Clinical Trial: Rilonacept for Treatment of Familial Mediterranean Fever (FMF)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Phase 2 Study of IL-1 Trap (Rilonacept) for Treatment of Familial Mediterranean Fever (FMF)

Brief Summary:

Familial Mediterranean fever (FMF) is a genetic disease resulting in recurrent attacks of fever, abdominal pain, chest pain, arthritis and rash. There are 5-15% of patients who continue to have FMF attacks despite treatment with colchicine or who cannot tolerate colchicine. Currently there are no alternatives to colchicine. Pyrin, the protein that has a defect in FMF has an important role in the regulation of a molecule called interleukin (IL)-1 beta production and activity. This molecule is very important in the process of inflammation in FMF.

Therefore we propose to use IL-1 Trap (Rilonacept), a medication that binds and neutralizes IL-1.

We will enroll in this study 17 subjects from the age of 4 years, including adults with active FMF despite colchicine therapy. Subjects will receive in random order two 3-month courses of Rilonacept at 2.2 mg/kg (maximum 160 mg) by weekly subcutaneous injection and two 3-month courses of placebo injection. If patients have at least two FMF attacks during a treatment course they will be able to get if they choose the other treatment until the end of that treatment course. Our hypothesis is that Rilonacept will decrease the number of acute FMF attacks and will be safe to use. This study may confirm the importance of IL-1 in the cause of FMF.

Funding source - FDA Office of Orphan Products Development

Detailed Summary:

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory genetic disorder resulting in recurrent attacks of fever, serositis, arthritis and rash. Late complications of untreated FMF include the development of renal amyloidosis. FMF is a rare orphan disease in the United States. Treatment with colchicine is effective in reducing the frequency of episodes in most patients and the development of amyloidosis in nearly all patients. However, there are still 5-15% of patients who continue to have acute FMF attacks despite colchicine therapy or are intolerant of colchicine, usually from gastrointestinal adverse effects. Currently there are no effective alternatives to colchicine. Pyrin, the mutated protein in FMF has an important role in the regulation of IL-1 beta production and activity. Mutations in pyrin result in increased IL-1 beta levels in mice and humans. IL-1 beta is an important pro-inflammatory cytokine. Thus, we hypothesize that inhibition of IL-1 will decrease acute attacks in patients with FMF. We propose to use IL-1 Trap (Rilonacept), a fusion protein consisting of human IL-1 cytokine receptor extracellular domains and the FC portion of human IgG1 that binds and neutralizes IL-1.

We will enroll 17 subjects from the age of 4 years, including adults, from multiple centers in the United States with active FMF (at least 1 attack per month) despite receiving at least 1.2-1.5 mg/d of colchicine (dose dependent on age) or are intolerant of colchicine. Subjects will be diagnosed by clinical criteria with at least one heterozygote mutation of the MEFV (pyrin) gene. After screening subjects will be monitored for a month to observe for acute FMF attacks or if they did not develop an attack in that month until they develop two attacks. We will then use a single-subject alternating treatments design with subjects receiving in random order two 3-month cour
Sponsor: The Cleveland Clinic

Current Primary Outcome:

• To Assess the Efficacy of Rilonacept in Decreasing the Number of Acute FMF Attacks. [ Time Frame: attacks were assessed at the end of each 3 month treatment course (overall up to 6 month of rilonacept and 6 months of placebo, each) ]
  Difference in number of attacks per treatment month between rilonacept and placebo
• To Determine if There is a Medically Important Difference Between the Safety Profiles of Rilonacept vs. Placebo. [ Time Frame: 12 months of entire study length ]
  Differences in adverse events (AEs) between rilonacept and placebo per patient-month of treatment. We separately analyzed injection site reactions and infectious adverse events. Other adverse events were too small in number to analyze. The upper table (and first statistical analysis) regards injection site reactions and lower table (and second statistical analysis) regards infections.

Original Primary Outcome:

• To assess the efficacy of IL-1 Trap in decreasing the number of acute FMF attacks in this single-subject alternating treatments design trial. [ Time Frame: 3 months (each treatment course, overall 12 months) ]
• To determine if there is a medically important difference between the safety profiles of Treatment Arms A and B. [ Time Frame: 3 months (each treatment course, overall 12 months) ]

Current Secondary Outcome:

• To Determine the Difference in the Length of Attacks During Treatment With Rilonacept vs. Placebo. [ Time Frame: 12 months ]
  This outcome was the difference in days in the length of attacks between rilonacept and placebo.
• Percentage of Treatment Courses Without FMF Attacks in Rilonacept Courses as Compared to Placebo Courses. [ Time Frame: Each treatment course of up to 3 months ]
  The percentage of rilonacept and placebo treatment courses without FMF attacks.
• To Determine the Proportion of Courses in Which Subjects Attained at Least a 50% Decrease in Acute FMF Attacks During Rilonacept Courses as Compared to Placebo Courses. [ Time Frame: Up to 3 months for each treatment course ]
  Differences between rilonacept and placebo in the percentage of courses that attained at least a 50% decrease in FMF attacks when compared to attacks in the screening period.
• To Determine Differences in the Time to the Development of Attacks Between the Treatment Arms (Rilonacept vs. Placebo). [ Time Frame: 3 months ]
  In a survival analysis we measured the difference (in days) until the development of the first and second attack within a treatment course of up to 3 months and examined differences in this parameter between rilonacept and placebo. Data regarding the development of the second attack are reported below. In regards to the first attack there were no significant differences between rilonacept and placebo (20 days (7.5,>90)for rilonacept; 15 (8,32) for placebo, P=0.066).
• To Determine the Differences in the Erythrocyte Sedimentation Rate Between the Treatment Arms (Rilonacept vs. Placebo). [ Time Frame: 3 months (each treatment course, overall 12 months) ]
  Erythrocyte sedimentation rate - ESR (mm/h)
• To Determine the Differences in C-Reactive Protein Between the Treatment Arms (Rilonacept vs. Placebo) [ Time Frame: 3 months (each treatment course, overall 12 months) ]
  Differences between the treatment courses in the C-Reactive Protein levels mg/L
• To Determine the Differences in the Platelet Count Between the Treatment Arms (Rilonacept vs. Placebo) [ Time Frame: 3 months (each treatment course, overall 12 months) ]
  The difference between the treatment arms in the platelet count X 10 to the power of 9
• To Determine the Differences in the Fibrinogen Levels Between the Treatment Arms (Rilonacept vs. Placebo) [ Time Frame: 3 months (each treatment course, overall 12 months) ]
  The differences between treatment arms in the fibrinogen level (micromol/L)
• To Determine the Differences in Serum Amyloid A Levels Between the Treatment Arms (Rilonacept vs. Placebo) [ Time Frame: 3 months (each treatment course, overall 12 months) ]
  The difference between the treatment arms in serum amyloid A levels (mg/L)
• To Determine the Differences in the Quality of Life Between the Treatment Arms (Rilonacept vs. Placebo). [ Time Frame: 12 months ]
  Differences in the health-related quality of life (HRQOL) during treatment with rilonacept vs. placebo. HRQOl was measured by the Childhood Health Questionnaire which was adopted also for adults. There are 2 summary scores: 1. Physical summary score. 2. Psychosocial summary score. The data reported below in the upper table is the physical summary composite score and in the lower table the psychosocial summary composite score. Scores were from 0-100 (higher is better) with a score of 50 representing the mean of the normal population.
• To Determine the Differences in the FMF Severity Score of the Subjects Between the Treatment Arms (Rilonacept vs. Placebo). [ Time Frame: overall 12 months ]
  Differences in the Armenian Evaluation Score between rilonacept and placebo courses. The Armenian Evaluation Score is a composite score of disease severity based on the frequency, duration and character of attacks (degree of fever and severity of serositis). It was adapted to calculate a score for a 3-month treatment course. The lowest (best) score is 0 and higher values are worse. In theory there is no upper limit to the scale. The total score is reported (there are no subscales).
• To Determine the Differences in the Proportion of Time Subjects Received Rilonacept vs Placebo [ Time Frame: 12 months ]
  The proportion of time within the trial that participants received rilonacept as opposed to placebo. The reason for this outcome is that participants who had at least 2 attacks within an individual treatment course were able to "escape" in a blinded manner to the other treatment arm until the end of that treatment course and then resume the original randomization sequence. Thus participants may have been treated for a longer time with one treatment arm or the other.

Original Secondary Outcome:

• To determine the proportion of subjects who have no acute FMF attacks in each treatment arm. [ Time Frame: 3 months (each treatment course, overall 12 months) ]
• To determine the proportion of subjects who attain at least a 50% decrease in acute FMF attacks during active medication courses as compared to placebo courses. [ Time Frame: 3 months (each treatment course, overall 12 months) ]
• To determine the differences in the FMF severity score of the subjects between the treatment groups. [ Time Frame: 3 months (each treatment course, overall 12 months) ]
• To determine the differences in acute phase reactants between the treatment arms. [ Time Frame: 3 months (each treatment course, overall 12 months) ]
• To determine the differences in the numbers of days subjects receive Treatment Arm A vs Treatment Arm B [ Time Frame: 12 months ]
• To determine the differences in the quality of life between the treatment arms. [ Time Frame: 3 months (each treatment course, overall 12 months) ]

Dates:
Date Received: December 19, 2007
Date Started: August 2008
Date Completion:
Last Updated: February 5, 2013
Last Verified: February 2013