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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 86
- 试验地点
- 21
- 主要终点
- Time to Pericarditis Recurrence in the RW Period
研究概览
简要总结
The primary objective of this study was to assess the efficacy of rilonacept treatment in participants with recurrent pericarditis.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female aged 12 or older
- •Has a diagnosis of recurrent pericarditis
- •Must provide Informed Consent
- •Presents with at least the third episode of pericarditis during screening.
- •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
- •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.
- •Must be up-to-date with all immunizations, in agreement with current local immunization guidelines for immunosuppressed subjects, before first study drug administration.
- •Is able to adequately maintain a daily subject diary according to protocol.
- •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.
排除标准
- •Has a diagnosis of pericarditis that is secondary to specific prohibited etiologies.
- •Has a history of immunosuppression, including positive human immunodeficiency virus (HIV) test results.
- •Has a history of myeloproliferative disorder.
- •Has a history of demyelinating disease or symptoms suggestive of multiple sclerosis.
- •Has a history of active or latent tuberculosis (TB) prior to screening
- •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.
- •Has a history of positive or intermediate results for hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C virus antibody at screening.
- •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).
- •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.
- •Has had an organ transplant.
- •In the Investigator's opinion, has a history of alcoholism or drug/chemical abuse within 2 years before screening.
- •Has a known hypersensitivity to rilonacept or to any of its excipients.
- •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.
- •In the Investigator's opinion, has any other medical condition that could adversely affect the subject's participation or interfere with study evaluations.
研究组 & 干预措施
Rilonacept
RI period: single-blind rilonacept 320 mg (or 4.4 mg/kg in pediatric participants) SC, followed by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly.
RW period: eligible participants randomized to double-blinded administration of rilonacept 160 mg (or 2.2 mg/kg in pediatric participants) 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 NRS and have 1 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 participants]) irrespective of randomized treatment assignment and as soon as at least 5 days have passed since the last study drug injection.
LTE period: open-label administration of rilonacept 160 mg (or 2.2 mg/kg in pediatric participants) SC injections once weekly.
干预措施: Rilonacept (Drug)
Placebo
RI period: single-blind rilonacept 320 mg (or 4.4 mg/kg in pediatric participants) SC, followed by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly.
RW period: eligible participants randomized to 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 NRS and have 1 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 participants]) irrespective of randomized treatment assignment and as soon as at least 5 days have passed since the last study drug injection.
LTE period: open-label administration of rilonacept 160 mg (or 2.2 mg/kg in pediatric participants) SC injections once weekly.
干预措施: Rilonacept (Drug)
Placebo
RI period: single-blind rilonacept 320 mg (or 4.4 mg/kg in pediatric participants) SC, followed by 160 mg (or 2.2 mg/kg in pediatric participants) injections once weekly.
RW period: eligible participants randomized to 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 NRS and have 1 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 participants]) irrespective of randomized treatment assignment and as soon as at least 5 days have passed since the last study drug injection.
LTE period: open-label administration of rilonacept 160 mg (or 2.2 mg/kg in pediatric participants) SC injections once weekly.
干预措施: Placebo (Drug)
结局指标
主要结局
Time to Pericarditis Recurrence in the RW Period
时间窗: RW Period (mean 24.8 weeks)
Time to pericarditis recurrence (from randomization to 1st recurrence). Kaplan-Meier. Clinical Events Committee (CEC)-confirmed recurrences used for primary analysis. Recurrence defined as recurrence typical pericarditis pain with supportive objective evidence. CEC-adjudicated recurrences defined as:1) Re-appearance/worsening pericarditis pain (1 NRS ≥ 4) AND elevated CRP (≥1.0 mg/dL) on same day/separated by ≤ 7 days OR 2) Re-appearance/worsening pericarditis pain (1 NRS ≥ 4) AND abnormal CRP (\> 0.5 mg/dL) on same day/separated by ≤ 7 days AND 1 supportive evidence OR 3) Re-appearance/worsening pericarditis pain (no NRS ≥ 4) AND elevated CRP (≥ 1.0 mg/dL) not attributable to other causes AND 1 supportive evidence. Supportive evidence: White blood cell count \> upper limit normal, fever \> 38C, pericardial rub, electrocardiogram changes consistent with pericarditis, new/worsening pericardial effusion (echocardiogram), new/worsening pericardial inflammation (magnetic resonance imaging).
次要结局
- Major Secondary Efficacy Endpoint: Percentage of Participants Who Maintained Clinical Response at Week 16 of the RW Period(RW Period Week 16)
- 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(RW Period Week 16)
- Major Secondary Efficacy Endpoint: Percentage of Days With No or Minimal Pericarditis Pain at Week 16 of the RW Period(RW Period Week 16)
- Percentage of Participants Who Maintained Clinical Response at Week 24 of the RW Period(RW Period Week 24)
- Percentage of Participants Who Maintained Clinical Response at Week 8 of the RW Period(RW Period Week 8)
- Percentage of Days With No or Minimal Pericarditis Pain at Week 24 of the RW Period(RW Period Week 24)
- Percentage of Participants With Absent or Minimal Pericarditis Symptoms at Week 24 of the RW Period Based on the PGIPS(RW Period Week 24)
- Percentage of Days With No or Minimal Pericarditis Pain at Week 8 of the RW Period(RW Period Week 8)
- Percentage of Participants Without Pericarditis Recurrence in the First 24 Weeks of the RW Period(up to 24 weeks in the RW Period)
- Time to Pericarditis Pain ≥ 4 on the NRS in the RW Period(RW Period (mean 24.8 weeks))
- Time to New or Worsening Pericardial Effusion on Echocardiography (ECHO) in the RW Period(RW Period (mean 24.8 weeks))
- Percentage of Participants With Absent or Minimal Pericarditis Symptoms at Week 8 of the RW Period Based on the PGIPS(RW Period Week 8)
- Time to CRP Level ≥ 1 mg/dL in the RW Period(RW Period (mean 24.8 weeks))
- Time to Pericardial Rub in the RW Period(RW Period (mean 24.8 weeks))
- Time to Widespread ST-segment Elevation or PR-segment Depression on Electrocardiogram (ECG) in the RW Period(RW Period (mean 24.8 weeks))
- Number of Participants in ECHO Pericardial Effusion Size Categories at RW Period Baseline, RW Week 24 and Worst Post-baseline in the RW Period(RW Period Baseline, RW Period Week 24, RW Period (mean 24.8 weeks))
- Change From RW Period Baseline Over Time in CRP Levels in RW Period(RW Period Baseline, RW Period Weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 56)
- Change From RW Period Baseline Over Time in Weekly Average of Pericarditis Pain in the RW Period(RW Period Baseline, RW Period Weeks 1-50, 54)
- Percentage of Participants With Absent or Minimal Pericarditis Symptoms Over Time After RW Period Week 24 Based on the PGIPS(RW Period Weeks 32, 40, 48, 56)
- 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)(RW Period Baseline, RW Period Weeks 8, 16, 24, 32, 40, 48, 56)
- Change From RW Period Baseline in Short Form-36 (SF-36) Physical and Mental Component Scores at RW Period Week 24(RW Period Baseline, RW Period Week 24)
- Change From RW Baseline in SF-36 Individual Scores at RW Period Week 24(RW Period Baseline, RW Period Week 24)
- Change From RW Period Baseline in the Short Form Health Survey-6 Domains (SF-6D) Utility Index Score at RW Period Week 24(RW Period Baseline, RW Period Week 24)
- Change From RW Period Baseline in 5-level EuroQoL-5 Dimensions (EQ-5D-5L) Individual Scores and Index Value to RW Period Week 24(RW Period Baseline, RW Period Week 24)
- Change From RW Period Baseline in Insomnia Severity Index (ISI) Total Score at RW Period Week 24(RW Period Baseline, RW Period Week 24)
- Change in ISI Categories From RW Period Baseline to RW Period Week 24(RW Period Baseline (BL), RW Period Week (Wk) 24)
- Percentage of Participants With Pericardial Delayed Hyperenhancement, Myocardial Delayed Hyperenhancement or Pericardial Effusion on Magnetic Resonance Imaging (MRI) at RW Week 24(RW Period Week 24)
- Percentage of Participants Using Oral Rescue Therapy (ORT), Corticosteroid, or Bailout Rilonacept for Pericarditis Every 4 Weeks Cumulatively in the RW Period(RW Period (mean 24.8 weeks))
- Percentage of Participants Using ORT for Pericarditis in the First 24 Weeks of RW Period(RW Period (up to Week 24))
- Time From First Dose to Rilonacept Monotherapy in RI Period(RI Period (up to 12 weeks))
- Time From First Dose to Pain Response in the RI Period(RI Period (up to 12 weeks))
- Time From First Dose to CRP Normalization in the RI Period(RI Period (up to 12 weeks))
- Time From First Dose to Treatment Response in RI Period(RI Period (up to 12 weeks))
- Percentage of Participants Achieving Clinical Response at RI Period Week 12(RI Period Week 12)
- Percentage of Participants With CRP Normalization at RI Period Week 12(RI Period Week 12)
- Change From Baseline Over Time in Weekly Average of Pericarditis Pain NRS Score in RI Period(RI Period Baseline, RI Period Weeks 1-12)
- Change From Baseline Over Time in CRP Levels in RI Period(RI Period Baseline, RI Period Day 4, Weeks 1, 2, 4, 6, 12)
- Percentage of Participants With Resolution of Pericarditis-Related ECHO and ECG Abnormalities at Week 12 of the RI Period(RI Period Baseline, RI Period Week 12)
- Percentage of Days With No or Minimal Pain in the RI Period While on Treatment(RI Period (up to Week 12))
- Percentage of Participants With No or Minimal Pericarditis Symptoms Over Time in the RI Period, Based on the PGIPS(RI Period Baseline, RI Period Weeks 6 and 12)
- Percentage of Participants With No or Minimal Pericarditis Activity Over Time in the RI Period, Based on the PGA-PA(RI Period Baseline, RI Period Weeks 6 and 12)
- Annualized Rate of Pericarditis Recurrence in the Long-Term Extension (LTE) Period Based on Investigator's Assessment (Based on Investigators' Judgement)(LTE Period, through LTE Follow up (up to Week 48))
- Percentage of Participants With Absent or Minimal Pericarditis Activity In the LTE Period Based on the PGIPS(LTE Baseline, LTE Month 12, LTE Month 24)
- Change From LTE Baseline in ISI Total Score(LTE Baseline, LTE Week 24)
- Change From RI Period Baseline in the SF-36 Domain Scores and Physical and Mental Scores to RI Period Week 12(RI Period Baseline, RI Period Week 12)
- Change From RI Period Baseline in SF-6D Scores at RI Period Week 12(RI Period Baseline, RI Period Week 12)
- Change From RI Period Baseline in ISI Total Score at RI Period Week 12(RI Period Baseline, RI Period Week 12)
- Change From RI Period Baseline in 5-level EuroQoL-5 Dimensions (EQ-5D-5L) Individual Scores and Index Value at RI Period Week 12(RI Period Baseline, RI Period Week 12)
- Change in ISI Categories From RI Period Baseline to RI Period Week 12(RI Period Baseline (BL), RI Period Week (Wk) 12)
- Number of Participants Who Were Off Background Pericarditis Medication on or Before RI Period Weeks 4, 8, 10, and 12(RI Period Baseline, RI Period Weeks 4, 8, 10, 12)
- Percentage of Participants With Absent or Minimal Pericarditis Activity Over Time in the LTE Period Based on the PGA-PA(LTE Baseline, LTE Week 12, LTE Week 24)
- Change From LTE Baseline in the SF-36 Domain Scores and Physical and Mental Scores(LTE Baseline, LTE Week 24)
- Change From LTE Baseline in Pericardial Signs in MRI(LTE Baseline, LTE Week 24)
- Change From LTE Baseline Over Time in CRP Levels(LTE Baseline, LTE Week 12, LTE Week 24)
- Change From LTE Baseline in SF-6D Health Utility Index Score(LTE Baseline, LTE Week 24)
- Change From LTE Baseline in EQ-5D-5L Individual Scores and Index Value(LTE Baseline, LTE Week 24)
- Change From LTE Baseline in ISI Categories(LTE Baseline (BL), LTE Week 24)
- Change From LTE Baseline in Pericardial Signs in ECG(LTE Baseline, LTE Week 24)
- Percentage of Participants Requiring Addition of Standard of Care (SOC) Pericarditis Therapy Every 4 Weeks Cumulatively in the LTE Period(LTE Period, through LTE Follow up (up to Week 24))
- Change From LTE Baseline in Pericardial Signs in ECHO(LTE Baseline, LTE Week 24)
- Number of Participants With Pericardial Delayed Hyperenhancement, Myocardial Delayed Hyperenhancement or Pericardial Effusion at LTE Period Week 24(LTE Week 24)
- Annualized Rate of Pericarditis Recurrence in LTE Periods Based on Investigator's Assessment(LTE Period, through LTE Follow up (up to Week 48))
- Annualized Rate of Pericarditis Recurrence in RW Period Based on CEC Adjudication(RW Period (mean 24.8 weeks))