Clinical trial NCT00288704: Rilonacept for Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS)
Official title: IL1T-AI-0505: A Multi-center, Double-Blind, Placebo-Controlled Study of the Safety, Tolerability, & Efficacy of Rilonacept in Subjects With Cryopyrin-Associated Periodic Syndromes (CAPS) Using Parallel Group & Randomized Withdrawal Designs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Familial Cold Autoinflammatory Syndrome (FCAS)
Familial Cold Urticaria
Muckle-Wells Syndrome (MWS)
Genetic Diseases, Inborn
Keywords: Familial Cold Autoinflammatory Syndrome (FCAS)
Muckle-Wells Syndrome (MWS)
CIAS1
NLRP-3
PYPAF1
Cryopyrin
CAPS
Interleukin-1
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2006-02-08
Enrollment: 104
Sex: ALL
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Inflammatory symptoms of Cryopyrin-Associated Periodic Syndrome (CAPS) are due to mutations in a the NLRP-3 gene (previously known as Cold Induced Autoinflammatory Syndrome-1 or CIAS1). These mutations result in the body's overproduction of interleukin-1 (IL-1), a protein that stimulates the inflammatory process. IL-1 Trap (rilonacept) was designed to bind to the interleukin-1 cytokine and prevent it from binding to its receptors in the body.

Detailed description: Primary Objective:

The primary objective of this study was to assess the effect of rilonacept on the clinical signs and symptoms of Cryopyrin-Associated Periodic Syndrome (CAPS) when used for chronic therapy as evaluated by the subjects themselves over time using a validated patient-reported outcomes tool.

Secondary Objective(s):

The secondary objectives were as follows:

* To determine the safety and tolerability of rilonacept in subjects with CAPS
* To assess the effect of rilonacept on laboratory measures of inflammation such as acute phase reactants

This was a multi-center, two-part, double-blind, placebo-controlled study (Parts A and B) designed to assess the efficacy, safety, and tolerability of weekly subcutaneous (SC) doses of 160 mg of rilonacept in adult subjects with active CAPS. These phases were followed by extended open-label phases. After written informed consent was obtained, subjects who met the protocol eligibility criteria were enrolled at one of 27 study sites in the United States. The study consisted of a 3-week screening period preceding Part A, a 6-week long double-blind, randomized phase of the study. All subjects were then treated with single-blind rilonacept for 9-weeks, followed by a subsequent 9-week, double-blind, withdrawal phase during which subjects were re-randomized to either rilonacept or placebo. Subjects then continued treatment in a 24-week open-label extension phase (OLE) and a further 112-week long-term open-label extension (LTOLE), during which all subjects received rilonacept and a 6-week post-treatment follow-up period. Amendments 4 and 6 allowed eligible adult and pediatric subjects aged 7 and above to enroll directly into the open-label phases of the trial.

For reporting purposes, the 24-week OLE and the 112-week LTOLE was considered one Open Label Extension (OLE) phase. This occurred after the 24-week double blind (Parts A and B ) phase. In other words, OLE Week 1 corresponded to the week 25 in the study.

OLE Week 72 was the final timepoint where efficacy was measured. Safety continued after that timepoint until the end of the study.

Eligibility criteria: Inclusion Criteria:

* Double-blind phases: adults age 18 and above; Open-label extension: Adults and children aged 7 years and older.
* Was diagnosed with Familial Cold Auto-inflammatory Syndrome (FCAS) or Muckle-Wells Syndrome (MWS) based upon clinical signs and symptoms
* Had documented mutation in NLRP-3 (Cold Induced Autoinflammatory Syndrome-1 or CIAS1) in subject or relative, and willingness to have a confirmatory genetic (Deoxyribonucleic acid or DNA) test (cheek swab).
* Was able to understand and comply with study procedures and was able to provide informed consent
* If female, was not currently pregnant and was willing to use contraception during the study

Exclusion Criteria:

* Had evidence of untreated tuberculosis or other conditions/therapies that made the subject inappropriate for this study.

Primary outcomes:
measure: Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS)
timeFrame: Baseline (Days -21 to -1) and Week 6 (Days 21-42)
measure: Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B)
timeFrame: Week 15 through Week 24 (randomized withdrawal)
Secondary outcomes:
Other outcomes:
measure: Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient
timeFrame: Baseline to Week 6 (Part A)
measure: Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment
timeFrame: Baseline to Week 6 (Part A)
measure: Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment
timeFrame: Baseline to Week 6 (Part A)
measure: Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L)
timeFrame: Baseline to Endpoint of Part A
measure: Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L)
timeFrame: Baseline to Endpoint of Part A
measure: Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
timeFrame: Baseline to Endpoint (Week 6)
measure: Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
timeFrame: Baseline to Week 6 (Part A)
measure: Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6)
timeFrame: Baseline to Week 6 (Part A)
measure: Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS
timeFrame: From Baseline (week 0) to OLE Week 72
measure: Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment
timeFrame: From Baseline (Week 0) to OLE Week 72
measure: Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days
timeFrame: From Baseline (Week 0) to OLE Week 72
Locations:
city: Little Rock
country: United States
state: Arkansas
city: Palm Desert
country: United States
state: California
city: Upland
country: United States
state: California
city: Jacksonville
country: United States
state: Florida
city: Stuart
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Columbus
country: United States
state: Georgia
city: Aurora
country: United States
state: Illinois
city: Louisville
country: United States
state: Kentucky
city: Shreveport
country: United States
state: Louisiana
city: Chesterfield
country: United States
state: Michigan
city: St. Louis
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: Raleigh
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Duncansville
country: United States
state: Pennsylvania
city: Columbia
country: United States
state: South Carolina
city: Greer
country: United States
state: South Carolina
city: Chattanooga
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Waco
country: United States
state: Texas
city: Cedar City
country: United States
state: Utah
city: Forest
country: United States
state: Virginia
city: Lakewood
country: United States
state: Washington
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Robert Evans, PharmD.
role: STUDY_DIRECTOR
References:
citation: Hoffman HM, Throne ML, Amar NJ, Cartwright RC, Kivitz AJ, Soo Y, Weinstein SP. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin Ther. 2012 Oct;34(10):2091-103. doi: 10.1016/j.clinthera.2012.09.009. Epub 2012 Sep 29.
citation: Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, Weinstein SP, Belomestnov P, Yancopoulos GD, Stahl N, Mellis SJ. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008 Aug;58(8):2443-52. doi: 10.1002/art.23687.