Rilonacept for Treatment of Familial Mediterranean Fever (FMF)

NCT00582907 | Completed Phase 2 Results DMC

• 2 other identifiers: 1R01FD003435-01FDA 1RO1FD003435-01
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 5

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

Conditions

Familial Mediterranean Fever

Keywords

FMF; IL1 Trap (Rilonacept); Periodic fever syndromes; Autoinflammatory syndromes; Familial Mediterranean Fever; colchicine

Outcome Measures

Primary Outcomes (2)

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

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

  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)

• To Determine if There is a Medically Important Difference Between the Safety Profiles of Rilonacept vs. Placebo.

  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.

  12 months of entire study length

Secondary Outcomes (12)

• To Determine the Difference in the Length of Attacks During Treatment With Rilonacept vs. Placebo.

  12 months

• Percentage of Treatment Courses Without FMF Attacks in Rilonacept Courses as Compared to Placebo Courses.

  Each treatment course of up to 3 months

• 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

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

  3 months

• To Determine the Differences in the Erythrocyte Sedimentation Rate Between the Treatment Arms (Rilonacept vs. Placebo).

  3 months (each treatment course, overall 12 months)

Study Arms (2)

1

EXPERIMENTAL

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

PLACEBO COMPARATOR

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

Interventions

Rilonacept DRUG

2.2 mg/kg/wk by subcutaneous injection, for 3 months

Also known as: Arcalyst, IL-1 Trap

1

Placebo DRUG

placebo by subcutaneous injection weekly for 3 months

2

Eligibility Criteria

• Age: 4 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• The Cleveland Clinic: lead

Study Sites (5)

Children's Hospital Los Angeles/Cedars-Sinai Medical Center

Los Angeles, California, 90027, United States

Location

Children's Hospital of Central California

Madera, California, 93638, United States

Location

NIH

Bethesda, Maryland, 20892, United States

Location

NYU Hospital for Joint Diseases

New York, New York, 10003, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Related Publications (3)

• Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, Barron KS, Weisman MH, Pashinian N, Reiff AO, Samuels J, Wright DA, Kastner DL, Lovell DJ. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012 Oct 16;157(8):533-41. doi: 10.7326/0003-4819-157-8-201210160-00003.

  PMID: 23070486 RESULT

• Hashkes PJ, Spalding SJ, Hajj-Ali R, Giannini EH, Johnson A, Barron KS, Weisman MH, Pashinian N, Reiff AO, Samuels J, Wright D, Lovell DJ, Huang B. The effect of rilonacept versus placebo on health-related quality of life in patients with poorly controlled familial Mediterranean fever. Biomed Res Int. 2014;2014:854842. doi: 10.1155/2014/854842. Epub 2014 May 15.

  PMID: 25147819 DERIVED

• Huang B, Giannini EH, Lovell DJ, Ding L, Liu Y, Hashkes PJ. Enhancing crossover trial design for rare diseases: limiting ineffective exposure and increasing study power by enabling patient choice to escape early. Contemp Clin Trials. 2014 Jul;38(2):204-12. doi: 10.1016/j.cct.2014.05.001. Epub 2014 May 12.

  PMID: 24833067 DERIVED

MeSH Terms

Conditions

Familial Mediterranean Fever

Interventions

rilonacept

Condition Hierarchy (Ancestors)

Hereditary Autoinflammatory Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

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

Results Point of Contact

• Title: Philip Hashkes, MD, MSc
• Organization: Shaare Zedek Medical Center/Cleveland Clinic

hashkesp@szmc.org.il

972-2-6555307

Study Officials

• Philip J Hashkes, MD, MSc

  Shaare Zedek Medical Center/The Cleveland Clinic Foundation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Study Director

Study Record Dates

• First Submitted: December 19, 2007
• First Posted: December 28, 2007
• Study Start: August 1, 2008
• Primary Completion: September 1, 2011
• Study Completion: September 1, 2011
• Last Updated: February 11, 2013
• Results First Posted: October 31, 2012

Record last verified: 2013-02

Locations

US (5)