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Rilonacept for Treatment of Familial Mediterranean Fever (FMF)

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: NCT00582907
Recruitment Status : Completed
First Posted : December 28, 2007
Results First Posted : October 31, 2012
Last Update Posted : February 11, 2013
Sponsor:
Information provided by (Responsible Party):
Philip Hashkes, Shaare Zedek Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Familial Mediterranean Fever
Interventions Drug: Rilonacept
Drug: Placebo
Enrollment 14
Recruitment Details Participants were recruited from October 2008 until February 2010. The study was conducted in 6 clinics in the United States in FMF clinics or clinics in regions where a higher prevalence of FMF is expected based on local population ethnicity.
Pre-assignment Details Participants had an estimated mean ≥1 FMF attack/month for 3 months before screening, and ≥1 attack/month during screening/run-in period. There was a wash-out period of other biologic medications for those using them at screening. 2 subjects withdrew consent, one lacked mutations and one had insufficient attacks and were excluded before baseline.
Arm/Group Title Rilonacept-Placebo-Rilonacept-Placebo Rilonacept-Placebo-Placebo-Rilonacept Placebo-Rilonacept-Placebo-Rilonacept Placebo-Rilonacept-Rilonacept-Placebo
Hide Arm/Group Description Patients received in the randomized sequence above two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine. Overall study was 12 months. Patients received in the randomized sequence above two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine. Overall study was 12 months. Patients received in the randomized sequence above two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine. Patients received in the randomized sequence above two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.
Period Title: 1st Course
Started 4 3 3 4
Completed 3 [1] 3 3 3 [2]
Not Completed 1 0 0 1
Reason Not Completed
Withdrawal by Subject             1             0             0             0
Lost to Follow-up             0             0             0             1
[1]
1 left after 1st course (transportation issues)
[2]
Patient lost to follow-up towards end of 1st course
Period Title: 2nd Course
Started 3 3 3 3
Completed 2 3 3 3
Not Completed 1 0 0 0
Reason Not Completed
Lack of Efficacy             1             0             0             0
Period Title: 3rd Course
Started 2 3 3 3
Completed 2 3 3 3
Not Completed 0 0 0 0
Period Title: 4th Course
Started 2 3 3 3
Completed 2 3 3 3
Not Completed 0 0 0 0
Arm/Group Title All Patients Received Both Rilonacept and Placebo
Hide Arm/Group Description

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Baseline Participants 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
<=18 years
4
  28.6%
Between 18 and 65 years
10
  71.4%
>=65 years
0
   0.0%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 14 participants
24.4  (11.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 14 participants
Female
6
  42.9%
Male
8
  57.1%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 14 participants
14
1.Primary Outcome
Title To Assess the Efficacy of Rilonacept in Decreasing the Number of Acute FMF Attacks.
Hide Description Difference in number of attacks per treatment month between rilonacept and placebo
Time Frame attacks were assessed at the end of each 3 month treatment course (overall up to 6 month of rilonacept and 6 months of placebo, each)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who received at least one complete treatment course and reported attacks were analyzed for the primary outcome measure.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 12
Median (Inter-Quartile Range)
Unit of Measure: number of attacks per month
0.77
(0.18 to 1.20)
2.00
(0.90 to 2.40)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Based upon FMF colchicine controlled studies showing an ~80% decrease in attacks, we estimated, based on baseline attacks every 4 weeks, there would be a difference of 0.5 attacks per month between rilonacept and placebo. With a two-sided 5% significance level and power of 80% we aimed for 14 evaluable participants who completed at least 2 treatment courses. The null hypothesis is that there would be no significant differences in the number of attacks between use of rilonacept and placebo.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.027
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio, log
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-3.4 to -0.1
Parameter Dispersion
Type: Standard Deviation
Value: 0.78
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments This analysis was done by Bayesian Statistics using a non-informative (neutral) prior (log normal distribution mean 9 [SD 10]). The null hypothesis was that the rilonacept/placebo FMF odds ratio of attacks was 1.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Bayesian modeling
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.59
Confidence Interval 95%
0.39 to 0.85
Parameter Dispersion
Type: Standard Deviation
Value: 0.12
Estimation Comments Attacks while receiving rilonacept is the numerator and attacks while receiving placebo is the denominator. In Bayesian statistics credible interval equals confidence interval.
2.Primary Outcome
Title To Determine if There is a Medically Important Difference Between the Safety Profiles of Rilonacept vs. Placebo.
Hide Description Differences in adverse events (AEs) between rilonacept and placebo per patient-month of treatment. We separately analyzed injection site reactions and infectious adverse events. Other adverse events were too small in number to analyze. The upper table (and first statistical analysis) regards injection site reactions and lower table (and second statistical analysis) regards infections.
Time Frame 12 months of entire study length
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis included all participants who received at least one dose of medication.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 14
Median (Inter-Quartile Range)
Unit of Measure: AEs per patient-month of treatment
Injection site reactions
1
(0 to 1.04)
0
(0 to 0.36)
Infections
0
(0 to 0.12)
0.18
(0 to 0.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There were no significant differences between rilonacept and placebo in the occurence of injection site reactions. No power calculations for this outcome.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.047
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-4 to 0
Parameter Dispersion
Type: Standard Deviation
Value: 1.26
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There were no significant differences between rilonacept and placebo in the occurence of infections. No power calculations for this outcome.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.13
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-0.56 to 0.17
Estimation Comments [Not Specified]
3.Secondary Outcome
Title To Determine the Difference in the Length of Attacks During Treatment With Rilonacept vs. Placebo.
Hide Description This outcome was the difference in days in the length of attacks between rilonacept and placebo.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received any treatment and had recorded attacks
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 14
Median (95% Confidence Interval)
Unit of Measure: Number of days
2.8
(1 to 3.3)
3.2
(2.7 to 4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There were no significant differences in the length of attacks during rilonacept vs. placebo treatment courses. Since this was a secondary outcome there were no power calculations performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -1.2
Confidence Interval 95%
-2.4 to 0.5
Parameter Dispersion
Type: Standard Deviation
Value: 0.5
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Treatment Courses Without FMF Attacks in Rilonacept Courses as Compared to Placebo Courses.
Hide Description The percentage of rilonacept and placebo treatment courses without FMF attacks.
Time Frame Each treatment course of up to 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who at least one complete treatment course.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 13
Measure Type: Number
Unit of Measure: Percentage of courses
29 0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept
Comments Null hypothesis: There are no significant differences in the number of treatment courses without attacks between rilonacept and placebo. As a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.004
Comments [Not Specified]
Method McNemar
Comments [Not Specified]
Method of Estimation Estimation Parameter Differences in percent of courses
Estimated Value 29
Estimation Comments [Not Specified]
5.Secondary Outcome
Title To Determine the Proportion of Courses in Which Subjects Attained at Least a 50% Decrease in Acute FMF Attacks During Rilonacept Courses as Compared to Placebo Courses.
Hide Description Differences between rilonacept and placebo in the percentage of courses that attained at least a 50% decrease in FMF attacks when compared to attacks in the screening period.
Time Frame Up to 3 months for each treatment course
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed at least one complete treatment course.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 13
Measure Type: Number
Unit of Measure: Percentage of courses
75 35
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept
Comments Null hypothesis: There are no significant differences in the number of treatment courses attaining at least a 50% decrease in attacks when compared to baseline between rilonacept and placebo courses.Since this was a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.006
Comments [Not Specified]
Method McNemar
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percent of courses
Estimated Value 40
Estimation Comments [Not Specified]
6.Secondary Outcome
Title To Determine Differences in the Time to the Development of Attacks Between the Treatment Arms (Rilonacept vs. Placebo).
Hide Description In a survival analysis we measured the difference (in days) until the development of the first and second attack within a treatment course of up to 3 months and examined differences in this parameter between rilonacept and placebo. Data regarding the development of the second attack are reported below. In regards to the first attack there were no significant differences between rilonacept and placebo (20 days (7.5,>90)for rilonacept; 15 (8,32) for placebo, P=0.066).
Time Frame 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received an intervention and developed an attack were analyzed.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 13 14
Median (Inter-Quartile Range)
Unit of Measure: days until second attack
90
(25 to 90)
36
(15 to 68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There were no significant differences between rilonacept and placebo in the number of days from the start of the treatment course until the development of the a second attack.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.009
Comments [Not Specified]
Method Kaplan-Meier survival analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Log Rank
Estimated Value 0.009
Estimation Comments [Not Specified]
7.Secondary Outcome
Title To Determine the Differences in the Erythrocyte Sedimentation Rate Between the Treatment Arms (Rilonacept vs. Placebo).
Hide Description Erythrocyte sedimentation rate - ESR (mm/h)
Time Frame 3 months (each treatment course, overall 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who completed at least one treatment course of both rilonacept and placebo.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: mm/h
5.8
(2 to 16)
14
(7 to 19)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no significant differences in the erythrocyte sedimentation rate between rilonacept and placebo. As a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.156
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 6.5
Confidence Interval (2-Sided) 95%
-0.5 to 12.5
Estimation Comments [Not Specified]
8.Secondary Outcome
Title To Determine the Differences in C-Reactive Protein Between the Treatment Arms (Rilonacept vs. Placebo)
Hide Description Differences between the treatment courses in the C-Reactive Protein levels mg/L
Time Frame 3 months (each treatment course, overall 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who received at least one course each of rilonacept and placebo
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: mg/L
2
(2 to 4)
4
(2 to 9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no differences in the C-reactive protein levels between the treatment courses. Since this was a secondary outcome measure no power calculations were performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.22
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.03 to 0.29
Estimation Comments [Not Specified]
9.Secondary Outcome
Title To Determine the Differences in the Platelet Count Between the Treatment Arms (Rilonacept vs. Placebo)
Hide Description The difference between the treatment arms in the platelet count X 10 to the power of 9
Time Frame 3 months (each treatment course, overall 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The number of patients who received at least one course each of rilonacept and placebo
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: cell count X10 to the power of 9
262
(246 to 318)
334
(305 to 352)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There were no differences between the platelet count between the rilonacept and placebo courses. Since this was a secondary outcome no power calculations were performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.078
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 29.4
Confidence Interval (2-Sided) 95%
0.4 to 78.1
Estimation Comments [Not Specified]
10.Secondary Outcome
Title To Determine the Differences in the Fibrinogen Levels Between the Treatment Arms (Rilonacept vs. Placebo)
Hide Description The differences between treatment arms in the fibrinogen level (micromol/L)
Time Frame 3 months (each treatment course, overall 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who received at least one course each of rilonacept and placebo
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: micromol/L
6.56
(6.41 to 9.70)
9.56
(9.26 to 10.17)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no differences between the treatment arms in the fibrinogen level. Since this was a secondary outcome no power calculations were performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.063
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 108
Confidence Interval (2-Sided) 95%
6.5 to 139.5
Estimation Comments [Not Specified]
11.Secondary Outcome
Title To Determine the Differences in Serum Amyloid A Levels Between the Treatment Arms (Rilonacept vs. Placebo)
Hide Description The difference between the treatment arms in serum amyloid A levels (mg/L)
Time Frame 3 months (each treatment course, overall 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who received at least one course each of rilonacept and placebo
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: mg/L
13
(0 to 40)
15
(0 to 192)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no differences between the treatment arms in the serum amyloid A levels. Since this was a secondary outcome no power calculations were performed.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.50
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-4 to 0
Estimation Comments [Not Specified]
12.Secondary Outcome
Title To Determine the Differences in the Quality of Life Between the Treatment Arms (Rilonacept vs. Placebo).
Hide Description Differences in the health-related quality of life (HRQOL) during treatment with rilonacept vs. placebo. HRQOl was measured by the Childhood Health Questionnaire which was adopted also for adults. There are 2 summary scores: 1. Physical summary score. 2. Psychosocial summary score. The data reported below in the upper table is the physical summary composite score and in the lower table the psychosocial summary composite score. Scores were from 0-100 (higher is better) with a score of 50 representing the mean of the normal population.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least one treatment course of rilonacept and placebo.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: Composite HRQOL summary score
Physical HRQOL summary composite score
33
(25.8 to 38.1)
20.3
(10.5 to 32.7)
Psychosocial HRQOL summary composite score
53.3
(48.6 to 57.2)
49.8
(42.5 to 59)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no significant differences in the physical health-related quality of life between rilonacept and placebo. As a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.021
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value -6.5
Confidence Interval (2-Sided) 95%
-11.1 to -2.3
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.42
Comments [Not Specified]
Method Signed Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value -4.2
Confidence Interval (2-Sided) 95%
-6.8 to 3.9
Estimation Comments [Not Specified]
13.Secondary Outcome
Title To Determine the Differences in the FMF Severity Score of the Subjects Between the Treatment Arms (Rilonacept vs. Placebo).
Hide Description Differences in the Armenian Evaluation Score between rilonacept and placebo courses. The Armenian Evaluation Score is a composite score of disease severity based on the frequency, duration and character of attacks (degree of fever and severity of serositis). It was adapted to calculate a score for a 3-month treatment course. The lowest (best) score is 0 and higher values are worse. In theory there is no upper limit to the scale. The total score is reported (there are no subscales).
Time Frame overall 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least one course each of placebo and rilonacept.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
5.5
(3 to 13)
11
(7.8 to 12.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no significant differences in the FMF Armenian Evaluation (severity) Score between rilonacept and placebo. As a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.136
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-2.3 to 9.8
Estimation Comments [Not Specified]
14.Secondary Outcome
Title To Determine the Differences in the Proportion of Time Subjects Received Rilonacept vs Placebo
Hide Description The proportion of time within the trial that participants received rilonacept as opposed to placebo. The reason for this outcome is that participants who had at least 2 attacks within an individual treatment course were able to "escape" in a blinded manner to the other treatment arm until the end of that treatment course and then resume the original randomization sequence. Thus participants may have been treated for a longer time with one treatment arm or the other.
Time Frame 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who received at least one treatment course of both rilonacept and placebo.
Arm/Group Title Rilonacept Placebo
Hide Arm/Group Description:

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Overall length of study for each participant is 12 months.

Overall Number of Participants Analyzed 12 12
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of time treated
52.5
(50.5 to 70.5)
47.5
(29.5 to 49.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rilonacept, Placebo
Comments Null hypothesis: There are no significant differences in the proportion of time participants were treated with rilonacept and placebo. As a secondary measure there were no power calculations.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.089
Comments [Not Specified]
Method Signed rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value -5
Confidence Interval (2-Sided) 95%
-15 to -1
Estimation Comments [Not Specified]
Time Frame 1 year
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Rilonacept
Hide Arm/Group Description

Adverse events during placebo treatment. Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

Adverse events during rilonacept treatment. Patients received in randomized sequences two 3-month courses of rilonacept (IL-1 Trap),2.2 mg/kg/wk (max 160 mg) by SC injection and two 3-month courses of equal volume placebo by weekly SC injection. This was in addition to the pre-study dose of colchicine.

Patients were randomized to 4 treatment sequences:

1. rilonacept- placebo-rilonacept-placebo; 2. placebo-rilonacept-placebo-rilonacept 3. rilonacept- placebo-placebo-rilonacept and 4. placebo-rilonacept-rilonacept-placebo.

All-Cause Mortality
Placebo Rilonacept
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Rilonacept
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/14 (21.43%)      3/13 (23.08%)    
Immune system disorders     
Hospitalization for FMF attack  1  2/14 (14.29%)  3 2/13 (15.38%)  4
Infections and infestations     
Pneumonia  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Respiratory Infection  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo Rilonacept
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/14 (85.71%)      11/13 (84.62%)    
Ear and labyrinth disorders     
Sore throat  1  1/14 (7.14%)  1 1/13 (7.69%)  1
Nose bleed  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Eye disorders     
Photophobia  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Gastrointestinal disorders     
Loss of appetite  1  0/14 (0.00%)  0 1/13 (7.69%)  3
Nausea, vomiting  1  1/14 (7.14%)  1 1/13 (7.69%)  1
General disorders     
Hypertension  1  0/14 (0.00%)  0 1/13 (7.69%)  2
Heat and cold sensitivity  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Fatigue  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Infections and infestations     
Upper respiratory infection/Otitis  1  3/14 (21.43%)  3 0/13 (0.00%)  0
Sinusitis  1  1/14 (7.14%)  1 1/13 (7.69%)  1
Herpes labialis  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Herpes Zoster  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Epstein Barr virus  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Otitis  1  1/14 (7.14%)  1 1/13 (7.69%)  1
Bronchitis  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Influenza  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Facial skin infection  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Oral thrush  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Conjunctivitis  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Injury, poisoning and procedural complications     
Injection site reaction  1  5/14 (35.71%)  13 7/13 (53.85%)  53
Fracture - toe  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Abrasion  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Investigations     
Alanine aminotransferase (ALT) elevation  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Creatine Kinase (CPK) elevation  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Arthralgia/bone pain  1  1/14 (7.14%)  1 2/13 (15.38%)  2
Nervous system disorders     
Headaches  1  1/14 (7.14%)  1 1/13 (7.69%)  1
Vertigo  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Renal and urinary disorders     
Overactive bladder  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Respiratory, thoracic and mediastinal disorders     
Asthma attack  1  1/14 (7.14%)  1 1/13 (7.69%)  1
Skin and subcutaneous tissue disorders     
Facial edema  1  1/14 (7.14%)  1 0/13 (0.00%)  0
Alopecia  1  0/14 (0.00%)  0 1/13 (7.69%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
  1. Small sample size - accounted for in study design and analysis plan.
  2. Carry over/lag effect of rilonacept - sensitivity analysis of shifting course time frame showed similar results.
  3. Heterogeneity of FMF mutations
  4. Different age groups
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Philip Hashkes, MD, MSc
Organization: Shaare Zedek Medical Center/Cleveland Clinic
Phone: 972-2-6555307
Responsible Party: Philip Hashkes, Shaare Zedek Medical Center
ClinicalTrials.gov Identifier: NCT00582907     History of Changes
Obsolete Identifiers: NCT00767143
Other Study ID Numbers: 1R01FD003435-01 ( U.S. FDA Grant/Contract )
FDA 1RO1FD003435-01
First Submitted: December 19, 2007
First Posted: December 28, 2007
Results First Submitted: August 25, 2012
Results First Posted: October 31, 2012
Last Update Posted: February 11, 2013