Rilonacept for Treatment of Familial Mediterranean Fever (FMF)

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00582907
• Collaborator: (none)
• Enrollment: 14
• Locations: 5
• Arms: 2
• Duration (Months): 37
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Familial Mediterranean fever (FMF) is a genetic disease resulting in recurrent attacks of fever, abdominal pain, chest pain, arthritis and rash. There are 5-15% of patients who continue to have FMF attacks despite treatment with colchicine or who cannot tolerate colchicine. Currently there are no alternatives to colchicine. Pyrin, the protein that has a defect in FMF has an important role in the regulation of a molecule called interleukin (IL)-1 beta production and activity. This molecule is very important in the process of inflammation in FMF.

Therefore we propose to use IL-1 Trap (Rilonacept), a medication that binds and neutralizes IL-1.

We will enroll in this study 17 subjects from the age of 4 years, including adults with active FMF despite colchicine therapy. Subjects will receive in random order two 3-month courses of Rilonacept at 2.2 mg/kg (maximum 160 mg) by weekly subcutaneous injection and two 3-month courses of placebo injection. If patients have at least two FMF attacks during a treatment course they will be able to get if they choose the other treatment until the end of that treatment course. Our hypothesis is that Rilonacept will decrease the number of acute FMF attacks and will be safe to use. This study may confirm the importance of IL-1 in the cause of FMF.

Funding source - FDA Office of Orphan Products Development

Condition or Disease	Intervention/Treatment	Phase
Familial Mediterranean Fever	Drug: Rilonacept; Drug: Placebo	Phase 2

Detailed Description

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory genetic disorder resulting in recurrent attacks of fever, serositis, arthritis and rash. Late complications of untreated FMF include the development of renal amyloidosis. FMF is a rare orphan disease in the United States. Treatment with colchicine is effective in reducing the frequency of episodes in most patients and the development of amyloidosis in nearly all patients. However, there are still 5-15% of patients who continue to have acute FMF attacks despite colchicine therapy or are intolerant of colchicine, usually from gastrointestinal adverse effects. Currently there are no effective alternatives to colchicine. Pyrin, the mutated protein in FMF has an important role in the regulation of IL-1 beta production and activity. Mutations in pyrin result in increased IL-1 beta levels in mice and humans. IL-1 beta is an important pro-inflammatory cytokine. Thus, we hypothesize that inhibition of IL-1 will decrease acute attacks in patients with FMF. We propose to use IL-1 Trap (Rilonacept), a fusion protein consisting of human IL-1 cytokine receptor extracellular domains and the FC portion of human IgG1 that binds and neutralizes IL-1.

We will enroll 17 subjects from the age of 4 years, including adults, from multiple centers in the United States with active FMF (at least 1 attack per month) despite receiving at least 1.2-1.5 mg/d of colchicine (dose dependent on age) or are intolerant of colchicine. Subjects will be diagnosed by clinical criteria with at least one heterozygote mutation of the MEFV (pyrin) gene. After screening subjects will be monitored for a month to observe for acute FMF attacks or if they did not develop an attack in that month until they develop two attacks. We will then use a single-subject alternating treatments design with subjects receiving in random order two 3-month courses of Rilonacept at 2.2 mg/kg (max 160 mg) by weekly SC injection and two 3-month courses of comparable volume placebo. Subjects will continue the usual colchicine dose they were on when they started the study. Subjects with 2 acute FMF attacks during a treatment course will be able to crossover to the other treatment arm until the end of that treatment course. There will be 10 study visits: 1. Screening. 2. Treatment baseline after one month or after subjects have developed FMF attacks as described above. After 1 month of each treatment course and at the end of each treatment course (overall 8 visits). At each visit subjects will return completed diary forms, used and unused drug, queried on adverse effects, undergo a physical examination and laboratory tests obtained for inflammation, safety and in some visits for translational studies. Subjects will also fill out quality of life questionnaires and give an overall estimation of the disease activity. Results will be analyzed by traditional frequency statistics (using an intent to treat analysis) and by Bayesian hierarchical modeling. Our primary aim is to assess the efficacy of Rilonacept in decreasing the number of acute FMF attacks while monitoring drug safety.

The significance of the study includes short and long-term benefits. Fewer FMF attacks will result in less functional impairment and a higher quality of life in colchicine resistant or intolerant patients. Once weekly injections have the potential to improve treatment compliance. Fewer acute attacks of arthritis may prevent the development of chronic joint damage. In the long-term, better FMF control may prevent amyloidosis. This study may confirm the importance of IL-1 in the pathogenesis of FMF and provide support for an FDA filing for use of Rilonacept in FMF. The study design may serve as a template for trials of new biologic drugs for rare diseases.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of IL-1 Trap (Rilonacept) for Treatment of Familial Mediterranean Fever (FMF)
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Treatment Arm A: Rilonacept (IL-1 Trap) at a dose of 2.2 mg/kg/wk (max 160 mg)given by subcutaneous injection for 3 months plus colchicine at a stable dose for those subjects already taking colchicine, or without colchicine for those intolerant or non-compliant with colchicine. Since the colchicine dose is stable throughout the study for each subject, at the prestudy dose, colchicine was not considered an intervention	Drug: Rilonacept; 2.2 mg/kg/wk by subcutaneous injection, for 3 months; Other Names: Arcalyst, IL-1 Trap
Placebo Comparator: 2 Treatment Arm B: Placebo given by subcutaneous injection weekly with or without colchicine for 3 months. Since the colchicine dose is stable throughout the study for each subject, at the prestudy dose, colchicine was not considered an intervention.	Drug: Placebo; placebo by subcutaneous injection weekly for 3 months

Outcome Measures

Primary Outcome Measures

1. To Assess the Efficacy of Rilonacept in Decreasing the Number of Acute FMF Attacks. [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)]

   Difference in number of attacks per treatment month between rilonacept and placebo

2. To Determine if There is a Medically Important Difference Between the Safety Profiles of Rilonacept vs. Placebo. [12 months of entire study length]

   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.

Secondary Outcome Measures

1. To Determine the Difference in the Length of Attacks During Treatment With Rilonacept vs. Placebo. [12 months]

   This outcome was the difference in days in the length of attacks between rilonacept and placebo.

2. Percentage of Treatment Courses Without FMF Attacks in Rilonacept Courses as Compared to Placebo Courses. [Each treatment course of up to 3 months]

   The percentage of rilonacept and placebo treatment courses without FMF attacks.

3. 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. [Up to 3 months for each treatment course]

   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.

4. To Determine Differences in the Time to the Development of Attacks Between the Treatment Arms (Rilonacept vs. Placebo). [3 months]

   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).

5. To Determine the Differences in the Erythrocyte Sedimentation Rate Between the Treatment Arms (Rilonacept vs. Placebo). [3 months (each treatment course, overall 12 months)]

   Erythrocyte sedimentation rate - ESR (mm/h)

6. To Determine the Differences in C-Reactive Protein Between the Treatment Arms (Rilonacept vs. Placebo) [3 months (each treatment course, overall 12 months)]

   Differences between the treatment courses in the C-Reactive Protein levels mg/L

7. To Determine the Differences in the Platelet Count Between the Treatment Arms (Rilonacept vs. Placebo) [3 months (each treatment course, overall 12 months)]

   The difference between the treatment arms in the platelet count X 10 to the power of 9

8. To Determine the Differences in the Fibrinogen Levels Between the Treatment Arms (Rilonacept vs. Placebo) [3 months (each treatment course, overall 12 months)]

   The differences between treatment arms in the fibrinogen level (micromol/L)

9. To Determine the Differences in Serum Amyloid A Levels Between the Treatment Arms (Rilonacept vs. Placebo) [3 months (each treatment course, overall 12 months)]

   The difference between the treatment arms in serum amyloid A levels (mg/L)

10. To Determine the Differences in the Quality of Life Between the Treatment Arms (Rilonacept vs. Placebo). [12 months]

    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.

11. To Determine the Differences in the FMF Severity Score of the Subjects Between the Treatment Arms (Rilonacept vs. Placebo). [overall 12 months]

    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).

12. To Determine the Differences in the Proportion of Time Subjects Received Rilonacept vs Placebo [12 months]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject has a definitive diagnosis of FMF as by the Tel-Hashomer clinical criteria (long version of criteria) with at least one mutation on one of the MEFV gene alleles. However, subjects with an isolated heterozygous mutation of exon 2 of the MEFV gene (including E148Q) will not be eligible.

• Subject must have an estimated mean of at least one acute FMF attack per month before and during the month of screening.

• Subject is at least four years of age (with no upper limit of age).

• Subjects must have received an adequate trial of colchicine defined as treatment of at least 1.5 mg/d for at least 3 months if ≥6 years old or 1.2 mg/d if less than 6 years, or an inability to tolerate colchicine due to adverse effects in a dose that controls acute attacks in the frequency of less than one attack per month.

• If subject is being treated with anakinra at the time of consent, washout must be done (about 3 days). Subject must experience 2 attacks before randomization visit can occur.

• If subject has been treated previously with anti-TNF drugs, appropriate washout must be done. Etanercept must be discontinued for 4 weeks prior to randomization; Adalimumab and Infliximab must be discontinued for 8 weeks prior to randomization.

• If subject is a female of childbearing potential, she must agree to use adequate contraception (adequate contraception can include abstinence) for the duration of the trial and 3 months after and must have a negative serum or urine pregnancy test prior to administration of study medication.

• If subject is a male and has reached puberty, he must agree to use adequate contraception or abstinence during the study and for 3 months after discontinuation from study.

• Subject's parent or legal guardian has provided written informed consent prior to screening for this study or if subject is older than 18 years has provided informed consent him/herself.

• Subject, if applicable, has assented to participate prior to screening for this study.

• Subject and, if applicable, parent/legal guardian, agree to comply with study requirements and are able to come to the clinic for all required study visits.

Exclusion Criteria:

• The subject has existing biopsy proven amyloidosis or proteinuria >0.5 gram per day.

• The subject has another active inflammatory rheumatic disease.

• The subject has an active malignancy of any type, or history of a malignancy.

• The subject has active GI disease (e.g., inflammatory bowel disease), a chronic or acute renal or hepatic disorder, or a significant coagulation defect.

• The subject has an AST (SGOT), ALT (SGPT) or BUN >2 x ULN or creatinine >1.5 mg/dL or any other laboratory abnormality considered by the examining physician to be clinically significant within 28 days before the Baseline visit.

• Current use of an anti-tumor necrosis factor drug.

• The subject has, in the investigator's opinion, a chronic condition (e.g., diabetes, epilepsy) that is either not stable or well-controlled and may interfere with the conduct of the study.

• The subject has received any investigational medication within 30 days before the first dose of study medication or is scheduled to receive an investigational drug, other than study medications described in this protocol, during the course of the study.

• The subject has chronic or active infection or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 30 days or oral antibiotics within 14 days prior to the screening evaluation.

• The subject has known positive human immunodeficiency virus (HIV) status.

• The subject has known past or current hepatitis.

• The subject has received a live virus vaccine within 1 month prior to the baseline visit.

• The subject has a positive PPD test.

• The subject is sexually active and not practicing effective birth control.

• The subject is pregnant or breast feeding a child.

• Any concurrent medical condition which would, in the investigator's opinion, compromise the subject's ability to tolerate the study drug or would make the subject unable to cooperate with the protocol.

• History of/or current psychiatric illness that would interfere with ability to comply with protocol requirements or give informed consent.

• Subject has a history of alcohol or drug abuse within the past 6 months that would interfere with ability to comply with protocol requirements.

• Inability to comply with the study requirements for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Los Angeles/Cedars-Sinai Medical Center	Los Angeles	California	United States	90027
2	Children's Hospital of Central California	Madera	California	United States	93638
3	NIH	Bethesda	Maryland	United States	20892
4	NYU Hospital for Joint Diseases	New York	New York	United States	10003
5	Cleveland Clinic	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Study Director: Philip J Hashkes, MD, MSc, Shaare Zedek Medical Center/The Cleveland Clinic Foundation

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Philip Hashkes, Study Director, Shaare Zedek Medical Center
• ClinicalTrials.gov Identifier: NCT00582907
• Other Study ID Numbers: 1R01FD003435-01; FDA 1RO1FD003435-01; NCT00767143
• First Posted: Dec 28, 2007
• Last Update Posted: Feb 11, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by Philip Hashkes, Study Director, Shaare Zedek Medical Center: FMF; IL1 Trap (Rilonacept); Periodic fever syndromes; Autoinflammatory syndromes; Familial Mediterranean Fever; colchicine
• Additional relevant MeSH terms: Brucellosis; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Fever; Hyperthermia; Rilonacept

Study Results

Participant Flow

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 Detail	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
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	3	3	3
NOT COMPLETED	1	0	0	1
Period Title: 1st Course
STARTED	3	3	3	3
COMPLETED	2	3	3	3
NOT COMPLETED	1	0	0	0
Period Title: 1st Course
STARTED	2	3	3	3
COMPLETED	2	3	3	3
NOT COMPLETED	0	0	0	0
Period Title: 1st Course
STARTED	2	3	3	3
COMPLETED	2	3	3	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	All Patients Received Both Rilonacept and Placebo
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 Participants	14
Age (Count of Participants)
<=18 years	4 28.6%
Between 18 and 65 years	10 71.4%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.4 (11.8)
Sex: Female, Male (Count of Participants)
Female	6 42.9%
Male	8 57.1%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	To Assess the Efficacy of Rilonacept in Decreasing the Number of Acute FMF Attacks.
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)

Outcome Measure Data

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
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.
Measure Participants	13	12
Median (Inter-Quartile Range) [number of attacks per month]	0.77	2.00

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
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	Signed rank
	Comments
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

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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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.
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

Outcome Measure Data

Analysis Population Description

Safety analysis included all participants who received at least one dose of medication.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	13	14
Injection site reactions	1	0
Infections	0	0.18

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
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Signed rank
	Comments
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

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
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Signed rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	To Determine the Difference in the Length of Attacks During Treatment With Rilonacept vs. Placebo.
Description	This outcome was the difference in days in the length of attacks between rilonacept and placebo.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Participants who received any treatment and had recorded attacks

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	13	14
Median (95% Confidence Interval) [Number of days]	2.8	3.2

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
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Signed rank
	Comments
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

4. Secondary Outcome

Title	Percentage of Treatment Courses Without FMF Attacks in Rilonacept Courses as Compared to Placebo Courses.
Description	The percentage of rilonacept and placebo treatment courses without FMF attacks.
Time Frame	Each treatment course of up to 3 months

Outcome Measure Data

Analysis Population Description

Participants who at least one complete treatment course.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	13	13
Number [Percentage of courses]	29	0

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
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Differences in percent of courses
	Estimated Value	29
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
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

Outcome Measure Data

Analysis Population Description

Participants who completed at least one complete treatment course.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	13	13
Number [Percentage of courses]	75	35

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
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	McNemar
	Comments
Method of Estimation	Estimation Parameter	Difference in percent of courses
	Estimated Value	40
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	To Determine Differences in the Time to the Development of Attacks Between the Treatment Arms (Rilonacept vs. Placebo).
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

Outcome Measure Data

Analysis Population Description

All participants who received an intervention and developed an attack were analyzed.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	13	14
Median (Inter-Quartile Range) [days until second attack]	90	36

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
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Kaplan-Meier survival analysis
	Comments
Method of Estimation	Estimation Parameter	Log Rank
	Estimated Value	0.009
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	To Determine the Differences in the Erythrocyte Sedimentation Rate Between the Treatment Arms (Rilonacept vs. Placebo).
Description	Erythrocyte sedimentation rate - ESR (mm/h)
Time Frame	3 months (each treatment course, overall 12 months)

Outcome Measure Data

Analysis Population Description

Participants who completed at least one treatment course of both rilonacept and placebo.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [mm/h]	5.8	14

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
Statistical Test of Hypothesis	p-Value	0.156
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	6.5
	Confidence Interval	(2-Sided) 95%; -0.5 to 12.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	To Determine the Differences in C-Reactive Protein Between the Treatment Arms (Rilonacept vs. Placebo)
Description	Differences between the treatment courses in the C-Reactive Protein levels mg/L
Time Frame	3 months (each treatment course, overall 12 months)

Outcome Measure Data

Analysis Population Description

Patients who received at least one course each of rilonacept and placebo

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [mg/L]	2	4

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
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	To Determine the Differences in the Platelet Count Between the Treatment Arms (Rilonacept vs. Placebo)
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)

Outcome Measure Data

Analysis Population Description

The number of patients who received at least one course each of rilonacept and placebo

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [cell count X10 to the power of 9]	262	334

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
Statistical Test of Hypothesis	p-Value	0.078
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	29.4
	Confidence Interval	(2-Sided) 95%; 0.4 to 78.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	To Determine the Differences in the Fibrinogen Levels Between the Treatment Arms (Rilonacept vs. Placebo)
Description	The differences between treatment arms in the fibrinogen level (micromol/L)
Time Frame	3 months (each treatment course, overall 12 months)

Outcome Measure Data

Analysis Population Description

Patients who received at least one course each of rilonacept and placebo

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [micromol/L]	6.56	9.56

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
Statistical Test of Hypothesis	p-Value	0.063
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	108
	Confidence Interval	(2-Sided) 95%; 6.5 to 139.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	To Determine the Differences in Serum Amyloid A Levels Between the Treatment Arms (Rilonacept vs. Placebo)
Description	The difference between the treatment arms in serum amyloid A levels (mg/L)
Time Frame	3 months (each treatment course, overall 12 months)

Outcome Measure Data

Analysis Population Description

Patients who received at least one course each of rilonacept and placebo

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [mg/L]	13	15

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
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -4 to 0
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	To Determine the Differences in the Quality of Life Between the Treatment Arms (Rilonacept vs. Placebo).
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

Outcome Measure Data

Analysis Population Description

Participants who received at least one treatment course of rilonacept and placebo.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Physical HRQOL summary composite score	33	20.3
Psychosocial HRQOL summary composite score	53.3	49.8

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
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Signed rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-6.5
	Confidence Interval	(2-Sided) 95%; -11.1 to -2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rilonacept, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Signed Rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95%; -6.8 to 3.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	To Determine the Differences in the FMF Severity Score of the Subjects Between the Treatment Arms (Rilonacept vs. Placebo).
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

Outcome Measure Data

Analysis Population Description

Participants who received at least one course each of placebo and rilonacept.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Median (Inter-Quartile Range) [units on a scale]	5.5	11

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
Statistical Test of Hypothesis	p-Value	0.136
	Comments
	Method	Signed rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -2.3 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	To Determine the Differences in the Proportion of Time Subjects Received Rilonacept vs Placebo
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

Outcome Measure Data

Analysis Population Description

Participants who received at least one treatment course of both rilonacept and placebo.

Arm/Group Title	Rilonacept	Placebo
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.
Measure Participants	12	12
Number (95% Confidence Interval) [Percentage of time treated]	52.5	47.5

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
Statistical Test of Hypothesis	p-Value	0.089
	Comments
	Method	Signed rank
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-5
	Confidence Interval	(2-Sided) 95%; -15 to -1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Arm/Group Title	Placebo		Rilonacept
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Rilonacept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/14 (21.4%)		3/13 (23.1%)
Immune system disorders
Hospitalization for FMF attack	2/14 (14.3%)	3	2/13 (15.4%)	4
Infections and infestations
Pneumonia	0/14 (0%)	0	1/13 (7.7%)	1
Respiratory Infection	1/14 (7.1%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Rilonacept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/14 (85.7%)		11/13 (84.6%)
Ear and labyrinth disorders
Sore throat	1/14 (7.1%)	1	1/13 (7.7%)	1
Nose bleed	1/14 (7.1%)	1	0/13 (0%)	0
Eye disorders
Photophobia	1/14 (7.1%)	1	0/13 (0%)	0
Gastrointestinal disorders
Loss of appetite	0/14 (0%)	0	1/13 (7.7%)	3
Nausea, vomiting	1/14 (7.1%)	1	1/13 (7.7%)	1
General disorders
Hypertension	0/14 (0%)	0	1/13 (7.7%)	2
Heat and cold sensitivity	1/14 (7.1%)	1	0/13 (0%)	0
Fatigue	1/14 (7.1%)	1	0/13 (0%)	0
Infections and infestations
Upper respiratory infection/Otitis	3/14 (21.4%)	3	0/13 (0%)	0
Sinusitis	1/14 (7.1%)	1	1/13 (7.7%)	1
Herpes labialis	1/14 (7.1%)	1	0/13 (0%)	0
Herpes Zoster	1/14 (7.1%)	1	0/13 (0%)	0
Epstein Barr virus	0/14 (0%)	0	1/13 (7.7%)	1
Otitis	1/14 (7.1%)	1	1/13 (7.7%)	1
Bronchitis	1/14 (7.1%)	1	0/13 (0%)	0
Influenza	0/14 (0%)	0	1/13 (7.7%)	1
Facial skin infection	1/14 (7.1%)	1	0/13 (0%)	0
Oral thrush	1/14 (7.1%)	1	0/13 (0%)	0
Conjunctivitis	0/14 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Injection site reaction	5/14 (35.7%)	13	7/13 (53.8%)	53
Fracture - toe	0/14 (0%)	0	1/13 (7.7%)	1
Abrasion	1/14 (7.1%)	1	0/13 (0%)	0
Investigations
Alanine aminotransferase (ALT) elevation	0/14 (0%)	0	1/13 (7.7%)	1
Creatine Kinase (CPK) elevation	1/14 (7.1%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia/bone pain	1/14 (7.1%)	1	2/13 (15.4%)	2
Nervous system disorders
Headaches	1/14 (7.1%)	1	1/13 (7.7%)	1
Vertigo	1/14 (7.1%)	1	0/13 (0%)	0
Renal and urinary disorders
Overactive bladder	0/14 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
Asthma attack	1/14 (7.1%)	1	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Facial edema	1/14 (7.1%)	1	0/13 (0%)	0
Alopecia	0/14 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

Small sample size - accounted for in study design and analysis plan. Carry over/lag effect of rilonacept - sensitivity analysis of shifting course time frame showed similar results. Heterogeneity of FMF mutations Different age groups

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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.