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    Clinical Trial Results:
    An Exploratory Trial Assessing Vascular Digital Perfusion, Pharmacokinetics, Safety and Tolerability Following a Single Dose of CAM2043 (Treprostinil Subcutaneous Depot) in Patients with Raynaud’s Phenomenon Secondary to Systemic Sclerosis

    Summary
    EudraCT number
    		 2019-002444-24
    Trial protocol
    		 GB  
    Global end of trial date
    14 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HS-18-638
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IRAS: 272415
    Sponsors
    Sponsor organisation name
    Camurus AB
    Sponsor organisation address
    Ideon Science Park, Lund, Sweden, 223 70
    Public contact
    Clinical Development, Camurus AB, +46 46 286 57 30,
    Scientific contact
    Clinical Development, Camurus AB, +46 46 286 57 30,
    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
    21 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the effect of a single subcutaneous (SC) dose of CAM2043 on skin temperature (an indirect measure of digital vascular perfusion), as evaluated by thermography following controlled cold challenge in patients with Raynaud’s phenomenon secondary to systemic sclerosis
    Protection of trial subjects
    Prophylactic treatment with ibuprofen or other non-steroid anti inflammatory drugs was provided on an attempt to avoid onset of pain.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 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
    United Kingdom: 10
    Worldwide total number of subjects
    10
    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)
    9
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at one site in the UK. Approximately 12 patients were planned to be included but recruitment was delayed due to issues caused by coronavirus disease 2019 (COVID-19) pandemic and only 10 patients received CAM2043 due to the delay in the enrollment.

    Pre-assignment
    Screening details
    		 Patients with a diagnosis of systemic sclerosis, as defined by 2013 American College of Rheumatology/European League against Rheumatism criteria. Patients with Raynaud Phenomenon secondary to systemic sclerosis with a minimum of 5 Raynaud Phenomenon attacks per week.

    Pre-assignment period milestones
    Number of subjects started
    		 13 [1]
    Number of subjects completed
    		 10

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Pregnancy or breastfeeding: 3
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Eleven patients were screened, and 3 patients were screen failures, out of the 3 screen failures, 2 were rescreened and enrolled in the trial with new identification numbers.
    Period 1
    Period 1 title
    Overall trial (Treatment and FU Periods) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 CAM2043 arm
    Arm description
    		 CAM2043, single, subcutaneous injection
    Arm type
    		 Experimental

    Investigational medicinal product name
    treprostinil subcutaneous depot
    Investigational medicinal product code
    CAM2043
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    CAM2043 (treprostinil subcutaneous depot), 10 mg/mL treprostinil, single dose, subcutaneous injection depot, injected in abdomen (upper or lower) or buttock.

    Number of subjects in period 1
    		CAM2043 arm
    Started
    10
    Completed
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (Treatment and FU Periods)
    Reporting group description
    		 Patients eligible for the 1-week open-label Treatment Period received a single dose of CAM2043. The second week of the trial was a Follow-up Period during which patients did not receive any IMP. At the end of the Follow-up Period (Day 15), patients visited the trial site for a Completion Visit where efficacy outcomes, PK sampling, and safety and tolerability were assessed.

    Reporting group values
    		 Overall trial (Treatment and FU Periods) Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.9 ± 6.7 -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 0 0
    With antibodies present at screening
    Units: Subjects
        Anticentromere
    		 10 10
        Anti-Scl-70
    		 0 0
        Anti-RNA polymerase
    		 0 0
    Known case of systemic sclerosis
    Units: Subjects
        yes
    		 10 10
        no
    		 0 0
    Known case of Raynaud’s phenomenon secondary to systemic sclerosis
    Units: Subjects
        yes
    		 10 10
        no
    		 0 0
    Child-Pugh score
    Units: Subjects
        Class A (5-6 points)
    		 10 10
        Class B (7-9 points)
    		 0 0
        Class C (10-15 points)
    		 0 0
    Time since diagnosis of systemic sclerosis
    Units: years
        arithmetic mean (standard deviation)
    		 11.5 ± 9.4 -
    Time since diagnosis of Raynaud’s phenomenon secondary to systemic sclerosis
    Units: years
        arithmetic mean (standard deviation)
    		 16.5 ± 9.4 -
    Number of episodes noticed per week
    Units: episodes/week
        arithmetic mean (standard deviation)
    		 19.9 ± 9.9 -
    Time to screening since last episode
    Units: days
        arithmetic mean (standard deviation)
    		 1.2 ± 0.6 -
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all patients who were administered CAM2043 and who had data from at least one time point after dosing.

    Subject analysis set title
    safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who were administered CAM2043 (identical to the intention-to-treat analysis set)

    Subject analysis set title
    Intention-to-treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) analysis set comprises all patients treated with CAM2043

    Subject analysis sets values
    		 Full analysis set (FAS) safety analysis set Intention-to-treat (ITT)
    Number of subjects
    10
    10
    10
    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)
    9
    9
    9
        From 65-84 years
    1
    1
    1
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.9 ± 6.7
    54.9 ± 6.7
    54.9 ± 6.7
    Gender categorical
    Units: Subjects
        Female
    10
    10
    10
        Male
    0
    0
    0
    With antibodies present at screening
    Units: Subjects
        Anticentromere
    10
    10
    10
        Anti-Scl-70
    0
    0
    0
        Anti-RNA polymerase
    0
    0
    0
    Known case of systemic sclerosis
    Units: Subjects
        yes
    10
    10
    10
        no
    0
    0
    0
    Known case of Raynaud’s phenomenon secondary to systemic sclerosis
    Units: Subjects
        yes
    10
    10
    10
        no
    0
    0
    0
    Child-Pugh score
    Units: Subjects
        Class A (5-6 points)
    10
    10
    10
        Class B (7-9 points)
    0
    0
    0
        Class C (10-15 points)
    0
    0
    0
    Time since diagnosis of systemic sclerosis
    Units: years
        arithmetic mean (standard deviation)
    11.5 ± 9.4
    11.5 ± 9.4
    11.5 ± 9.4
    Time since diagnosis of Raynaud’s phenomenon secondary to systemic sclerosis
    Units: years
        arithmetic mean (standard deviation)
    16.5 ± 9.4
    16.5 ± 9.4
    16.5 ± 9.4
    Number of episodes noticed per week
    Units: episodes/week
        arithmetic mean (standard deviation)
    19.9 ± 9.9
    19.9 ± 9.9
    19.9 ± 9.9
    Time to screening since last episode
    Units: days
        arithmetic mean (standard deviation)
    1.2 ± 0.6
    1.2 ± 0.6
    1.2 ± 0.6

    End points

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    End points reporting groups
    Reporting group title
    CAM2043 arm
    Reporting group description
    		 CAM2043, single, subcutaneous injection

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    all patients who were administered CAM2043 and who had data from at least one time point after dosing.

    Subject analysis set title
    safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who were administered CAM2043 (identical to the intention-to-treat analysis set)

    Subject analysis set title
    Intention-to-treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) analysis set comprises all patients treated with CAM2043

    Primary: Change from baseline to 6 hours post-dose in the AUCtherm as derived from thermography measurements

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    End point title
    		 Change from baseline to 6 hours post-dose in the AUCtherm as derived from thermography measurements [1]
    End point description
    The AUCtherm was derived from thermography measurements across 8 fingers (thumbs not included) over 15 minutes after the cold challenge. The temperature measurement prior to pre-dose cold challenge on Day 1 was used as a common baseline temperature for AUCtherm values derived at each post-dose time point. Summaries included 95% CIs and provided for observed cases and by using last observation carried forward (LOCF) on the FAS.
    End point type
    Primary
    End point timeframe
    From pre-dose on Day 1 to 6 hours post-dose on Day 1
    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. Single-arm treatment trial. Only descriptive statistics were used.
    End point values
    		 CAM2043 arm
    Number of subjects analysed
    10
    Units: C x sec
        arithmetic mean (confidence interval 95%)
    192.7 (-727.1 to 1112.6)
    No statistical analyses for this end point

    Secondary: Plasma concentrations of treprostinil

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    End point title
    		 Plasma concentrations of treprostinil
    End point description
    The FAS was used for the the summary of data
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 45 minutes of administration), 3 hours±15 minutes, 6 hours±30 minutes, 24±1 hours, 72 ±2 hours, 168 hours±1 day and 336 hours±1 day after administration.
    End point values
    		 CAM2043 arm
    Number of subjects analysed
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        Pre-dose (n=10)
    0.0000 ± 0.0000
        3 hours post-dose (n=10)
    1.5615 ± 0.6937
        6 hours post-dose (n=9)
    2.1478 ± 1.0366
        24 hours post-dose (n=8)
    0.5700 ± 0.2616
        72 hours post-dose (n=10)
    0.3252 ± 0.1897
        168 hours post-dose (n=10)
    0.1182 ± 0.0645
        336 hours post-dose (n=10)
    0.0474 ± 0.0432
    No statistical analyses for this end point

    Secondary: Change from baseline to Day 8 and Day 15 in Raynaud's Condition Score

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    End point title
    		 Change from baseline to Day 8 and Day 15 in Raynaud's Condition Score
    End point description
    The Raynaud's Condition Score (RCS) is a self-assessment, graded on a scale of 0 to 10 (corresponding to ‘no difficulty’- ‘extreme difficulty’), based on the patient’s perceived impact of the frequency, duration, and severity of the Raynaud’s Phenomenon. Summaries included 95% CIs for quantitative changes in scores. The FAS was used for the the summary of data.
    End point type
    Secondary
    End point timeframe
    From pre-dose on Day 1 to Day 8 and Day 15
    End point values
    		 CAM2043 arm
    Number of subjects analysed
    10
    Units: score units
    arithmetic mean (confidence interval 95%)
        Day 8
    -1.6 (-2.68 to -0.52)
        Day 15
    -1.6 (-3.33 to 0.19)
    No statistical analyses for this end point

    Secondary: Patient Global Assessment on Day 8

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    End point title
    		 Patient Global Assessment on Day 8
    End point description
    Patients rated their perception of change from baseline in their Raynaud's Phenomenon during the trial using a PGA scale. The FAS was used for the the summary of data.
    End point type
    Secondary
    End point timeframe
    On Day 8
    End point values
    		 CAM2043 arm
    Number of subjects analysed
    10
    Units: number of patients
        Much better
    0
        A little better
    4
        The same
    6
        A little worse
    0
        Much worse
    0
        Missing
    0
    No statistical analyses for this end point

    Secondary: Patient Global Assessment on Day 15

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    End point title
    		 Patient Global Assessment on Day 15
    End point description
    Patients rated their perception of change from baseline in their Raynaud's Phenomenon during the trial using a PGA scale. The FAS was used for the the summary of data.
    End point type
    Secondary
    End point timeframe
    On Day 15
    End point values
    		 CAM2043 arm
    Number of subjects analysed
    10
    Units: number of patients
        Much better
    1
        A little better
    3
        The same
    1
        A little worse
    2
        Much worse
    0
        Missing
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs (TEAEs): following start of treatment until end of trial participation. Serious AEs: from enrolment (informed consent signed) until end of trial participation.
    Adverse event reporting additional description
    Post-trial events: SAEs assessed as “possibly” or “probably” related to IMP were to be reported to the Sponsor by the Investigator regardless of the time that has elapsed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    CAM2043
    Reporting group description
    		 -

    Serious adverse events
    		 CAM2043
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CAM2043
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Investigations
    Blood urea increased
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Serum ferritin decreased
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vascular disorders
    Flushing
    Additional description: TEAEs
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    4
    Hypotension
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
    Additional description: TEAEs
         subjects affected / exposed
    9 / 10 (90.00%)
         occurrences all number
    12
    Presyncope
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Sinus headache
    Additional description: TEAEs
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    General disorders and administration site conditions
    Injection site erythema
    Additional description: TEAEs only
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    26
    Injection site pain
    Additional description: TEAEs
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    28
    Injection site swelling
    Additional description: TEAEs
         subjects affected / exposed
    9 / 10 (90.00%)
         occurrences all number
    23
    Ear and labyrinth disorders
    Tinnitus
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Eye disorders
    Photophobia
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
    Additional description: TEAEs
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    6
    Nausea
    Additional description: TEAEs
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Vomiting
    Additional description: TEAEs
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    5
    Skin and subcutaneous tissue disorders
    Dry skin
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Pain of skin
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Pruritus
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin ulcer haemorrhage
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal impairment
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain in jaw
    Additional description: TEAEs
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Musculoskeletal pain
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Pain in extremity
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hyperlipidaemia
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hyperuricaemia
    Additional description: TEAEs
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2020
    • The dose of CAM2043 was lowered from 5 to 2.5 mg • The section ‘Treatments for Injection Site Pain’ was amended to include consideration for patients with systemic sclerosis who could not tolerate ibuprofen or other non-steroid anti-inflammatory drugs (NSAIDs).
    11 May 2021
    • The exclusion of patients with 2 thermography assessments with more than 20% difference on the day of screening, was removed. • Administration of CAM2043 as an SC injection in the buttock by a trained healthcare professional was added to increase the number of sites for SC injection.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Dec 2021
    The recruitment was delayed due to issues caused by coronavirus disease 2019 (COVID-19) pandemic. This led to that only 10 patients received CAM2043 as the investigational medicinal product (IMP) batch reached its expiry date.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The COVID-19 pandemic and lockdown restrictions had a major impact on the conduct of the trial, difficulting screening and enrollment of patients.
    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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