Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Placebo-Controlled Study of the Efficacy and Safety of Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever
Brief Summary: 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.


Options:
A: Inclusion Criteria:

A subject must fulfil the following criteria in order to be included in the study:

1. 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).
2. 18-65 years of age
3. Verified as mutations in both alleles of the MEFV gene, thus including homozygous and compound heterozygous patients
4. Patient compliant with maximum tolerable dose of colchicine (up to 3 mg/day)
5. At least one FMF attack per month in chest, abdomen or joints (definition of attack see above)
6. 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:

1. Patient pregnant at enrolment visit
2. Prior or existing malignancy
3. Active infection
4. 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
5. Live vaccinations last three months before enrolment
6. Sociopsychological state threatening compliance with the treatment protocol
7. Alcohol or substance abuse
8. Concomitant medication with biological or anti-rheumatic disease-modifying drugs or systemic steroids
9. Any prior use of IL-1 inhibitory drugs
10. Associated disease that could interfere with clinical assessment:

    1. Rheumatic disorder
    2. Systemic disease, e.g. autoimmune or other autoinflammatory disorder, diabetes, hypertension, vasculitis, Behçet's disease
    3. Gastrointestinal disorder, e.g. Crohn's disease, ulcerative colitis, irritable bowel syndrome
    4. Cardiovascular disorder, e.g. post myocardial infarction, angina
    5. Pulmonary disorder, e.g. COPD, pulmonary hypertension
    6. Any other condition which in the opinion of the investigator makes the subject unsuitable for inclusion
11. Enrolment in another concurrent clinical study, or intake of an investigational drug, within three months prior to inclusion in this study
12. Failure or refusal to cooperate with given instructions

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B: Inclusion Criteria:

* Diagnosed with Familial Mediterranean Fever according to Yalcinkaya or
* Tel-Hashomer criteria
* Diagnosis confirmed with the genetic analysis as compound heterozygote or
* homozygote mutation
* Patients between ages of 5-16 and weighted 15-30 kg
* Not received any treatment for FMF

Exclusion criteria:

* Major congenital malformation
* Organ transplantation
* Hepatic disorder
* Chronic kidney disease
* AA amyloidosis
* Thyroid disease
* Rheumatologic disorders other than FMF
C: Inclusion Criteria:

1. Male or female 18 - 70 years of age
2. Previously met the preliminary criteria of ARA for the classification of the acute arthritis of primary gout
3. Presenting with an acute attack (flare) of gout within 48 hours of pain onset and pain of at least moderate severity
4. Must have at least 1 on the 0-3 scale for the swelling and the tenderness assessments of the gouty index joint
5. Current presentation of acute gout flare in 3 joints or less

Exclusion Criteria:

1. Treatment with any non-steroidal anti-inflammatory drug (NSAIDs) or opiates within 48 hours prior to baseline assessments. Treatment with long-acting NSAIDs within 1 month prior to baseline visit. Treatment with naproxen, meloxicam, nabumetone, celecoxib and indomethacin SR within 5 days prior to baseline visit.
2. Treatment with oral analgesics within 6 hours before baseline assessments. Treatment with topical analgesics within 12 hours before baseline assessments
3. History of NSAID intolerance
4. Participants with history of chronic, gouty arthritis
D: 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.

Answer: A