity
    Units: Subjects
        Not hispanic or latino
    		 6 6 12
    Height
    Units: cm
        arithmetic mean (full range (min-max))
    		 164.25 (155.0 to 171.5) 163.07 (154.0 to 180.0) -
    Weight
    Units: kg
        arithmetic mean (full range (min-max))
    		 64.92 (54.0 to 79.8) 68.32 (50.8 to 90.0) -
    BMI
    Units: kg/m2
        arithmetic mean (full range (min-max))
    		 24.2 (19.2 to 29.3) 25.6 (20.2 to 29.0) -

    End points

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    End points reporting groups
    Reporting group title
    PLA-C21
    Reporting group description
    		 Placebo followed by C21

    Reporting group title
    C21-PLA
    Reporting group description
    		 C21 followed by placebo
    Reporting group title
    C21 200 mg
    Reporting group description
    		 200 mg C21

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) consisted of all subjects/subjects who were randomised and received at least 1 dose of IMP and who had at least one post-baseline assessment of efficacy data allowing endpoint computation from each of the 2 treatment periods.

    Subject analysis set title
    PPAS
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol analysis set (PPAS) was a subset of FAS and consisted of all subjects who were randomised and completed the trial without any major protocol deviations that were judged to compromise the analysis of the data. In this trial, PPAS was equal to FAS.

    Subject analysis set title
    SAS
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set (SAS) consisted of all subjects who were randomised and received at least 1 dose of IMP.

    Primary: Area under the curve for rewarming of each finger after cold challenge (AUC) as measured by thermography

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    End point title
    		 Area under the curve for rewarming of each finger after cold challenge (AUC) as measured by thermography
    End point description
    End point type
    Primary
    End point timeframe
    For 15 minutes after cold challenge (40-55 minutes after a single dose of C21 or placebo)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: C*sec
        geometric mean (geometric coefficient of variation)
    20045.96 ± 7.68
    19558.43 ± 4.36
    Statistical analysis title
    		 Analysis of Thermography AUC
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3801
    Method
    		 ANCOVA
    Parameter type
    		 Ratio in least-square means
    Point estimate
    1.0146
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9859
         upper limit
    		 1.0442

    Secondary: Maximum skin temperature after rewarming (MAX)

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    End point title
    		 Maximum skin temperature after rewarming (MAX)
    End point description
    End point type
    Secondary
    End point timeframe
    For 15 min after cold challenge (40-55 min after IMP administration)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: °C
        geometric mean (geometric coefficient of variation)
    23.5336 ± 8.49
    22.5043 ± 3.73
    Statistical analysis title
    		 Analysis of thermography MAX
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0356
    Method
    		 ANCOVA
    Parameter type
    		 Ratio for least square means
    Point estimate
    1.0346
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.0086
         upper limit
    		 1.0613

    Secondary: The distal dorsal difference, defined as the difference in temperature between the dorsum and the finger (DDD)

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    End point title
    		 The distal dorsal difference, defined as the difference in temperature between the dorsum and the finger (DDD)
    End point description
    End point type
    Secondary
    End point timeframe
    From administration of IMP until before cold challenge (0 to 40 min)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: °C
    arithmetic mean (standard error)
        Baseline
    -2.4215 ± 0.4950
    -2.810 ± 0.3375
        10 min
    -3.395 ± 0.4580
    -3.2378 ± 0.3045
        20 min
    -3.1419 ± 0.4792
    -3.0596 ± 0.2323
        30 min
    -3.0347 ± 0.4037
    -3.1005 ± 0.1903
        40 min
    -2.9448 ± 0.333
    -2.7921 ± 0.1918
    Statistical analysis title
    		 Analysis of thermography DDD at 10 min
    Comparison groups
    Placebo v C21 200 mg
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0154
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS-means
    Point estimate
    -0.4991
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.8234
         upper limit
    		 -0.1749

    Secondary: Gradient of rewarming in the first 2 minutes post-cold challenge (GRAD)

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    End point title
    		 Gradient of rewarming in the first 2 minutes post-cold challenge (GRAD)
    End point description
    End point type
    Secondary
    End point timeframe
    2 min after cold challenge (40-42 min after IMP administration)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: °C/min
        geometric mean (geometric coefficient of variation)
    0.4482 ± 39.35
    0.5412 ± 42.26
    Statistical analysis title
    		 Analysis of thermography GRAD
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.282
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean ratio
    Point estimate
    0.8301
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.6206
         upper limit
    		 1.1102

    Other pre-specified: Change in finger temperature from intake of IMP to start of cold challenge

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    End point title
    		 Change in finger temperature from intake of IMP to start of cold challenge
    End point description
    End point type
    Other pre-specified
    End point timeframe
    From intake of IMP to start of cold challenge (0-40 min)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: °C
        arithmetic mean (standard error)
    -1.347 ± 0.343
    -0.697 ± 0.471
    Statistical analysis title
    		 Analysis of change in finger temperature
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3722
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least square means
    Point estimate
    -0.3989
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.1718
         upper limit
    		 0.3739

    Other pre-specified: Nailfold capillaroscopy

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    End point title
    		 Nailfold capillaroscopy
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Before cold challenge (at 40 min) and post-recovery (at 55 min)
    End point values
    		 C21 200 mg Placebo
    Number of subjects analysed
    12
    12
    Units: mm/sec
    arithmetic mean (standard error)
        Baseline
    0.369 ± 0.193
    0.122 ± 0.042
        Before cold
    0.207 ± 0.054
    0.302 ± 0.175
        Post recovery
    0.323 ± 0.149
    0.318 ± 0.140
    Statistical analysis title
    		 Analysis of capillaroscopy, before cold
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4982
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least square means
    Point estimate
    -0.109
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.4074
         upper limit
    		 0.1895
    Statistical analysis title
    		 Analysis of capillaroscopy, post recovery
    Comparison groups
    C21 200 mg v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6219
    Method
    		 ANCOVA
    Parameter type
    		 Difference in least square means
    Point estimate
    -0.0637
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.3037
         upper limit
    		 0.1763

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent until end of trial participation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    C21 200 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo C21 200 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placebo C21 200 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
    5 / 12 (41.67%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Skin tightness
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2020
    There was 1 protocol amendment during the conduct of the trial (protocol version 4.0, dated 22-Oct-2020). The key changes introduced in the protocol version 4.0 were as follows: Exclusion criteria number 2 with respect to body mass index (BMI) > 30 was changed to BMI > 35 to facilitate completion of recruitment. No subjects were recruited after the approval of this amendment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Mar 2020
    The trial was on hold once (from 18-Mar-2020 to 17-Aug-2020) due to lock down in the UK during the COVID-19 pandemic.
    17 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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