Interleukin-1 Trap to Treat Autoinflammatory Diseases
Condition: Inflammation; Familial Mediterranean Fever; Still's Disease, Adult-Onset
MeSH terms: Brucellosis; Still's Disease, Adult-Onset; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Inflammation
Intervention: IL-1 Trap
Intervention MeSH terms: Rilonacept
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Muckle Wells Syndrome; NOMID; Adult Stills Disease; Familial Mediterranean; Treatment Trial/Fever; Autoinflammatory Disease

Summary:

      Autoinflammatory diseases are illnesses characterized by episodes of inflammation that,
      unlike autoimmune disorders, lack the production of high titer autoantibodies or
      antigen-specific T cells. There is growing genetic and clinical evidence that Interleukin-1
      (IL-1) plays a pathogenic role in several of these diseases. This exploratory study aims to
      examine the utility of the experimental drug candidate, IL 1 Trap (Regeneron Pharmaceuticals,
      Inc.) in the treatment of adult subjects with the autoinflammatory disorders Neonatal Onset
      Multisystem Inflammatory Disease (NOMID), Muckle-Wells Syndrome (MWS), and Familial Cold
      Autoinflammatory Syndrome (FCAS), Familial Mediterranean Fever (FMF), and adult Still's
      disease. FMF is associated with mutations in pyrin encoding MEFV. NOMID, MWS and FCAS are
      associated with mutations in cryopyrin-encoding CIAS1.

      This pilot study is designed to address: 1) the utility of IL 1 Trap in the treatment of
      subjects with diseases known to respond to IL-1 blockade (NOMID/MWS/FCAS) as shown by
      response to treatment with anakinra [Kineret]; 2) the response to IL-1 blockade of subjects
      with Adult Still's disease and colchicine-resistant FMF once the efficacy of IL-1 Trap has
      been established in NOMID/MWS/FCAS subjects; and 3) the biochemistry and genetics of
      autoinflammatory diseases and IL-1 related inflammation.

      IL-1 Trap is a recombinant fusion protein with picomolar affinity for IL-1 and a half-life of
      approximately 7.5 days in humans. This agent is currently in Phase 2 clinical studies for the
      treatment of rheumatoid arthritis and initial studies have shown activity against clinical
      and biochemical indicators of inflammation. Compared with anakinra, this agent may exhibit
      improved dosing convenience, potential for fewer injection site reactions, and improved
      efficacy due to the extremely high affinity of IL-1Trap for its target.

      In this study, biochemical, genetic, and clinical correlates of autoinflammatory disease will
      initially be measured at baseline following a withdrawal of any TNF or IL-1 inhibitor
      medications where applicable. Subjects will receive a course of therapy with IL-1 Trap that
      is predicted to provide an estimated 3-4 weeks of anti-inflammatory activity. Clinical,
      biochemical, and genetic correlates of inflammation will be measured at appropriate intervals
      to ascertain response and to further elucidate disease mechanisms. Subjects will be eligible,
      based on clinical response, to enter a 1- year extension phase with IL-1 Trap. Those subjects
      who complete the 1-year extension phase, and maintain improved clinical and laboratory
      parameters compared to baseline values, may continue to receive study medication at their
      current dose until the study drug is commercially available.

      Investigator comment:

      This protocol (from the NIH standpoint) is a continuation of the ongoing protocol 05-AR-0014,
      with a new change in study sponsor, the NIH replacing Regeneron as sponsor. this protocol
      therefore still contains background and procedural information that refer to patients with
      FMF and FCAS and or MWS and Still's disease, however only patients with Still's disease will
      be newly enrolled from this point on, enrollment for the FCAS and or MWS patients has already
      been completed and it has been decided to not enroll any more FMF patients because the number
      of subjects is too low to reach reasonable conclusions, in addition it has been difficult to
      recruit patients that are eligible. The background section and study procedures have largely
      been left as in the currently IRB approved protocol.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Male or female subjects with inflammatory disease greater than or equal to 18 years of age.

        Participation in NIH study number 94-AR-0105 ("Genetics and Pathophysiology of FMF and
        Related Disorders")

        Subjects presenting with active NOMID, MWS, FCAS, FMF, or adult Still's disease based on
        clinical signs/symptoms and/or biochemical markers such as acute phase reactants (CRP, SAA
        or ESR). Subjects need not have both clinical features and biochemical markers of disease
        to be enrolled. However, both clinical and laboratory responses will be evaluated in each
        subject for improvement as outcome measures (even improvement of laboratory values found to
        be within the normal range at baseline).

          -  NOMID, MWS, and FCAS: Diagnosis will be based on the history of classical features of
             disease including fevers, rash, joint involvement, CNS involvement. Approximately half
             of all subjects with these clinical syndromes are mutation negative; however, in the
             experience of the principal investigator these subjects show favorable clinical
             response to IL-1 blockade with anakinra. Therefore, subjects with or without
             recognized mutations in CIAS1 will be eligible to enroll in this study. Active disease
             will be defined as either the presence of aforementioned classical features, or a
             history of such features that became quiescent in the setting of therapy with
             anakinra. However, before a patient who has quiescent disease and is currently taking
             anakinra can receive study drug, he/she must fulfill criteria for active disease after
             anakinra has been discontinued.

          -  FMF will be diagnosed on the basis of documented presence of one or two mutant alleles
             of MEFV as well as the history of classical clinical features of FMF such as periodic
             fevers, rash, arthritis, arthralgia, or episodes of serositis. Subjects must be
             considered non-responsive to colchicine (up to 2 milligrams per day) on the basis of
             continued symptoms or flares (greater than or equal to one per month) or elevated
             acute phase reactants (ESR, CRP or SAA greater than or equal to 1.5 times the upper
             limit of normal between attacks) despite treatment with maximally tolerated doses of
             colchicine. Positive genetic test will be required for FMF to rule out the possibility
             that non-response to colchicine is due to misdiagnosis.

          -  Adult Still's disease will be diagnosed on the basis of history of classical clinical
             features such as fevers, evanescent salmon-pink rash, arthritis, arthralgia, and
             myalgia. Active disease will be defined as presence of one or more of these features
             and/ or elevation of acute phase reactants (ESR, CRP or SAA greater than or equal to
             1.5 times the upper limit of normal).

          -  Subjects currently treated with anakinra may be enrolled in this study even though
             autoinflammatory disease may be quiescent. For these subjects a history of active
             autoinflammatory disease prior to treatment with anakinra will be sufficient. Subjects
             must be greater than 48 hours from their last dose of anakinra before beginning IL-1
             Trap therapy, and will not take anakinra for the remainder of their enrollment in the
             study. However, before study drug is administered subjects have to manifest signs of
             active disease as described above

        Stable dose of steroids, NSAIDs, DMARDs, or colchicine for four weeks prior to enrollment
        visit.

        Females of childbearing potential (young women who have had at least one menstrual period
        regardless of age) must have a negative urine pregnancy test at screening and a negative
        serum pregnancy test at baseline prior to performance of any radiologic procedure or
        administration of study medication.

        Women of childbearing age and men able to father a child, who are sexually active, who
        agree to use a form of effective birth control, including abstinence.

        Negative PPD test using 5 T.U. intradermal testing per CDC guidelines, and no evidence of
        active TB on chest X-ray. Subjects with latent TB (positive PPD test) currently treated
        with adequate therapy initiated for at least one month prior to first dose of study
        medication may be included. Full prophylaxis regimens will be completed. Subjects who have
        been BCG-vaccinated will also be skin-tested.

        Able to understand, and complete study-related questionnaires.

        Able and willing to give informed consent and abide with the study procedures.

        EXCLUSION CRITERIA:

        Treatment with a live virus vaccine during 3 months prior to baseline visit. No live
        vaccines will be allowed throughout the course of this study.

        Current treatment with TNF inhibitors or recent discontinuation of TNF inhibitors (use
        within less than 5 half-lives of TNF inhibitor agent).

        Presence of active infections or a history of pulmonary TB infection with or without
        documented adequate therapy. Subjects with current active TB, or recent close exposure to
        an individual with active TB are excluded from the study.

        Chest x-ray read by a radiologist with pleural scarring and/or calcified granuloma
        consistent with prior TB.

        Positive test for or prior history of HIV, Hepatitis B or C.

        History or concomitant diagnosis of congestive heart failure.

        History of malignancy. Subjects deemed cured of superficial malignancies such as cutaneous
        basal or squamous cell carcinomas, or in situ cervical cancer may be enrolled.

        Known hypersensitivity to CHO cell derived biologicals or any components of IL 1 Trap.

        Presence of any additional rheumatic disease or significant systemic disease. For example,
        major chronic infectious/ inflammatory/ immunologic disease (such as inflammatory bowel
        disease, psoriatic arthritis, spondyloarthropathy, SLE in addition to autoinflammatory
        disease).

        Presence of any of the following laboratory abnormalities at enrollment visit: creatinine
        greater than 1.5 times the upper limit of normal, WBC less than 3.6 x 10(9)/mm(3); platelet
        count less than 150,000 mm(3); ALT or AST greater than 2.0 x ULN (ALT/AST greater than 2.0
        x ULN in an adult Still's disease patient would prompt a hepatology consult prior to
        enrollment unless these abnormalities are considered by the Principal Investigator to be
        reflective of the underlying Still's disease).

        Lactating females or pregnant females.

        Subjects with asthma not adequately controlled on current therapy.

        Enrollment in any other investigational treatment study or use of an investigational agent,
        or has not yet completed at least 4 weeks or 5 half-lives, whichever is longer, since
        ending another investigational device or drug trial.

        Subjects for whom there is concern about compliance with the protocol procedures.

        Presence of other severe acute or chronic medical or psychiatric condition, or significant
        laboratory abnormality requiring further investigation that may cause undue risk for the
        subject's safety, inhibit protocol participation, or interfere with interpretation of study
        results, and in the judgment of the investigator would make the subject inappropriate for
        entry into this study.