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

Primary Purpose

Familial Mediterranean Fever

Status
Completed
Phase
Phase 3
Locations
Israel
Study Type
Interventional
Intervention
Kineret
Sponsored by
Sheba Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Mediterranean Fever focused on measuring Colchicine, Anakinra, Colchicine resistance, Familial Mediterranean fever

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

    -

Sites / Locations

  • Sheba Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Vehicle

Kineret (Anakinra)

Arm Description

•Patients randomized to placebo will receive syringes identical to active drug (100 mg prefilled syringes for subcutaneous injection) filled with drug vehicle

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
September 27, 2012
Last Updated
July 19, 2017
Sponsor
Sheba Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01705756
Brief Title
Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever
Acronym
FMF
Official Title
A Randomized Placebo-Controlled Study of the Efficacy and Safety of Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
November 2012 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
June 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Sheba Medical Center

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Mediterranean Fever
Keywords
Colchicine, Anakinra, Colchicine resistance, Familial Mediterranean fever

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Vehicle
Arm Type
Placebo Comparator
Arm Description
•Patients randomized to placebo will receive syringes identical to active drug (100 mg prefilled syringes for subcutaneous injection) filled with drug vehicle
Arm Title
Kineret (Anakinra)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Kineret
Other Intervention Name(s)
Anakinra
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of patients with less than a mean of one FMF attack per month
Description
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
Time Frame
4 months
Secondary Outcome Measure Information:
Title
Number of serious adverse events
Description
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
Time Frame
4 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Avi Livneh, professor
Organizational Affiliation
Sheba Medical Center, Tel- Hashomer, Ramat- Gan, Israel.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sheba Medical Center
City
Tel- Hashomer, Ramat- Gan
ZIP/Postal Code
52621
Country
Israel

12. IPD Sharing Statement

Citations:
PubMed Identifier
27860460
Citation
Ben-Zvi I, Kukuy O, Giat E, Pras E, Feld O, Kivity S, Perski O, Bornstein G, Grossman C, Harari G, Lidar M, Livneh A. Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol. 2017 Apr;69(4):854-862. doi: 10.1002/art.39995.
Results Reference
derived

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

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