<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01705756</url>
  </required_header>
  <id_info>
    <org_study_id>SHEBA-11-8557-AL-CTIL</org_study_id>
    <nct_id>NCT01705756</nct_id>
  </id_info>
  <brief_title>Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever</brief_title>
  <acronym>FMF</acronym>
  <official_title>A Randomized Placebo-Controlled Study of the Efficacy and Safety of Kineret (Anakinra), in Adult Patients With Colchicine-Resistant Familial Mediterranean Fever</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sheba Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      FMF is the most common periodic fever with a worldwide patient population estimated as&#xD;
      150,000, mainly located in the Eastern Mediterranean basin. colchicine is the established&#xD;
      therapy of choice ,however, around 20.000 patients worldwide fail to respond or cannot&#xD;
      tolerate therapeutic doses, thereby suffering from recurrent debilitating, severe, painful&#xD;
      attacks of peritonitis, pleuritis and synovitis and are at risk to die from reactive&#xD;
      amyloidosis .Mutation-induced reduction in pyrin/ marenostrin activity is thought to underlie&#xD;
      the disease by leading to NALP3 inflammasome activation ,and thereby to IL-1β related burst&#xD;
      of inflammation.&#xD;
&#xD;
      The IL-1 receptor antagonist Kineret (Anakinra), seems to be the most appropriate response to&#xD;
      the uncontrolled IL-1β elevation. Indeed, an increasing number of reports over the last few&#xD;
      years indicate a good response to Kineret (Anakinra), in colchicine-resistant FMF ,also in&#xD;
      children ,however, no controlled study has thoroughly evaluated the efficacy and safety of&#xD;
      this treatment.&#xD;
&#xD;
      Study outline:&#xD;
&#xD;
      The study aims to run at the FMF centre in Sheba Medical Center, covering more than 10,000&#xD;
      patients. The study will evaluate the effect of recombinant IL-1 receptor antagonist, Kineret&#xD;
      (Anakinra), on the frequency of FMF attacks in patients that, despite maximum tolerable dose&#xD;
      of colchicine, present with more than one attack per month.&#xD;
&#xD;
      The study is designed as a randomised, placebo-controlled, double-blind study. 50 patients&#xD;
      will be randomised to treatment with either Kineret (Anakinra), or placebo treatment for 4&#xD;
      months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">June 2015</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with less than a mean of one FMF attack per month</measure>
    <time_frame>4 months</time_frame>
    <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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of serious adverse events</measure>
    <time_frame>4 months</time_frame>
    <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:&#xD;
Death&#xD;
Life-threatening (i.e., at immediate risk of death)&#xD;
In-patient hospitalization or prolongation of existing hospitalization&#xD;
Persistent or significant disability/incapacity&#xD;
Congenital anomaly/birth defect</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Familial Mediterranean Fever</condition>
  <arm_group>
    <arm_group_label>Vehicle</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>•Patients randomized to placebo will receive syringes identical to active drug (100 mg prefilled syringes for subcutaneous injection) filled with drug vehicle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Kineret (Anakinra)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Kineret</intervention_name>
    <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.</description>
    <arm_group_label>Kineret (Anakinra)</arm_group_label>
    <arm_group_label>Vehicle</arm_group_label>
    <other_name>Anakinra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        A subject must fulfil the following criteria in order to be included in the study:&#xD;
&#xD;
          1. FMF diagnosed as per the Tel-Hashomer criteria -(Criteria for the diagnosis of&#xD;
             familial Mediterranean fever. Arthritis Rheum.1998 Aug; 41(8):1516-7-Livneh A,&#xD;
             Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M).&#xD;
&#xD;
          2. 18-65 years of age&#xD;
&#xD;
          3. Verified as mutations in both alleles of the MEFV gene, thus including homozygous and&#xD;
             compound heterozygous patients&#xD;
&#xD;
          4. Patient compliant with maximum tolerable dose of colchicine (up to 3 mg/day)&#xD;
&#xD;
          5. At least one FMF attack per month in chest, abdomen or joints (definition of attack&#xD;
             see above)&#xD;
&#xD;
          6. Adequate contraception for sexually active male and female patients&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The presence of any of the following will exclude a subject from inclusion in the study:&#xD;
&#xD;
          1. Patient pregnant at enrolment visit&#xD;
&#xD;
          2. Prior or existing malignancy&#xD;
&#xD;
          3. Active infection&#xD;
&#xD;
          4. Manifest renal failure with Creatinine clearance &lt;30mL/min as determined by the&#xD;
             equation Creatinine clearance (ml/min) = (140-age) x Wight (Kg) /72 x serum creatinine&#xD;
             (mg/dcl) For women one should multiply the results by 0.8&#xD;
&#xD;
          5. Live vaccinations last three months before enrolment&#xD;
&#xD;
          6. Sociopsychological state threatening compliance with the treatment protocol&#xD;
&#xD;
          7. Alcohol or substance abuse&#xD;
&#xD;
          8. Concomitant medication with biological or anti-rheumatic disease-modifying drugs or&#xD;
             systemic steroids&#xD;
&#xD;
          9. Any prior use of IL-1 inhibitory drugs&#xD;
&#xD;
         10. Associated disease that could interfere with clinical assessment:&#xD;
&#xD;
               1. Rheumatic disorder&#xD;
&#xD;
               2. Systemic disease, e.g. autoimmune or other autoinflammatory disorder, diabetes,&#xD;
                  hypertension, vasculitis, Behçet's disease&#xD;
&#xD;
               3. Gastrointestinal disorder, e.g. Crohn's disease, ulcerative colitis, irritable&#xD;
                  bowel syndrome&#xD;
&#xD;
               4. Cardiovascular disorder, e.g. post myocardial infarction, angina&#xD;
&#xD;
               5. Pulmonary disorder, e.g. COPD, pulmonary hypertension&#xD;
&#xD;
               6. Any other condition which in the opinion of the investigator makes the subject&#xD;
                  unsuitable for inclusion&#xD;
&#xD;
         11. Enrolment in another concurrent clinical study, or intake of an investigational drug,&#xD;
             within three months prior to inclusion in this study&#xD;
&#xD;
         12. Failure or refusal to cooperate with given instructions&#xD;
&#xD;
             -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Avi Livneh, professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheba Medical Center, Tel- Hashomer, Ramat- Gan, Israel.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sheba Medical Center</name>
      <address>
        <city>Tel- Hashomer, Ramat- Gan</city>
        <zip>52621</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>September 27, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>July 19, 2017</last_update_submitted>
  <last_update_submitted_qc>July 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Prof.Avi Livneh</investigator_full_name>
    <investigator_title>Principal Investigator, Head of Internal Medicine &quot;F&quot; , Director of national center of FMF, Israel</investigator_title>
  </responsible_party>
  <keyword>Colchicine</keyword>
  <keyword>Anakinra</keyword>
  <keyword>Colchicine resistance</keyword>
  <keyword>Familial Mediterranean fever</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brucellosis</mesh_term>
    <mesh_term>Familial Mediterranean Fever</mesh_term>
    <mesh_term>Hereditary Autoinflammatory Diseases</mesh_term>
    <mesh_term>Fever</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01705756
org study id: SHEBA-11-8557-AL-CTIL
nct id: NCT01705756
lead sponsor: 
has dmc: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of patients with less than a mean of one FMF attack per month
time frame: 4 months
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
measure: Number of serious adverse events
time frame: 4 months
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
arm group label: Vehicle
arm group type: Placebo Comparator
description: •Patients randomized to placebo will receive syringes identical to active drug (100 mg prefilled syringes for subcutaneous injection) filled with drug vehicle
arm group label: Kineret (Anakinra)
arm group type: Experimental
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: Kineret
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.
arm group label: Kineret (Anakinra)
arm group label: Vehicle
other name: Anakinra
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Avi Livneh, professor
role: Principal Investigator
affiliation: Sheba Medical Center, Tel- Hashomer, Ramat- Gan, Israel.
facility: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Prof.Avi Livneh
investigator title: Principal Investigator, Head of Internal Medicine "F" , Director of national center of FMF, Israel
mesh term: Brucellosis
mesh term: Familial Mediterranean Fever
mesh term: Hereditary Autoinflammatory Diseases
mesh term: Fever
mesh term: Interleukin 1 Receptor Antagonist Protein