Clinical trial NCT03737110: Study to Assess the Efficacy and Safety of Rilonacept Treatment in Participants With Recurrent Pericarditis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Recurrent Pericarditis
Lead sponsor: Kiniksa Pharmaceuticals International, plc
Sponsor class: INDUSTRY
First posted: 2018-11-09
Enrollment: 86
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study was to assess the efficacy of rilonacept treatment in participants with recurrent pericarditis.

Detailed description: In the single-blind run-in (RI) period, rilonacept 320 mg (or 4.4 mg/kg in pediatric participants ≥12 and \<18 years old) subcutaneous (SC), followed by 160 mg (or 2.2 mg/kg in pediatric participants ≥12 and \<18 years old) injections once weekly.

During the Randomized-Withdrawal (RW) period, eligible participants are randomized 1:1 to double-blinded administration of study drug:

* Rilonacept 160 mg (or 2.2 mg/kg in pediatric participants ≥12 and \<18 years old) SC injections once weekly
* Matching placebo SC injections once weekly.

Participants with pericarditis recurrence who meet the protocol criteria for bailout rilonacept (report at least 1 day with pericarditis pain ≥4 on the 11-point numerical rating scale (NRS) and have 1 C-reactive protein (CRP) value ≥ 1 mg/dL \[either on the same day or separated by no more than 7 days\]) receive bailout rilonacept (2 open-label injections of 160 mg rilonacept \[or 4.4 mg/kg for pediatric subjects\]) irrespective of randomized treatment assignment and as soon as at least 5 days have passed since the last study drug injection.

Upon completion of the RW period (i.e., when the prespecified number of primary efficacy endpoints \[clinical events committee-confirmed pericarditis recurrence\] events have occurred), all participants who did not discontinue study drug have an option to continue treatment with open-label rilonacept in the Long-Term Extension (LTE) or to withdraw from the study. Participants still in the RI period at the time that the RW period has ended and the LTE is opened will have the option to enter the LTE directly when they have completed the RI period and have met the definition of clinical response or to withdraw from the study.

Eligibility criteria: Key Inclusion Criteria:

1. Male or female aged 12 or older
2. Has a diagnosis of recurrent pericarditis
3. Must provide Informed Consent
4. Presents with at least the third episode of pericarditis during screening.
5. Has received nonsteroidal anti-inflammatory drugs (NSAIDs) and/or colchicine and/or corticosteroids (in any combination), if used, at stable dose levels (or at least not increased) for at least 3 days prior to first study drug administration
6. Female subjects must be postmenopausal, or incapable of pregnancy or permanently sterile, or if of childbearing potential must agree to use highly-effective method of contraception.
7. Must be up-to-date with all immunizations, in agreement with current local immunization guidelines for immunosuppressed subjects, before first study drug administration.
8. Is able to adequately maintain a daily subject diary according to protocol.
9. Agrees to refrain from making any new, major lifestyle changes that may affect pericarditis symptoms (e.g., changing exercise pattern) from the time that the informed consent form (ICF) is signed through the end of the double-blind randomized withdrawal period.

Key Exclusion Criteria:

1. Has a diagnosis of pericarditis that is secondary to specific prohibited etiologies.
2. Has a history of immunosuppression, including positive human immunodeficiency virus (HIV) test results.
3. Has a history of myeloproliferative disorder.
4. Has a history of demyelinating disease or symptoms suggestive of multiple sclerosis.
5. Has a history of active or latent tuberculosis (TB) prior to screening
6. Has chest x-ray at screening or within 12 weeks before receiving first administration of study drug, with evidence of malignancy or abnormality consistent with prior or active TB infection.
7. Has a history of positive or intermediate results for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C virus antibody at screening.
8. Has a history of malignancy of any organ system within the past 5 years before screening (other than a successfully treated non metastatic cutaneous squamous cell carcinoma or basal cell carcinoma and/or localized carcinoma in situ of the cervix).
9. Has a known or suspected current active infection or a history of chronic or recurrent infectious disease, including, but not limited to, chronic renal infection, chronic chest infection, sinusitis, recurrent urinary tract infection, or an open, draining infected skin wound.
10. Has had an organ transplant.
11. In the Investigator's opinion, has a history of alcoholism or drug/chemical abuse within 2 years before screening.
12. Has a known hypersensitivity to rilonacept or to any of its excipients.
13. Has received an investigational drug during the 30 days before screening or is planning to receive an investigational drug (other than that administered during this study) or use an investigational device at any time during the study.
14. In the Investigator's opinion, has any other medical condition that could adversely affect the subject's participation or interfere with study evaluations.

Primary outcomes:
measure: Time to Pericarditis Recurrence in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
Secondary outcomes:
measure: Major Secondary Efficacy Endpoint: Percentage of Participants Who Maintained Clinical Response at Week 16 of the RW Period
timeFrame: RW Period Week 16
measure: Major Secondary Efficacy Endpoint: Percentage of Days With No or Minimal Pericarditis Pain at Week 16 of the RW Period
timeFrame: RW Period Week 16
measure: Major Secondary Efficacy Endpoint: Percentage of Participants With Absent or Minimal Pericarditis Symptoms Based on the Patient Global Impression of Pericarditis Severity (PGIPS) at Week 16 of the RW Period
timeFrame: RW Period Week 16
measure: Percentage of Participants Who Maintained Clinical Response at Week 24 of the RW Period
timeFrame: RW Period Week 24
measure: Percentage of Participants Who Maintained Clinical Response at Week 8 of the RW Period
timeFrame: RW Period Week 8
measure: Percentage of Days With No or Minimal Pericarditis Pain at Week 24 of the RW Period
timeFrame: RW Period Week 24
measure: Percentage of Days With No or Minimal Pericarditis Pain at Week 8 of the RW Period
timeFrame: RW Period Week 8
measure: Percentage of Participants With Absent or Minimal Pericarditis Symptoms at Week 24 of the RW Period Based on the PGIPS
timeFrame: RW Period Week 24
measure: Percentage of Participants With Absent or Minimal Pericarditis Symptoms at Week 8 of the RW Period Based on the PGIPS
timeFrame: RW Period Week 8
measure: Percentage of Participants Without Pericarditis Recurrence in the First 24 Weeks of the RW Period
timeFrame: up to 24 weeks in the RW Period
measure: Time to Pericarditis Pain ≥ 4 on the NRS in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Time to CRP Level ≥ 1 mg/dL in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Time to Pericardial Rub in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Time to Widespread ST-segment Elevation or PR-segment Depression on Electrocardiogram (ECG) in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Time to New or Worsening Pericardial Effusion on Echocardiography (ECHO) in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Number of Participants in ECHO Pericardial Effusion Size Categories at RW Period Baseline, RW Week 24 and Worst Post-baseline in the RW Period
timeFrame: RW Period Baseline, RW Period Week 24, RW Period (mean 24.8 weeks)
measure: Change From RW Period Baseline Over Time in CRP Levels in RW Period
timeFrame: RW Period Baseline, RW Period Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 56
measure: Change From RW Period Baseline Over Time in Weekly Average of Pericarditis Pain in the RW Period
timeFrame: RW Period Baseline, RW Period Weeks 1-50, 54
measure: Percentage of Participants With Absent or Minimal Pericarditis Symptoms Over Time After RW Period Week 24 Based on the PGIPS
timeFrame: RW Period Weeks 32, 40, 48, 56
measure: Percentage of Participants With Absent or Minimal Pericarditis Activity Over Time in the RW Period Based on the Physician Global Assessment of Pericarditis Activity (PGA-PA)
timeFrame: RW Period Baseline, RW Period Weeks 8, 16, 24, 32, 40, 48, 56
measure: Change From RW Period Baseline in Short Form-36 (SF-36) Physical and Mental Component Scores at RW Period Week 24
timeFrame: RW Period Baseline, RW Period Week 24
measure: Change From RW Baseline in SF-36 Individual Scores at RW Period Week 24
timeFrame: RW Period Baseline, RW Period Week 24
measure: Change From RW Period Baseline in the Short Form Health Survey-6 Domains (SF-6D) Utility Index Score at RW Period Week 24
timeFrame: RW Period Baseline, RW Period Week 24
measure: Change From RW Period Baseline in 5-level EuroQoL-5 Dimensions (EQ-5D-5L) Individual Scores and Index Value to RW Period Week 24
timeFrame: RW Period Baseline, RW Period Week 24
measure: Change From RW Period Baseline in Insomnia Severity Index (ISI) Total Score at RW Period Week 24
timeFrame: RW Period Baseline, RW Period Week 24
measure: Change in ISI Categories From RW Period Baseline to RW Period Week 24
timeFrame: RW Period Baseline (BL), RW Period Week (Wk) 24
measure: Percentage of Participants Using Oral Rescue Therapy (ORT), Corticosteroid, or Bailout Rilonacept for Pericarditis Every 4 Weeks Cumulatively in the RW Period
timeFrame: RW Period (mean 24.8 weeks)
measure: Percentage of Participants Using ORT for Pericarditis in the First 24 Weeks of RW Period
timeFrame: RW Period (up to Week 24)
measure: Percentage of Participants With Pericardial Delayed Hyperenhancement, Myocardial Delayed Hyperenhancement or Pericardial Effusion on Magnetic Resonance Imaging (MRI) at RW Week 24
timeFrame: RW Period Week 24
measure: Time From First Dose to Pain Response in the RI Period
timeFrame: RI Period (up to 12 weeks)
measure: Time From First Dose to CRP Normalization in the RI Period
timeFrame: RI Period (up to 12 weeks)
measure: Time From First Dose to Rilonacept Monotherapy in RI Period
timeFrame: RI Period (up to 12 weeks)
measure: Time From First Dose to Treatment Response in RI Period
timeFrame: RI Period (up to 12 weeks)
measure: Percentage of Participants Achieving Clinical Response at RI Period Week 12
timeFrame: RI Period Week 12
measure: Percentage of Participants With CRP Normalization at RI Period Week 12
timeFrame: RI Period Week 12
measure: Change From Baseline Over Time in Weekly Average of Pericarditis Pain NRS Score in RI Period
timeFrame: RI Period Baseline, RI Period Weeks 1-12
measure: Change From Baseline Over Time in CRP Levels in RI Period
timeFrame: RI Period Baseline, RI Period Day 4, Weeks 1, 2, 4, 6, 12
measure: Percentage of Participants With Resolution of Pericarditis-Related ECHO and ECG Abnormalities at Week 12 of the RI Period
timeFrame: RI Period Baseline, RI Period Week 12
measure: Percentage of Days With No or Minimal Pain in the RI Period While on Treatment
timeFrame: RI Period (up to Week 12)
measure: Percentage of Participants With No or Minimal Pericarditis Symptoms Over Time in the RI Period, Based on the PGIPS
timeFrame: RI Period Baseline, RI Period Weeks 6 and 12
measure: Percentage of Participants With No or Minimal Pericarditis Activity Over Time in the RI Period, Based on the PGA-PA
timeFrame: RI Period Baseline, RI Period Weeks 6 and 12
measure: Change From RI Period Baseline in the SF-36 Domain Scores and Physical and Mental Scores to RI Period Week 12
timeFrame: RI Period Baseline, RI Period Week 12
measure: Change From RI Period Baseline in SF-6D Scores at RI Period Week 12
timeFrame: RI Period Baseline, RI Period Week 12
measure: Change From RI Period Baseline in 5-level EuroQoL-5 Dimensions (EQ-5D-5L) Individual Scores and Index Value at RI Period Week 12
timeFrame: RI Period Baseline, RI Period Week 12
measure: Change From RI Period Baseline in ISI Total Score at RI Period Week 12
timeFrame: RI Period Baseline, RI Period Week 12
measure: Change in ISI Categories From RI Period Baseline to RI Period Week 12
timeFrame: RI Period Baseline (BL), RI Period Week (Wk) 12
measure: Number of Participants Who Were Off Background Pericarditis Medication on or Before RI Period Weeks 4, 8, 10, and 12
timeFrame: RI Period Baseline, RI Period Weeks 4, 8, 10, 12
measure: Annualized Rate of Pericarditis Recurrence in the Long-Term Extension (LTE) Period Based on Investigator's Assessment (Based on Investigators' Judgement)
timeFrame: LTE Period, through LTE Follow up (up to Week 48)
measure: Change From LTE Baseline Over Time in CRP Levels
timeFrame: LTE Baseline, LTE Week 12, LTE Week 24
measure: Percentage of Participants With Absent or Minimal Pericarditis Activity In the LTE Period Based on the PGIPS
timeFrame: LTE Baseline, LTE Month 12, LTE Month 24
measure: Percentage of Participants With Absent or Minimal Pericarditis Activity Over Time in the LTE Period Based on the PGA-PA
timeFrame: LTE Baseline, LTE Week 12, LTE Week 24
measure: Change From LTE Baseline in the SF-36 Domain Scores and Physical and Mental Scores
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in SF-6D Health Utility Index Score
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in EQ-5D-5L Individual Scores and Index Value
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in ISI Total Score
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in ISI Categories
timeFrame: LTE Baseline (BL), LTE Week 24
measure: Percentage of Participants Requiring Addition of Standard of Care (SOC) Pericarditis Therapy Every 4 Weeks Cumulatively in the LTE Period
timeFrame: LTE Period, through LTE Follow up (up to Week 24)
measure: Change From LTE Baseline in Pericardial Signs in ECHO
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in Pericardial Signs in ECG
timeFrame: LTE Baseline, LTE Week 24
measure: Change From LTE Baseline in Pericardial Signs in MRI
timeFrame: LTE Baseline, LTE Week 24
measure: Number of Participants With Pericardial Delayed Hyperenhancement, Myocardial Delayed Hyperenhancement or Pericardial Effusion at LTE Period Week 24
timeFrame: LTE Week 24
measure: Annualized Rate of Pericarditis Recurrence in LTE Periods Based on Investigator's Assessment
timeFrame: LTE Period, through LTE Follow up (up to Week 48)
measure: Annualized Rate of Pericarditis Recurrence in RW Period Based on CEC Adjudication
timeFrame: RW Period (mean 24.8 weeks)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Institute
state: California
city: Atlanta
country: United States
facility: Arthritis and Rheumatology of Georgia
state: Georgia
city: Chicago
country: United States
facility: The Loretto Hospital
state: Illinois
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - PPDS
state: Minnesota
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Yardley
country: United States
facility: Cardiology Consultants of Philadelphia
state: Pennsylvania
city: Murray
country: United States
facility: Intermountain Healthcare
state: Utah
city: Burlington
country: United States
facility: University Of Vermont Medical Center
state: Vermont
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Milton
country: Australia
facility: HeartCare Partners Clinical Research Unit
state: Queensland
city: Doncaster East
country: Australia
facility: GenesisCare - Cardiology Research
state: Victoria
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Ramat Gan
country: Israel
facility: Sheba Medical Center at Tel-Hashomer
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
state: Lazio
city: Milan
country: Italy
facility: ASST Fatebenefratelli Sacco - Ospedale Fatebenefratelli e Oftalmico
state: Lombardy
city: Turin
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
state: Piedmont
Study officials:
affiliation: Kiniksa Pharmaceuticals (UK), Ltd.
name: Clinical Operations Study Director
role: STUDY_DIRECTOR
References:
citation: Klein AL, Imazio M, Cremer P, Brucato A, Abbate A, Fang F, Insalaco A, LeWinter M, Lewis BS, Lin D, Luis SA, Nicholls SJ, Pano A, Wheeler A, Paolini JF; RHAPSODY Investigators. Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis. N Engl J Med. 2021 Jan 7;384(1):31-41. doi: 10.1056/NEJMoa2027892. Epub 2020 Nov 16.
citation: Brucato A, Wheeler A, Luis SA, Abbate A, Cremer PC, Zou L, Insalaco A, Lewinter M, Lewis BS, Lin D, Nicholls S, Pancrazi M, Klein AL, Imazio M, Paolini JF. Transition to rilonacept monotherapy from oral therapies in patients with recurrent pericarditis. Heart. 2023 Jan 27;109(4):297-304. doi: 10.1136/heartjnl-2022-321328.
citation: Brucato A, Lim-Watson MZ, Klein A, Imazio M, Cella D, Cremer P, LeWinter MM, Luis SA, Lin D, Lotan D, Pancrazi M, Trotta L, Klooster B, Litcher-Kelly L, Zou L, Magestro M, Wheeler A, Paolini JF; RHAPSODY Investigators. Interleukin-1 Trap Rilonacept Improved Health-Related Quality of Life and Sleep in Patients With Recurrent Pericarditis: Results From the Phase 3 Clinical Trial RHAPSODY. J Am Heart Assoc. 2022 Oct 18;11(20):e023252. doi: 10.1161/JAHA.121.023252. Epub 2022 Oct 17.
citation: Klein AL, Imazio M, Brucato A, Cremer P, LeWinter M, Abbate A, Lin D, Martini A, Beutler A, Chang S, Fang F, Gervais A, Perrin R, Paolini JF. RHAPSODY: Rationale for and design of a pivotal Phase 3 trial to assess efficacy and safety of rilonacept, an interleukin-1alpha and interleukin-1beta trap, in patients with recurrent pericarditis. Am Heart J. 2020 Oct;228:81-90. doi: 10.1016/j.ahj.2020.07.004. Epub 2020 Jul 14.