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    Clinical Trial Results:
    KPL-716-C201: A Phase 2a/b, Randomized, Double-Blind, Placebo Controlled Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of KPL-716 in Reducing Pruritus in Subjects with Prurigo Nodularis

    Summary
    EudraCT number
    		 2020-004198-38
    Trial protocol
    		 CZ   DE   FR   BE   IT   AT  
    Global end of trial date
    24 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2024
    First version publication date
    07 Jul 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    KPL-716-C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03816891
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 132912
    Sponsors
    Sponsor organisation name
    Kiniksa Pharmaceuticals, Ltd
    Sponsor organisation address
    100 Hayden Avenue, Lexington, Massachusetts, United States, 02421
    Public contact
    Chrissy Lundquist, Kiniksa Pharmaceuticals, Ltd. , +1 7813170276, clundquist@kiniksa.com
    Scientific contact
    Chrissy Lundquist, Kiniksa Pharmaceuticals, Ltd. , +1 7813170276, clundquist@kiniksa.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
    26 Mar 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of subcutaneous (SC) KPL-716 vs. placebo in reducing pruritus in Prurigo Nodularis (PN) subjects experiencing severe pruritus
    Protection of trial subjects
    (1) Independent Ethics Committee (IEC) or Institutional Review Board (IRB): The core study documents (Protocol and subsequent amendments, Investigator's Brochure (IB), Patient facing materials [Informed Consent Form (ICF), Subject recruitment procedures (e.g. advertisements), any other written information provided to subjects] were reviewed and approved by the IRB/ IEC before implementation. Additionally, the IRBs/IECs were informed by the Investigator of serious and unexpected SAEs in accordance with the reporting requirements. (2) Ethical Conduct: The study was conducted (a) in accordance with the protocol (b) per consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines (c) per applicable International Council for/Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines (d) per applicable country and local laws and regulations. (3) ICF: The investigator or their representative explained the nature of the study to the participants or their legally authorized representative before signing the ICF. Participants were re-consented to the most current version of the ICF(s) during their participation in the study. A copy of the ICF(s) was provided to the participant or the participant’s legally authorized representative.
    Background therapy
    		 There are no approved therapies for PN. Topical therapies such as topical corticosteroids, calcineurin inhibitors, calcipotriol, and capsaicin, systemic corticosteroids, thalidomide, systemic immunomodulatory drugs such as methotrexate and cyclosporin, antiepileptics and antidepressants, phototherapy and photochemotherapy are often tried with limited success.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 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
    Poland: 7
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    United States: 72
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Taiwan: 16
    Worldwide total number of subjects
    190
    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)
    137
    From 65 to 84 years
    53
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 443 participants were screened and 190 participants enrolled subjects were randomized at 1:1:1:1 ratio into one of the 4 arms to receive different dosing regimens of or placebo. At the end of the Double-Blind Period, all participants had the option to enter the Open Label Extension Period to receive KPL-716.

    Pre-assignment
    Screening details
    		 After ICF was signed, 443 participants entered the Screening Period for assessment of eligibility. A full physical examination was performed to assess the following systems: head/neck/thyroid; eyes/ears/nose/throat (EENT); respiratory; cardiovascular; lymph nodes; abdomen; skin; musculoskeletal; and neurological.

    Period 1
    Period 1 title
    Double Blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    An Interact Web Response System issued a unique treatment code to each subject, which assigned the treatment for the subject. The investigator, the sponsor study team, and remaining clinical site staff (other than the unblinded pharmacist or unblinded designee) were blinded to treatment assignment. The unblinded treatment assignment for individual participant was made available to the investigator only in the event of a medical emergency or or an adverse reaction.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 KPL-716 was administered subcutaneously at the dose of 540 mg every 4 weeks for 16 weeks during double blind period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KPL-716
    Investigational medicinal product code
    Other name
    Vixarelimab
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Cutaneous use
    Dosage and administration details
    KPL-716 is provided as a sterile liquid formulation and supplied as a single-use vial for SC injection.

    Arm title
    		 Arm B
    Arm description
    		 KPL-716 was administered subcutaneously at the dose of 360 mg every 4 weeks for 16 weeks during the double-blind period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KPL-716
    Investigational medicinal product code
    Other name
    Vixarelimab
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Cutaneous use
    Dosage and administration details
    KPL-716 is provided as a sterile liquid formulation and supplied as a single-use vial for SC injection.

    Arm title
    		 Arm C
    Arm description
    		 KPL-716 was administered subcutaneously at the dose of 120 mg every 4 weeks for 16 weeks during double blind period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    KPL-716
    Investigational medicinal product code
    Other name
    Vixarelimab
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Cutaneous use
    Dosage and administration details
    KPL-716 was provided as a sterile liquid formulation and supplied as a single-use vial for SC injection.

    Arm title
    		 Arm D
    Arm description
    		 Placebo was administered subcutaneously every 4 weeks for 16 weeks during the double-blind period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Placebo matching to KPL-716 excipients was provided as a sterile liquid formulation and supplied for SC injection

    Number of subjects in period 1
    		Arm A Arm B Arm C Arm D
    Started
    47
    47
    47
    49
    Completed
    45
    44
    47
    47
    Not completed
    2
    3
    0
    2
         Physician decision
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    -
    -
         Adverse event, non-fatal
    2
    1
    -
    -
         Lost to follow-up
    -
    -
    -
    1
         Early discontinuation
    -
    -
    -
    1
    Period 2
    Period 2 title
    Open Label Extension
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Treatment
    Arm description
    		 Open label extension participants who previously received KPL-716 during Double-Blind period. KPL-716 was administered subcutaneously at the dose of 360 mg every 2 weeks for 36 weeks (starting at week 16 and with the last dosing at the week 48 visit).
    Arm type
    		 Experimental

    Investigational medicinal product name
    KPL-716
    Investigational medicinal product code
    Other name
    Vixarelimab
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Cutaneous use
    Dosage and administration details
    KPL-716 is provided as a sterile liquid formulation and supplied as a single-use vial for SC injection.

    Number of subjects in period 2 [1]
    		Treatment
    Started
    181
    Completed
    157
    Not completed
    24
         Consent withdrawn by subject
    9
         Adverse event, non-fatal
    8
         Lost to follow-up
    3
         Lack of efficacy
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Per study design, all subjects in doble blind period (DB) had an option of receive KPL-716 360 mg SC, Q2W during the Open Label Extension (OLE) Period to evaluate the long-term safety and PK. Out of 190 subjects randomized in DB period, 181 consented to OLE.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 540 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Arm B
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 360 mg every 4 weeks for 16 weeks during the double-blind period.

    Reporting group title
    Arm C
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 120 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Arm D
    Reporting group description
    		 Placebo was administered subcutaneously every 4 weeks for 16 weeks during the double-blind period.

    Reporting group values
    		 Arm A Arm B Arm C Arm D Total
    Number of subjects
    		 47 47 47 49 190
    Age categorical
    KPL-716 was administered subcutaneously at the dose of 360 mg every 2 weeks for 36 weeks (starting at week 16 and with the last dosing at the week 48 visit).
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 31 35 35 36 137
        From 65-84 years
    		 16 12 12 13 53
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.7 ( 12.18 ) 55.9 ( 13.73 ) 54.4 ( 16.11 ) 54.8 ( 13.35 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 28 28 29 114
        Male
    		 18 19 19 20 76
    Subject analysis sets

    Subject analysis set title
    mITT efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who receive at least 1 dose of KPL-716 or placebo and have at least 1 post-baseline efficacy assessment in the double-blind treatment period were included in the modified intent-to-treat (mITT) analysis set.

    Subject analysis sets values
    		 mITT efficacy analysis
    Number of subjects
    189
    Age categorical
    KPL-716 was administered subcutaneously at the dose of 360 mg every 2 weeks for 36 weeks (starting at week 16 and with the last dosing at the week 48 visit).
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    136
        From 65-84 years
    53
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.4 ( 13.83 )
    Gender categorical
    Units: Subjects
        Female
    114
        Male
    75

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 540 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Arm B
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 360 mg every 4 weeks for 16 weeks during the double-blind period.

    Reporting group title
    Arm C
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 120 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Arm D
    Reporting group description
    		 Placebo was administered subcutaneously every 4 weeks for 16 weeks during the double-blind period.
    Reporting group title
    Treatment
    Reporting group description
    		 Open label extension participants who previously received KPL-716 during Double-Blind period. KPL-716 was administered subcutaneously at the dose of 360 mg every 2 weeks for 36 weeks (starting at week 16 and with the last dosing at the week 48 visit).

    Subject analysis set title
    mITT efficacy analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized subjects who receive at least 1 dose of KPL-716 or placebo and have at least 1 post-baseline efficacy assessment in the double-blind treatment period were included in the modified intent-to-treat (mITT) analysis set.

    Primary: 1. Percent change from baseline in weekly average Worst Itch–Numeric Rating Scale (WI-NRS) at Week 16

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    End point title
    		 1. Percent change from baseline in weekly average Worst Itch–Numeric Rating Scale (WI-NRS) at Week 16
    End point description
    All efficacy analyses were performed in the mITT analysis set.
    End point type
    Primary
    End point timeframe
    Percent change from baseline in weekly average WI-NRS was measured at week 16 using mITT analysis set
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    45
    45
    47
    47
    Units: Score
        arithmetic mean (standard deviation)
    -56.2 ( 35.7 )
    -51.2 ( 31.91 )
    -33 ( 34.31 )
    -14.8 ( 25.86 )
    Statistical analysis title
    		 Analysis of covariance
    Statistical analysis description
    The primary efficacy endpoint (percentage change from baseline of WI-NRS at Week 16) was analyzed with ANCOVA with treatment and randomization stratification factors of sex and years since the first nodule observed (i.e., ≥10 versus <10 years) as fixed effect factors, baseline as covariates.
    Comparison groups
    Arm A v Arm D
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Analysis of covariance
    Statistical analysis description
    The primary efficacy endpoint (percentage change from baseline of WI-NRS at Week 16) was analyzed with ANCOVA with treatment and randomization stratification factors of sex and years since the first nodule observed (i.e., ≥10 versus <10 years) as fixed effect factors, baseline as covariates
    Comparison groups
    Arm B v Arm D
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Analysis of covariance
    Statistical analysis description
    The primary efficacy endpoint (percentage change from baseline of WI-NRS at Week 16) was analyzed with ANCOVA with treatment and randomization stratification factors of sex and years since the first nodule observed (i.e., ≥10 versus <10 years) as fixed effect factors, baseline as covariates.
    Comparison groups
    Arm C v Arm D
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0061
    Method
    		 ANCOVA
    Confidence interval

    Secondary: 2.1 Proportion of subjects achieving at least a 6-point reduction from baseline in weekly average WI-NRS at Week 16

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    End point title
    		 2.1 Proportion of subjects achieving at least a 6-point reduction from baseline in weekly average WI-NRS at Week 16
    End point description
    All efficacy analyses were performed in the mITT analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    47
    47
    46
    48
    Units: Percentage
        number (confidence interval 95%)
    42.6 (28.3 to 57.8)
    23.4 (12.3 to 38)
    17.4 (7.8 to 31.4)
    2.1 (0.1 to 11.1)
    No statistical analyses for this end point

    Secondary: 2.2 Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS at Week 16

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    End point title
    		 2.2 Proportion of subjects achieving at least a 4-point reduction from baseline in weekly average WI-NRS at Week 16
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to week 16
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    47
    47
    47
    48
    Units: Percentage
        number (confidence interval 95%)
    66 (50.7 to 79.1)
    61.7 (46.4 to 75.5)
    29.8 (17.3 to 44.9)
    16.7 (7.5 to 30.2)
    No statistical analyses for this end point

    Secondary: 2.3 Proportion of subjects achieving 0 or 1 in Prurigo Nodularis - Investigator Global Assessment at week 16

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    End point title
    		 2.3 Proportion of subjects achieving 0 or 1 in Prurigo Nodularis - Investigator Global Assessment at week 16
    End point description
    Proportion of subjects achieving clear (0) or almost Clear (1) in PN-IGA score at week 16 (mITT Analysis Set)
    End point type
    Secondary
    End point timeframe
    At week 16
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    47
    47
    47
    48
    Units: Percentage
        number (confidence interval 95%)
    38.3 (24.5 to 53.6)
    29.8 (17.3 to 44.9)
    14.9 (6.2 to 28.3)
    10.4 (3.5 to 22.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were observed or reported during the study from the time the subject signs the ICF through the EOS Visit. Serious Adverse Event and Adverse Event of Special Interest were reported to the Sponsor or designee within 24 hours of occurrence.
    Adverse event reporting additional description
    Data presented here reports Treatment-Emergent Adverse Events of Any Grade Occurring in ≥ 5% of the Subjects During the Double-Blind and Open-Label Extension Period (Safety Analysis Set)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Double Blind-Arm A
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 540 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Double Blind-Arm B
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 360 mg every 4 weeks for 16 weeks during the double-blind period.

    Reporting group title
    Double Blind-Arm C
    Reporting group description
    		 KPL-716 was administered subcutaneously at the dose of 120 mg every 4 weeks for 16 weeks during double blind period.

    Reporting group title
    Double Blind-Arm D
    Reporting group description
    		 Placebo was administered subcutaneously every 4 weeks during the double-blind period.

    Reporting group title
    Open-Label Extension Period
    Reporting group description
    		 Data presented here reports Treatment-Related Adverse Events of Any Grade Occurring in ≥ 5% of the Subjects During the Open-Label Extension Period (Safety Analysis Set)

    Serious adverse events
    		 Double Blind-Arm A Double Blind-Arm B Double Blind-Arm C Double Blind-Arm D Open-Label Extension Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    3 / 48 (6.25%)
    8 / 181 (4.42%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fusion fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial Paralysis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Ulcer
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema nummular
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    2 / 181 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Periorbital cellulitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    0 / 181 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double Blind-Arm A Double Blind-Arm B Double Blind-Arm C Double Blind-Arm D Open-Label Extension Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 47 (74.47%)
    29 / 47 (61.70%)
    21 / 47 (44.68%)
    26 / 48 (54.17%)
    135 / 181 (74.59%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences all number
    1
    0
    1
    0
    1
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 47 (0.00%)
    2 / 47 (4.26%)
    4 / 48 (8.33%)
    9 / 181 (4.97%)
         occurrences all number
    3
    0
    2
    4
    9
    General disorders and administration site conditions
    General disorders and administration site conditions
         subjects affected / exposed
    7 / 47 (14.89%)
    7 / 47 (14.89%)
    4 / 47 (8.51%)
    7 / 48 (14.58%)
    17 / 181 (9.39%)
         occurrences all number
    7
    7
    4
    7
    17
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences all number
    2
    0
    0
    0
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences all number
    1
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 47 (4.26%)
    2 / 47 (4.26%)
    2 / 48 (4.17%)
    16 / 181 (8.84%)
         occurrences all number
    1
    2
    2
    2
    16
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 47 (2.13%)
    1 / 47 (2.13%)
    3 / 48 (6.25%)
    8 / 181 (4.42%)
         occurrences all number
    1
    1
    1
    3
    8
    Investigations
    Investigations
         subjects affected / exposed
    4 / 47 (8.51%)
    5 / 47 (10.64%)
    3 / 47 (6.38%)
    4 / 48 (8.33%)
    18 / 181 (9.94%)
         occurrences all number
    4
    5
    3
    4
    18
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural complications
         subjects affected / exposed
    6 / 47 (12.77%)
    4 / 47 (8.51%)
    5 / 47 (10.64%)
    3 / 48 (6.25%)
    15 / 181 (8.29%)
         occurrences all number
    6
    4
    5
    3
    15
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
    1 / 181 (0.55%)
         occurrences all number
    0
    0
    1
    0
    1
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    7 / 47 (14.89%)
    3 / 47 (6.38%)
    5 / 47 (10.64%)
    0 / 48 (0.00%)
    13 / 181 (7.18%)
         occurrences all number
    7
    3
    5
    0
    13
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    0 / 48 (0.00%)
    5 / 181 (2.76%)
         occurrences all number
    1
    0
    1
    0
    5
    Ear and labyrinth disorders
    Ear and labyrinth disorders
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    3 / 181 (1.66%)
         occurrences all number
    0
    0
    0
    1
    3
    Eye disorders
    Eye disorders
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    5 / 181 (2.76%)
         occurrences all number
    4
    1
    0
    0
    5
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    6 / 47 (12.77%)
    5 / 47 (10.64%)
    5 / 47 (10.64%)
    4 / 48 (8.33%)
    22 / 181 (12.15%)
         occurrences all number
    6
    5
    5
    4
    22
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
    1 / 48 (2.08%)
    1 / 181 (0.55%)
         occurrences all number
    0
    0
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    10 / 47 (21.28%)
    13 / 47 (27.66%)
    5 / 47 (10.64%)
    3 / 48 (6.25%)
    49 / 181 (27.07%)
         occurrences all number
    10
    13
    5
    3
    49
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    2 / 181 (1.10%)
         occurrences all number
    0
    0
    0
    1
    2
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    0 / 47 (0.00%)
    1 / 48 (2.08%)
    1 / 181 (0.55%)
         occurrences all number
    0
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
    0 / 48 (0.00%)
    25 / 181 (13.81%)
         occurrences all number
    3
    1
    0
    0
    25
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    14 / 47 (29.79%)
    11 / 47 (23.40%)
    11 / 47 (23.40%)
    14 / 48 (29.17%)
    87 / 181 (48.07%)
         occurrences all number
    14
    11
    11
    14
    87
    Metabolism and nutrition disorders
    Metabolism and nutrition disorders
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 47 (8.51%)
    0 / 47 (0.00%)
    3 / 48 (6.25%)
    11 / 181 (6.08%)
         occurrences all number
    1
    4
    0
    3
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2021
    EU specific Protocol Amendment v1.0_06Aug2021: Global Protocol v5.0, dated 21 December 2020, was updated to a European Union Regional Protocol, v1.0, dated 06 August 2021, to incorporate comments and changes requested by European Regulatory Authorities during the initial clinical trial application review process. In summary the following important updates were made: (1) Clarified that the PN-IGA measures the overall assessment at Week 16 (2) Clarifications on sexually active female subjects, methods of contraception, and pregnancy test sections were included (3) Exclusion criteria were revised to reduce screen failures (4) Subject withdrawal and replacement section was updated per Germany regulatory authority (5) A new subsection "Suspected Unexpected Serious Adverse Reactions" was added to Safety and Tolerability Assessments.

    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
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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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