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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study to Evaluate the Efficacy and Safety of RIST4721 in Subjects with Palmoplantar Pustulosis

    Summary
    EudraCT number
    		 2018-004176-35
    Trial protocol
    		 DE  
    Global end of trial date
    19 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2020
    First version publication date
    30 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RIST4721-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03988335
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aristea Therapeutics, Inc.
    Sponsor organisation address
    12770 High Bluff Drive, Suite #380, San Diego, United States, 92130
    Public contact
    Aristea Therapeutics, Aristea Therapeutics, info@aristeatx.com
    Scientific contact
    Aristea Therapeutics, Aristea Therapeutics, info@aristeatx.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
    19 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the efficacy of RIST4721 versus placebo in adult subjects with moderate to severe palmoplantar pustulosis (PPP) using a range of efficacy endpoints
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 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
    Germany: 12
    Country: Number of subjects enrolled
    Canada: 23
    Worldwide total number of subjects
    35
    EEA total number of subjects
    12
    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)
    34
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects must have at least a 6-month history of PPP and have moderate or severe PPP.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This study was double blind. In order to reduce risk of breaking the blind, investigators, the study staff, the CRO, and the sponsor’s study team did not receive absolute and relative neutrophil and WBC count results, starting on Day 7. A medical monitor reviewed the blinded data and ensured that the safety of all enrolled subjects was preserved.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RIST4721 300 mg
    Arm description
    		 This arm was randomized to receive 300 mg of RIST4721 once daily for 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RIST4721
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    RIST4721 300 mg oral solution was to be taken once daily for 28 days.

    Arm title
    		 Placebo
    Arm description
    		 This arm was randomized to receive placebo once daily for 28 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral solution was to be taken once daily for 28 days.

    Number of subjects in period 1
    		RIST4721 300 mg Placebo
    Started
    16
    19
    Completed
    14
    18
    Not completed
    2
    1
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RIST4721 300 mg
    Reporting group description
    		 This arm was randomized to receive 300 mg of RIST4721 once daily for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 This arm was randomized to receive placebo once daily for 28 days.

    Reporting group values
    		 RIST4721 300 mg Placebo Total
    Number of subjects
    		 16 19 35
    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)
    		 15 19 34
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 12 16 28
        Male
    		 4 3 7
    Subject analysis sets

    Subject analysis set title
    RIST4721 300 mg (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of RIST4721 300 mg.

    Subject analysis set title
    Placebo (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of Placebo.

    Subject analysis sets values
    		 RIST4721 300 mg (mITT) Placebo (mITT)
    Number of subjects
    15
    19
    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)
    14
    19
        From 65-84 years
    1
    0
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    12
    16
        Male
    3
    3

    End points

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    End points reporting groups
    Reporting group title
    RIST4721 300 mg
    Reporting group description
    		 This arm was randomized to receive 300 mg of RIST4721 once daily for 28 days.

    Reporting group title
    Placebo
    Reporting group description
    		 This arm was randomized to receive placebo once daily for 28 days.

    Subject analysis set title
    RIST4721 300 mg (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of RIST4721 300 mg.

    Subject analysis set title
    Placebo (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    All subjects who received at least one dose of Placebo.

    Primary: Relative change from baseline in fresh pustule count at Day 28

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    End point title
    		 Relative change from baseline in fresh pustule count at Day 28
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Day 28
    End point values
    		 RIST4721 300 mg (mITT) Placebo (mITT)
    Number of subjects analysed
    15
    19
    Units: Relative change
        arithmetic mean (standard deviation)
    0.86 ± 0.692
    0.53 ± 0.561
    Statistical analysis title
    		 Hochberg’s method
    Comparison groups
    Placebo (mITT) v RIST4721 300 mg (mITT)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.24
    Method
    		 Hochberg’s method
    Confidence interval
    Notes
    [1] - The primary endpoints were first tested at alpha of 10% (2-sided). If the larger p-value was less than 10% (2‑sided), both primary endpoints were to be declared statistically significant. If the larger p‑value was greater than 10%, but the smaller p-value was less than 5% (2-sided), then the primary endpoint with the smaller p-value was to be declared statistically significant.

    Primary: Relative change from baseline in total pustule count at Day 28

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    End point title
    		 Relative change from baseline in total pustule count at Day 28
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Day 28
    End point values
    		 RIST4721 300 mg (mITT) Placebo (mITT)
    Number of subjects analysed
    15
    19
    Units: Relative change
        arithmetic mean (standard deviation)
    0.99 ± 0.667
    0.96 ± 0.672
    Statistical analysis title
    		 Hochberg’s method
    Statistical analysis description
    The primary endpoints were first tested at alpha of 10% (2-sided). If the larger p-value was less than 10% (2‑sided), both primary endpoints were to be declared statistically significant. If the larger p‑value was greater than 10%, but the smaller p-value was less than 5% (2-sided), then the primary endpoint with the smaller p-value was to be declared statistically significant.
    Comparison groups
    RIST4721 300 mg (mITT) v Placebo (mITT)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.804
    Method
    		 Hochberg’s method.
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From ICF signature to end of study participation.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    RIST4721 300 mg
    Reporting group description
    		 All subjects that received at least one dose of RIST4721.

    Reporting group title
    Placebo
    Reporting group description
    		 All subjects that received at least one dose of Placebo.

    Serious adverse events
    		 RIST4721 300 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 19 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 RIST4721 300 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 15 (86.67%)
    7 / 19 (36.84%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Bacterial test
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Ligament sprain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Concussion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 15 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    6
    1
    Abnormal faeces
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Skin fissures
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urine odour abnormal
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Micturition disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Post procedural cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2019
    The purpose of this amendment was to revise inclusion and exclusion criteria, to substantiate the potential risks, benefits, and risk-benefit analysis, to provide clarification about optional sub-studies and to specify where the Reference Safety Information could be found. Other minor edits were also made for completeness.
    22 Mar 2019
    The purpose of this amendment was to add an exclusion criteria following the update of the IB regarding possible drug-drug interactions and to add a lifestyle consideration regarding consumption of grapefruit-containing products due to possible interactions with CYP3A4. The Physician's Global Assessment Scale was also revised for accuracy.

    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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