Philip J. Hashkes, MD, MSc; Steven J. Spalding, MD; Edward H. Giannini, DrPH, MSc; Bin Huang, PhD; Anne Johnson, CCRP; Grace Park, MD, MPH; Karyl S. Barron, MD; Michael H. Weisman, MD; Noune Pashinian, MD; Andreas O. Reiff, MD; Jonathan Samuels, MD; Dowain A. Wright, MD, PhD; Daniel L. Kastner, MD, PhD; Daniel J. Lovell, MD, MPH
Acknowledgment: The authors thank the following site study coordinators, nurses, and pharmacists: Tara Barker, RN, and John Petrich, RPh, from the Cleveland Clinic; Anne Jones, RN, Beverly Barham, RN, and Judith Starling, RPh, from the National Institutes of Health; Ana Cabrera, CCRC, and John Pech, MS, from the Children's Hospital of Los Angeles; and Claudine Davis, RN, from New York University Medical Center. They also thank Professor Philip Hawkins from the National Amyloidosis Centre at the Royal Free Hospital for measurement of serum amyloid A levels.
Grant Support: By the U.S. Food and Drug Administration, Office of Orphan Products Development (R01 FD003435). This trial was also supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Human Genome Research Institute, and the Cleveland Clinic Foundation. Rilonacept and placebo were supplied by Regeneron Pharmaceuticals. Target Health provided and partially subsidized the electronic data capture system and electronic database.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-3106.
Reproducible Research Statement:Study protocol: Available from Dr. Hashkes (e-mail, firstname.lastname@example.org). Statistical code: Available in Appendix 1. Data set: Available to approved individuals through written agreements with the trial steering committee (contact Dr. Hashkes).
Requests for Single Reprints: Philip J. Hashkes, MD, MSc, Pediatric Rheumatology Unit, Shaare Zedek Medical Center, POB 3235, Jerusalem, 91031 Israel; e-mail, email@example.com.
Current Author Addresses: Dr. Hashkes: Pediatric Rheumatology Unit, Shaare Zedek Medical Center, POB 3235, Jerusalem, 91031 Israel.
Dr. Spalding: Pediatric Rheumatology-A111, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.
Drs. Giannini, Huang, and Lovell and Ms. Johnson: Pediatric Rheumatology, Cincinnati Children's Medical Center, 3333 Burnet Avenue, MLC 4010, Cincinnati, OH 45229-3039.
Dr. Park: National Human Genome Research Institute, MSC 1517, 10 Center Drive, Bethesda, MD 20892-1517.
Dr. Barron: National Institute of Allergy and Infectious Diseases, MSC 3207, 33 North Drive, Bethesda, MD 20892-3207.
Drs. Weisman and Pashinian: Division of Rheumatology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B131, Los Angeles, CA 90048.
Dr. Reiff: Children's Hospital Los Angeles, 4650 Sunset Boulevard, MS#60, Los Angeles, CA 90027.
Dr. Samuels: New York University Langone Hospital for Joint Disease, 246 East 20th Street, New York, NY 10003.
Dr. Wright: Children's Hospital Central California, 9300 Valley Children's Place, MB08, Madera, CA 93636.
Dr. Kastner: National Human Genome Research Institute, MSC 8002, 50 South Drive, Bethesda, MD 20892-8002.
Author Contributions: Conception and design: P.J. Hashkes, E.H. Giannini, B. Huang, K.S. Barron, M.H. Weisman, D.L. Kastner, D.J. Lovell.
Analysis and interpretation of the data: P.J. Hashkes, S.J. Spalding, E.H. Giannini, B. Huang, M.H. Weisman, N. Pashinian, A.O. Reiff, D.L. Kastner, D.J. Lovell.
Drafting of the article: P.J. Hashkes, E.H. Giannini, B. Huang, J. Samuels, D.L. Kastner, D.J. Lovell.
Critical revision of the article for important intellectual content: P.J. Hashkes, E.H. Giannini, B. Huang, K.S. Barron, M.H. Weisman, A.O. Reiff, J. Samuels, D.A. Wright, D.L. Kastner, D.J. Lovell.
Final approval of the article: P.J. Hashkes, S.J. Spalding, E.H. Giannini, B. Huang, A. Johnson, G. Park, K.S. Barron, M.H. Weisman, A.O. Reiff, J. Samuels, D.A. Wright, D.L. Kastner, D.J. Lovell.
Provision of study materials or patients: P.J. Hashkes, S.J. Spalding, K.S. Barron, M.H. Weisman, N. Pashinian, D.A. Wright, D.L. Kastner.
Statistical expertise: E.H. Giannini, B. Huang.
Obtaining of funding: P.J. Hashkes, E.H. Giannini, D.L. Kastner, D.J. Lovell.
Administrative, technical, or logistic support: S.J. Spalding, A. Johnson, M.H. Weisman, D.L. Kastner, D.J. Lovell.
Collection and assembly of data: P.J. Hashkes, S.J. Spalding, E.H. Giannini, A. Johnson, G. Park, K.S. Barron, N. Pashinian, A.O. Reiff, J. Samuels, D.A. Wright, D.L. Kastner.
Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, et al. Rilonacept for Colchicine-Resistant or -Intolerant Familial Mediterranean Fever: A Randomized Trial. Ann Intern Med. 2012;157:533-541. doi: 10.7326/0003-4819-157-8-201210160-00003
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Published: Ann Intern Med. 2012;157(8):533-541.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
Currently, there is no proven alternative therapy for patients with familial Mediterranean fever (FMF) that is resistant to or intolerant of colchicine. Interleukin-1 is a key proinflammatory cytokine in FMF.
To assess the efficacy and safety of rilonacept, an interleukin-1 decoy receptor, in treating patients with colchicine-resistant or -intolerant FMF.
Randomized, double-blind, single-participant alternating treatment study. (ClinicalTrials.gov number: NCT00582907).
6 U.S. sites.
Patients with FMF aged 4 years or older with 1 or more attacks per month.
One of 4 treatment sequences that each included two 3-month courses of rilonacept, 2.2 mg/kg (maximum, 160 mg) by weekly subcutaneous injection, and two 3-month courses of placebo.
Differences in the frequency of FMF attacks and adverse events between rilonacept and placebo.
8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept–placebo attack risk ratio was 0.45 (SD, 0.13) (equal-tail 95% credible interval, 0.26 to 0.77). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, −1.74 [95% CI, −3.4 to −0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [−0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of −4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events.
Small sample size, heterogeneity of FMF mutations, age, and participant indication (colchicine resistance or intolerance) were study limitations.
Rilonacept reduces the frequency of FMF attacks and seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF.
U.S. Food and Drug Administration, Office of Orphan Products Development.
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