Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever

Study Overview
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Brief Summary
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FMF is the most common periodic fever with a worldwide patient population estimated as 150,000, mainly located in the Eastern Mediterranean basin. colchicine is the established therapy of choice ,however, around 20.000 patients worldwide fail to respond or cannot tolerate therapeutic doses, thereby suffering from recurrent debilitating, severe, painful attacks of peritonitis, pleuritis and synovitis and are at risk to die from reactive amyloidosis .Mutation-induced reduction in pyrin/ marenostrin activity is thought to underlie the disease by leading to NALP3 inflammasome activation ,and thereby to IL-1β related burst of inflammation. The IL-1 receptor antagonist Kineret (Anakinra), seems to be the most appropriate response to the uncontrolled IL-1β elevation. Indeed, an increasing number of reports over the last few years indicate a good response to Kineret (Anakinra), in colchicine-resistant FMF ,also in children ,however, no controlled study has thoroughly evaluated the efficacy and safety of this treatment. Study outline: The study aims to run at the FMF centre in Sheba Medical Center, covering more than 10,000 patients. The study will evaluate the effect of recombinant IL-1 receptor antagonist, Kineret (Anakinra), on the frequency of FMF attacks in patients that, despite maximum tolerable dose of colchicine, present with more than one attack per month. The study is designed as a randomised, placebo-controlled, double-blind study. 50 patients will be randomised to treatment with either Kineret (Anakinra), or placebo treatment for 4 months.

Official Title
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A Randomized Placebo-Controlled Study of the Efficacy and Safety of Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever

Conditions
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Familial Mediterranean Fever

Intervention / Treatment
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* Drug: Kineret


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject must fulfil the following criteria in order to be included in the study: FMF diagnosed as per the Tel-Hashomer criteria -(Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum.1998 Aug; 41(8):1516-7-Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M). 18-65 years of age Verified as mutations in both alleles of the MEFV gene, thus including homozygous and compound heterozygous patients Patient compliant with maximum tolerable dose of colchicine (up to 3 mg/day) At least one FMF attack per month in chest, abdomen or joints (definition of attack see above) Adequate contraception for sexually active male and female patients Exclusion Criteria: The presence of any of the following will exclude a subject from inclusion in the study: Patient pregnant at enrolment visit Prior or existing malignancy Active infection Manifest renal failure with Creatinine clearance <30mL/min as determined by the equation Creatinine clearance (ml/min) = (140-age) x Wight (Kg) /72 x serum creatinine (mg/dcl) For women one should multiply the results by 0.8 Live vaccinations last three months before enrolment Sociopsychological state threatening compliance with the treatment protocol Alcohol or substance abuse Concomitant medication with biological or anti-rheumatic disease-modifying drugs or systemic steroids Any prior use of IL-1 inhibitory drugs Associated disease that could interfere with clinical assessment: Rheumatic disorder Systemic disease, e.g. autoimmune or other autoinflammatory disorder, diabetes, hypertension, vasculitis, Behçet's disease Gastrointestinal disorder, e.g. Crohn's disease, ulcerative colitis, irritable bowel syndrome Cardiovascular disorder, e.g. post myocardial infarction, angina Pulmonary disorder, e.g. COPD, pulmonary hypertension Any other condition which in the opinion of the investigator makes the subject unsuitable for inclusion Enrolment in another concurrent clinical study, or intake of an investigational drug, within three months prior to inclusion in this study Failure or refusal to cooperate with given instructions -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle<br>•Patients randomized to placebo will receive syringes identical to active drug (100 mg prefilled syringes for subcutaneous injection) filled with drug vehicle | Drug: Kineret<br>* Patients randomized to active drug will receive Kineret(Anakinra), 100 mg prefilled syringes for subcutaneous injection, once a day for 4 months. The syringes will arrive relabeled from the supplier (SOBI) to Sheba Medical Center. They will be stored at the PI's store room in a temperature controlled refrigerator.<br>* Other names: Anakinra;|
| Experimental: Kineret (Anakinra)<br>Patients randomized to active drug will receive Kineret (Anakinra), 100 mg prefilled syringes for subcutaneous injection, once a day for 4 months. The syringes will arrive relabeled from the supplier (SOBI) to Sheba Medical Center. They will be stored at the PI's store room in a temperature controlled refrigerator. | Drug: Kineret<br>* Patients randomized to active drug will receive Kineret(Anakinra), 100 mg prefilled syringes for subcutaneous injection, once a day for 4 months. The syringes will arrive relabeled from the supplier (SOBI) to Sheba Medical Center. They will be stored at the PI's store room in a temperature controlled refrigerator.<br>* Other names: Anakinra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with less than a mean of one FMF attack per month | Total number of FMF attacks in abdominal, thoracic, skin or joint locations during the observational period (4 months) as recorded in the patient diary, devided by 4 for each patient will result in number of attacks per one month. The number of patients with less than 1 attack per month will be compared between the 2 study groups | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of serious adverse events | Secondary endpoint is defined as total number of serious adverse events per 4 months in each study group. SAE is defined as an adverse event that meets one or more of the following criteria/outcomes: Death Life-threatening (i.e., at immediate risk of death) In-patient hospitalization or prolongation of existing hospitalization Persistent or significant disability/incapacity Congenital anomaly/birth defect | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colchicine, Anakinra, Colchicine resistance, Familial Mediterranean fever