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    Clinical Trial Results:
    Phase 3, double-blind, placebo-controlled, randomized withdrawal study with open-label extension, to assess the efficacy and safety of Rilonacept treatment in subjects with recurrent pericarditis

    Summary
    EudraCT number
    		 2018-002719-87
    Trial protocol
    		 IT  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jan 2025
    First version publication date
    24 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KPL-914-C002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03737110
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Kiniksa Pharmaceuticals (UK), Ltd.
    Sponsor organisation address
    Third Floor, 23 Old Bond Street, London, United Kingdom, W1S 4PZ
    Public contact
    Kiniksa Pharmaceuticals (UK), Ltd. c/o Kiniksa Pharmaceuticals Corp., Kiniksa Medical Information Group, +1 7814319100, studyinfo@kiniksa.com
    Scientific contact
    Kiniksa Pharmaceuticals (UK), Ltd. c/o Kiniksa Pharmaceuticals Corp., Kiniksa Medical Information Group, +1 7814319100, studyinfo@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
    12 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the efficacy of rilonacept treatment in subjects with recurrent pericarditis.
    Protection of trial subjects
    The protocol, informed consent form (ICF), advertisements to be used for the recruitment of study subjects, and any other written information regarding this study was approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) before any study procedures were performed. Any subsequent protocol amendments or informed consent revisions were approved by the IRB before any changes were initiated. Documentation of all IRB/IEC approvals and of the IRB/IEC compliance with International Council for Harmonisation (ICH) harmonized tripartite guideline E6(R2): Good Clinical Practice (GCP) were maintained by the site. This study was designed and monitored in accordance with sponsor procedures, which comply with the ethical principles of GCP as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki. Written informed consent to participate in the study was obtained from each subject or subject’s parent or legal guardian before any study-specific procedures were performed. Each subject was provided with an ICF describing the study and was given time to read this document and ask questions. Pediatric subjects (ages 12 to 17) signed a written assent form, which explained the study.
    Background therapy
    		 During the single-blind Run-In period, in parallel with treatment with blinded rilonacept, the subjects were tapered off background standard-of-care (SOC) therapy for pericarditis: corticosteroids, NSAIDs, and colchicine. Some subjects used analgesics/opioid analgesics if needed under the Investigator's discretion.
    Evidence for comparator
    		 There was not a comparator medicinal product because patients presented in active flare having failed standard of care therapies.
    Actual start date of recruitment
    09 Jan 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Israel: 10
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    86
    EEA total number of subjects
    21
    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)
    7
    Adults (18-64 years)
    71
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 46 study centers were activated in Australia, Israel, Italy and USA. 31 centers screened subjects, 21 enrolled at least 1 subject. 86 subjects were enrolled, treated, and included in safety analysis set; 61 had been randomized at the time the event-driven trial closure was attained, comprising the ITT analysis set for the primary efficacy endpoint.

    Pre-assignment
    Screening details
    		 Patients (12+ year old) with diagnosis recurrent pericarditis, who received a standard-of-care background therapy at stable dose level and were willing and able to taper and discontinue those medications. Screening procedures were repeated at the discretion of the investigator; subjects who initially failed screening were eligible to be rescreened.

    Period 1
    Period 1 title
    Run-in Period (RI)
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    All subjects received blinded rilonacept and were blinded to the duration of the RI period and the timing of randomization. Subjects who did not achieve clinical response on rilonacept monotherapy at RI Week 12 were discontinued from study drug, transitioned to SOC pericarditis therapy at the investigator’s discretion, and were followed through the end of the Randomized Withdrawal (RW) period.

    Arms
    Arm title
    		 Rilonacept (RI)
    Arm description
    		 Single-blinded participants received initial dose of 320 mg (or 4.4 mg/kg in pediatric participants) rilonacept subcutaneous (SC), following by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly. In the first week rilonacept was administered in addition to background SOC therapy. During following 9 weeks the background standard-of-care therapy was tapered off, and it was required that rilonacept be administered as monotherapy after Week 10. Subjects who stopped background SOC therapy, achieved clinical response, and were on rilonacept monotherapy at RI period Week 12 were transitioned to the RW period. Fifteen subjects were still in the RI period at the time when the event-driven RW period ended and randomization closed; these 15 patients continued directly to the Long Term Extension (LTE) period, as they had completed the RI period and had met the definition of clinical response.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept
    Investigational medicinal product code
    KPL-914
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each rilonacept vial contained 220 mg of rilonacept lyophilized powder. After reconstitution with 2.3 mL sterile water for injection, the rilonacept vial contained 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5. No preservatives were present. First administration of 320 mg (or 4.4 mg/kg in pediatric participants) SC injection, followed by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly.

    Number of subjects in period 1
    		Rilonacept (RI)
    Started
    86
    Completed
    61
    Not completed
    25
         Physician decision
    2
         Completed, Continuing directly into LTE
    15
         Adverse event, non-fatal
    4
         Not specified
    1
         Lack of efficacy
    3
    Period 2
    Period 2 title
    Randomized Withdrawal Period (RW)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Neither the subject nor any of the site staff, clinical research organization (CRO) staff, or sponsor staff who were involved in the treatment or clinical evaluation of the subjects were aware of the treatment received.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rilonacept (RW)
    Arm description
    		 Participants assigned to Rilonacept 160 mg (or 2.2 mg/kg in pediatric subjects ≥12 and <18 years old) administered by SC injections once weekly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept
    Investigational medicinal product code
    KPL-914
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each rilonacept vial contained 220 mg of rilonacept lyophilized powder. After reconstitution with 2.3 mL sterile water for injection, the rilonacept vial contained 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5. No preservatives were present. Product was administered as a SC injection of 160 mg (or 2.2 mg/kg in pediatric participants) once weekly.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received matching placebo SC injections once weekly.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo is a vial with lyophilized powder. After reconstitution with 2.3 mL sterile water for injection, the placebo vial contained 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5. No preservatives were present.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The trial design assessed the efficacy of the IMP vs Placebo in the RW period. The purpose of the Run-in period was to prepare subjects for randomization to rilonacept or placebo at Week 12. The Run-in period was carried out in order for patients to switch from background standard-of care therapy to the monotherapy with the IMP. Pivotal efficacy data were collected in the second period, the Randomized Withdrawal period.
    Number of subjects in period 2 [2]
    		Rilonacept (RW) Placebo
    Started
    30
    31
    Completed
    29
    30
    Not completed
    1
    1
         Consent withdrawn by subject
    -
    1
         Completed, Not Continuing into LTE
    1
    -
    Notes
    [2] - 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: 86 subjects entered the Run-In period (Period 1), and 61 subjects entered Period 2. Fifteen subjects who were still in the Run-in (RI) period at the time when randomization into the event-driven Randomized Withdrawal (RW) period had ended and the Long-term Extension (LTE) had opened were given the option to enter the LTE directly (after they had completed the RI period and had met the definition of clinical response).
    Period 3
    Period 3 title
    Long-term extension period (LTE)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Rilonacept (LTE)
    Arm description
    		 All participants who had completed the RW period and participants still in the RI period (at the time when the RW period had ended) who met clinical response criteria at Week 12 were eligible for inclusion in the LTE period (up to 24 months of additional open-label rilonacept).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rilonacept
    Investigational medicinal product code
    KPL-914
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Each rilonacept vial contained 220 mg of rilonacept lyophilized powder. After reconstitution with 2.3 mL sterile water for injection, the rilonacept vial contained 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5. No preservatives were present. Product was administered as a SC injection of 160 mg (or 2.2 mg/kg in pediatric participants) once weekly.

    Number of subjects in period 3 [3]
    		Rilonacept (LTE)
    Started
    29
    Completed
    69
    Not completed
    5
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    1
         Lost to follow-up
    1
    Joined
    45
         Transffered from Placebo (RW)
    30
         Transfered from RI directly into LTE
    15
    Notes
    [3] - 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: 15 patients completed the RI period continued in LTE period. Patients randomized in Placebo arm of RW joined Rilonacept (RW) arm.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rilonacept (RW)
    Reporting group description
    		 Participants assigned to Rilonacept 160 mg (or 2.2 mg/kg in pediatric subjects ≥12 and <18 years old) administered by SC injections once weekly.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo SC injections once weekly.

    Reporting group values
    		 Rilonacept (RW) Placebo Total
    Number of subjects
    		 30 31 61
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 2 3
        Adults (18-64 years)
    		 24 27 51
        From 65-84 years
    		 5 2 7
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 48.0 (17 to 71) 44.8 (16 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16 32
        Male
    		 14 15 29
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Intent-to-treat (ITT) analysis set included all subjects who were randomized in the RW period. ITT analysis set was the same as the safety analysis set in the RW period.

    Subject analysis sets values
    		 Intent-to-treat analysis set
    Number of subjects
    61
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    3
        Adults (18-64 years)
    51
        From 65-84 years
    7
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    46.4 (16 to 71)
    Gender categorical
    Units: Subjects
        Female
    32
        Male
    29

    End points

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    End points reporting groups
    Reporting group title
    Rilonacept (RI)
    Reporting group description
    		 Single-blinded participants received initial dose of 320 mg (or 4.4 mg/kg in pediatric participants) rilonacept subcutaneous (SC), following by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly. In the first week rilonacept was administered in addition to background SOC therapy. During following 9 weeks the background standard-of-care therapy was tapered off, and it was required that rilonacept be administered as monotherapy after Week 10. Subjects who stopped background SOC therapy, achieved clinical response, and were on rilonacept monotherapy at RI period Week 12 were transitioned to the RW period. Fifteen subjects were still in the RI period at the time when the event-driven RW period ended and randomization closed; these 15 patients continued directly to the Long Term Extension (LTE) period, as they had completed the RI period and had met the definition of clinical response.
    Reporting group title
    Rilonacept (RW)
    Reporting group description
    		 Participants assigned to Rilonacept 160 mg (or 2.2 mg/kg in pediatric subjects ≥12 and <18 years old) administered by SC injections once weekly.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received matching placebo SC injections once weekly.
    Reporting group title
    Rilonacept (LTE)
    Reporting group description
    		 All participants who had completed the RW period and participants still in the RI period (at the time when the RW period had ended) who met clinical response criteria at Week 12 were eligible for inclusion in the LTE period (up to 24 months of additional open-label rilonacept).

    Subject analysis set title
    Intent-to-treat analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Intent-to-treat (ITT) analysis set included all subjects who were randomized in the RW period. ITT analysis set was the same as the safety analysis set in the RW period.

    Primary: The primary efficacy endpoint was time to pericarditis recurrence in the Randomized Withdrawal period

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    End point title
    		 The primary efficacy endpoint was time to pericarditis recurrence in the Randomized Withdrawal period
    End point description
    Investigator-assessed pericarditis recurrence was defined as the recurrence of typical pericarditis pain associated with or without supportive objective evidence of pericarditis; these investigator-assessed events were adjudicated according to the Clinical Endpoint Committee (CEC) charter to confirm whether they met objective criteria for inclusion in the primary efficacy endpoint analysis. Please see ClinicalTrials.gov for full analysis of secondary endpoints. (https://clinicaltrials.gov/study/NCT03737110?cond=recurrent%20pericarditis&rank=8&tab=results)
    End point type
    Primary
    End point timeframe
    Time from randomization till the end of the RW period (event-driven). The closure of the RW period was triggered when the prespecified number of primary efficacy endpoint (CEC-confirmed pericarditis recurrence) events (N=22) had accrued.
    End point values
    		 Rilonacept (RW) Placebo
    Number of subjects analysed
    30
    31
    Units: number
    number (not applicable)
        Time to recurrence (weeks)
    0
    8.6
    Statistical analysis title
    		 Kaplan-Meier method
    Comparison groups
    Rilonacept (RW) v Placebo
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Log Rank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.18

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs registered from patient enrollment during any period of the study: Run-In Period, Randomized Withdrawal Period (without or with bailout rilonacept) and Long-term Extension Period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    RI Period
    Reporting group description
    		 All patients enrolled in the study and received at least 1 dose of rilonacept.

    Reporting group title
    RW Period: Rilonacept Only, Before Bailout Rilonacept
    Reporting group description
    		 -

    Reporting group title
    RW Period: Rilonacept, Including Bailout Rilonacept
    Reporting group description
    		 -

    Reporting group title
    RW Period: Placebo Only, Before Bailout Rilonacept
    Reporting group description
    		 -

    Reporting group title
    RW Period: Placebo, Including Bailout Rilonacept
    Reporting group description
    		 -

    Reporting group title
    LTE Period: Overall
    Reporting group description
    		 -

    Serious adverse events
    		 RI Period RW Period: Rilonacept Only, Before Bailout Rilonacept RW Period: Rilonacept, Including Bailout Rilonacept RW Period: Placebo Only, Before Bailout Rilonacept RW Period: Placebo, Including Bailout Rilonacept LTE Period: Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    3 / 31 (9.68%)
    6 / 74 (8.11%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac flutter
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Acute endocarditis
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 RI Period RW Period: Rilonacept Only, Before Bailout Rilonacept RW Period: Rilonacept, Including Bailout Rilonacept RW Period: Placebo Only, Before Bailout Rilonacept RW Period: Placebo, Including Bailout Rilonacept LTE Period: Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 86 (63.95%)
    18 / 30 (60.00%)
    18 / 30 (60.00%)
    7 / 31 (22.58%)
    13 / 31 (41.94%)
    43 / 74 (58.11%)
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    1
    2
    2
    0
    0
    3
    High density lipoprotein increased
         subjects affected / exposed
    0 / 86 (0.00%)
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    0
    3
    3
    0
    0
    1
    Lipids increased
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 74 (1.35%)
         occurrences all number
    0
    2
    2
    0
    1
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 86 (2.33%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    7 / 74 (9.46%)
         occurrences all number
    2
    1
    1
    1
    1
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 86 (8.14%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    7
    0
    0
    0
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    3 / 74 (4.05%)
         occurrences all number
    2
    2
    2
    0
    1
    3
    Injection site erythema
         subjects affected / exposed
    18 / 86 (20.93%)
    6 / 30 (20.00%)
    7 / 30 (23.33%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    3 / 74 (4.05%)
         occurrences all number
    18
    6
    7
    0
    1
    3
    Injection site pruritus
         subjects affected / exposed
    5 / 86 (5.81%)
    4 / 30 (13.33%)
    5 / 30 (16.67%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    0 / 74 (0.00%)
         occurrences all number
    5
    4
    5
    0
    1
    0
    Injection site swelling
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    5
    1
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    4 / 74 (5.41%)
         occurrences all number
    1
    3
    3
    1
    1
    4
    Pyrexia
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 86 (5.81%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    5
    0
    0
    0
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 74 (1.35%)
         occurrences all number
    5
    1
    1
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    1
    3
    3
    0
    0
    2
    Sinus congestion
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    2
    2
    2
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 86 (9.30%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    2 / 31 (6.45%)
    4 / 74 (5.41%)
         occurrences all number
    8
    1
    1
    0
    2
    4
    Back pain
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    4 / 74 (5.41%)
         occurrences all number
    3
    1
    1
    1
    2
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    4 / 31 (12.90%)
    4 / 31 (12.90%)
    11 / 74 (14.86%)
         occurrences all number
    3
    1
    1
    4
    4
    11
    Myalgia
         subjects affected / exposed
    9 / 86 (10.47%)
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    9
    1
    1
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    1 / 86 (1.16%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    1
    2
    2
    0
    0
    0
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    0 / 86 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    10 / 74 (13.51%)
         occurrences all number
    0
    0
    0
    0
    0
    10
    Influenza
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    2 / 31 (6.45%)
    0 / 74 (0.00%)
         occurrences all number
    1
    0
    0
    1
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 86 (6.98%)
    2 / 30 (6.67%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    6
    2
    2
    0
    0
    5
    Sinusitis
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    1
    3
    3
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 86 (1.16%)
    3 / 30 (10.00%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    5 / 74 (6.76%)
         occurrences all number
    1
    3
    3
    0
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Apr 2019
    Amendment 1, 12 April 2019 • Revised one of the criteria for permanent discontinuation of study drug • Added a baseline PK drug level measurement • Removed the 10-subject cap for the cardiac MRI Substudy • Revised the text regarding full physical examinations
    10 Mar 2020
    Amendment 2, 10 March 2020 The following changes were made based on discussion with the FDA from the Type B meeting (04 March 2020): • The primary efficacy endpoint analysis to be triggered at 22 CEC-confirmed (adjudicated) pericarditis events. The requirement for 24 weeks of follow-up in the RW period for all subjects was eliminated. • Increased enrolled population to up to 100 subjects and clarified exclusion language regarding antibiotic use • Allowed subjects in the RI when randomization is closed and who met the definition of a clinical responder to directly enter the LTE period • The LTE period was extended to 24 months, and the off-treatment observation follow-up was eliminated and replaced with a 6-week safety follow up. • Added an assessment in the LTE at 18 months from most recent recurrence and allowed subjects at the 18-month decision milestone to either continue rilonacept, suspend treatment and remain in the study for off-treatment observation (and resume open-label rilonacept in event of a subsequent recurrence), or discontinue treatment and exit the study. • Added additional secondary endpoints; made 16 weeks the primary time point in the RW for secondary endpoint and designated analyses at Weeks 8 and 24 as sensitivity analyses.

    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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