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Rilonacept for Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00288704
Recruitment Status : Completed
First Posted : February 8, 2006
Results First Posted : November 13, 2009
Last Update Posted : December 6, 2011
Sponsor:
Information provided by (Responsible Party):
Regeneron Pharmaceuticals

Study Description
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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.

Condition or disease Intervention/treatment Phase
Familial Cold Autoinflammatory Syndrome (FCAS) Familial Cold Urticaria Muckle-Wells Syndrome (MWS) Genetic Diseases, Inborn Drug: rilonacept 160 mg Drug: Placebo Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : December 2005
Actual Primary Completion Date : June 2008
Actual Study Completion Date : August 2008

Resource links provided by the National Library of Medicine

Drug Information available for: Rilonacept

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Placebo
Some subjects were treated with Placebo in the Study. This occurred (if subject randomized to Placebo) either during the first 6 weeks of the study or during the randomized withdrawal (weeks 15-24).
 Drug: Placebo
Subcutaneous injection of Placebo occurred during first 6 weeks of the study or during randomized withdrawal (weeks 15-24). On Day 1, subjects received two placebo injections.
Active Comparator: rilonacept 160 mg

If randomized to rilonacept, subjects received this treatment during the first 6 weeks of the study or during the randomized withdrawal (weeks 15-24). All subjects received rilonacept 160 mg during weeks 6-14 (between Parts A and B).

Study drug is administered as a 2.0 mL subcutaneous injection once a week. At baseline (week 0) subjects receive a loading dose of rilonacept 320 mg.

 Drug: rilonacept 160 mg
Rilonacept was given by subcutaneous injection. It was administered weekly at the dose of 160mg. On Day 1, subjects received two injections of rilonacept (for a total of 320 mg).
Other Name: Rilonacept
Open-Label rilonacept 160 mg

After week 24 (the end of part B), all subjects went into weekly dosing of open label rilonacept 160 mg. During this phase of the study, adolescents aged 7 and above were entered into the study and rilonacept was dosed as 2.2 mg/kg injections, up to 160 mg, per week.

Study drug is administered as a 2.0 mL subcutaneous injection once a week.

 Drug: rilonacept 160 mg
Rilonacept was given by subcutaneous injection. It was administered weekly at the dose of 160mg. No loading dose was given for subjects who entered directly into the open-label.


Outcome Measures
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Primary Outcome Measures :
  1. Change From Baseline to Week-6 (Part A) Endpoint in Mean Key Symptom Score (KSS) [ Time Frame: Baseline (Days -21 to -1) and Week 6 (Days 21-42) ]

    The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was averaged over two 21-day daily reporting periods (the 3 weeks prior to both baseline and week 6). In part A, a negative change in mean values indicated improvement under treatment with rilonacept in symptoms.

    The DHAF was used because it is a validated instrument to collect subject's self-reported responses.


  2. Mean Change in Key Symptom Score (KSS) From Week 15 to Week 24 (During the Randomized Withdrawal Phase or Part B) [ Time Frame: Week 15 through Week 24 (randomized withdrawal) ]

    The mean Key Symptom Score (KSS --from the validated, patient-administered DHAF) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).

    Subjects all received rilonacept 160 mg from week 6 through week 14. At week 15, subjects were re-randomized in a 1:1 ratio between Placebo and rilonacept 160 mg. Subjects baseline period was the 21-day period prior to week 15 randomization.

    A positive score indicated a worsening of symptoms versus an active treatment rilonacept baseline period.



Other Outcome Measures:
  1. Mean Change From Baseline to Endpoint (Week 6) in Number of Disease Flare Days Per Patient [ Time Frame: Baseline to Week 6 (Part A) ]

    A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The KSS was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue). KSS was calculated for 21 Day Periods at baseline and at the endpoint (from Weeks 3 - 6). The difference in the number of flares between the two periods was averaged for all subjects.

    The DHAF was used because it is a validated instrument to collect subject's self-reported responses. It was the basis for the KSS and the flare day count.


  2. Change From Baseline to Endpoint (Week 6) in Physician's Global Assessment [ Time Frame: Baseline to Week 6 (Part A) ]
    The Physician's Global Assessment was an evaluation at each visit on a scale of 0=no disease activity to 10=severe disease activity. A negative value in change in Physician's Global Assessment is indicative of an improvement.

  3. Mean Change From Baseline to Endpoint (Week 6) in Patient's Global Assessment [ Time Frame: Baseline to Week 6 (Part A) ]
    The Patient's Global Assessment was a question on the Daily Health Assessment Form "Considering all the ways that Familial Cold Autoinflmatory Syndrome (FCAS) /Muckle-Wells Syndrome (MWS) affects you, please rate how you are doing based on the following scale" 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement.

  4. Median Change From Baseline to Week 6 (Part A) Endpoint in C-Reactive Protein (mg/L) [ Time Frame: Baseline to Endpoint of Part A ]
    An abnormal value for CRP was considered > 8.4 mg/L.

  5. Median Change From Baseline to Week 6 (Part A) Endpoint in Serum Amyloid A (mg/L) [ Time Frame: Baseline to Endpoint of Part A ]
    An abnormal value for SAA was considered > 6.4 mg/L.

  6. Number of Subjects With at Least 30% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) [ Time Frame: Baseline to Endpoint (Week 6) ]
    The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).

  7. Number of Subjects With at Least 50% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) [ Time Frame: Baseline to Week 6 (Part A) ]
    The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).

  8. Number of Subjects With at Least 75% Improvement in Key Symptoms Scores (KSS) From Baseline to Endpoint (Week 6) [ Time Frame: Baseline to Week 6 (Part A) ]
    The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).

  9. Summary of Mean Change From Baseline to Open-Label Extension Week 72 in KSS [ Time Frame: From Baseline (week 0) to OLE Week 72 ]

    OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis.

    The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).

    A negative change in mean values indicated improvement in symptoms.


  10. Change From Baseline to Open-Label Extension Week 72 in Patient's Global Assessment [ Time Frame: From Baseline (Week 0) to OLE Week 72 ]

    The Patient's Global Assessment was a question on the Daily Health Assessment Form "Considering all the ways that FCAS/MWS affects you, please rate how you are doing based on the following scale" 0=very well to 10=very poor. A negative value in change in Patient's Global Assessment is indicative of an improvement.

    OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis.


  11. Change From Baseline to Open-Label Extension Week 72 in Number of Disease Flare Days [ Time Frame: From Baseline (Week 0) to OLE Week 72 ]

    OLE Week 72 was the last timepoint at which efficacy was measured in the study. 56 of the 101 OLE subjects were included in the analysis.

    A Disease flare day was any day where the mean Key Symptom Score (KSS) was greater than 3. The mean Key Symptom Score (KSS --from the validated, patient-administered Daily Health Assessment Form(DHAF)) was the average on a 0-10 scale (0=None, 10=Very Severe) of 5 separate scales -- rash, feeling of fever/chills, joint pain, eye redness/pain, and fatigue).



Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   7 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00288704


Locations
Layout table for location information
United States, Arkansas
Little Rock, Arkansas, United States, 72204
United States, California
Palm Desert, California, United States, 92260
Upland, California, United States, 91786
United States, Florida
Jacksonville, Florida, United States, 32216
Stuart, Florida, United States, 34996
United States, Georgia
Atlanta, Georgia, United States, 30342
Columbus, Georgia, United States, 31904
United States, Illinois
Aurora, Illinois, United States, 60504
United States, Kentucky
Louisville, Kentucky, United States, 40215
United States, Louisiana
Shreveport, Louisiana, United States, 71105
United States, Michigan
Chesterfield, Michigan, United States, 48047
United States, Missouri
St. Louis, Missouri, United States, 63141
United States, New York
New York, New York, United States, 10023
United States, North Carolina
Raleigh, North Carolina, United States, 27609
United States, Ohio
Cincinnati, Ohio, United States, 45236
United States, Pennsylvania
Duncansville, Pennsylvania, United States, 16635
United States, South Carolina
Columbia, South Carolina, United States, 29201
Greer, South Carolina, United States, 29651
United States, Tennessee
Chattanooga, Tennessee, United States, 37403
United States, Texas
Dallas, Texas, United States, 75235
Waco, Texas, United States, 76712
United States, Utah
Cedar City, Utah, United States, 84720
United States, Virginia
Forest, Virginia, United States, 24551
United States, Washington
Lakewood, Washington, United States, 98499
Sponsors and Collaborators
Regeneron Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Robert Evans, PharmD. Regeneron Pharmaceuticals
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Layout table for additonal information
Responsible Party: Regeneron Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00288704    
Other Study ID Numbers: IL1T-AI-0505
First Posted: February 8, 2006    Key Record Dates
Results First Posted: November 13, 2009
Last Update Posted: December 6, 2011
Last Verified: December 2011
Keywords provided by Regeneron Pharmaceuticals:
Familial Cold Autoinflammatory Syndrome (FCAS)
Muckle-Wells Syndrome (MWS)
CIAS1
NLRP-3
 PYPAF1
Cryopyrin
CAPS
Interleukin-1
Additional relevant MeSH terms:
Layout table for MeSH terms
Genetic Diseases, Inborn
Cryopyrin-Associated Periodic Syndromes
Urticaria
Syndrome
Disease
Pathologic Processes
Skin Diseases, Vascular
Skin Diseases
 Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Hereditary Autoinflammatory Diseases
Skin Diseases, Genetic
Rilonacept
Anti-Inflammatory Agents