This study will examine the safety and effectiveness of interleukin-1 (IL-1) Trap for treating patients with autoinflammatory diseases-conditions with intense episodes of inflammation, such as fever, rash, or joint swelling. IL-1 Trap blocks a substance called IL-1 that may be important in causing the inflammation in these diseases.

Patients 18 years of age and older who were evaluated in NIAMS protocol 94-AR-0105 ("Genetics and Pathophysiology of FMF and Related Disorders") and who have autoinflammatory diseases, including neonatal onset multisystem inflammatory disease, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, familial Mediterranean fever, or adult Still's disease, may be eligible for this study.

Participants are admitted to the NIH Clinical Center for a baseline evaluation (see procedures below) and treatment with IL-1 Trap. On the evening of admission, patients are taught to give themselves IL-1 Trap injections under the skin on the thigh, upper arm, or abdomen. They have the first injection the evening of admission (study day 1), the second on the next day before hospital discharge, and the third at home in the afternoon. (Patients taking the drug anakinra, or Kineret, are withdrawn from the medication under observation in the hospital for up to 7 days before beginning treatment with IL-1 Trap.) Patients have blood tests 2 to 4 days after going home and return to NIH 10 days after the first injection for blood tests and a physical examination. Patients who respond well to IL-1 Trap are observed for up to 8 weeks with no additional treatment and have weekly blood tests starting on study day 14. During this period we expect patients to develop a clinical flare of their disease. Patients flaring will return to the NIH. If the medication seemed beneficial, treatment with weekly injections of IL-1 TRAP may continue for up to 1 year in an extension phase of the study. In this extension phase, patients take 100 mg of IL-1 Trap once a day for 3 days and then once a week. Patients are seen at NIH at 3, 6, 9, and 12 months and are checked at home by telephone at months 1, 2, 4, 5, 7, 8, 10, 11, and 13 for a review of their general health, side effects, and other medications. At the 12-month visit, the tests and evaluations done at the first visit are repeated. Study procedures include:

- Quality of life questionnaires and daily diary of symptoms and medication doses

- X-rays at study day 1 and 12 months

- Dermatologic (skin) evaluations at each follow-up visit for patients with a rash

- Magnetic resonance imaging (MRI) of affected joints on study day 1 and month 12

- Clinical photography of areas of rash, inflammation, or swollen joints either before or after treatment begins

- Blood tests on study days 1, 6, 10, weekly from day 14 to time of flare and monthly thereafter

Patients with neonatal onset multisystem inflammatory disease and Muckle-Wells syndrome undergo the following additional procedures:

- MRI of the brain at months 3, 6, and 12

- Lumbar puncture (if appropriate for the patient's signs and symptoms) at study day 1 for patients who have not had a normal lumbar puncture within 3 months. This test is repeated at months 6 and 12 if the first test was abnormal.

- Eye examination at each follow-up visit

- Hearing test and examination by an ear, nose, and throat specialist at each follow-up visit

- Neurologic examination, if appropriate for the patient's signs and symptoms, during each follow-up visit

Condition	Treatment or Intervention	Phase
Inflammation Familial Mediterranean Fever Still's Disease, Adult-Onset	Drug: IL-1 Trap	Phase II

Further Study Details: 

Expected Total Enrollment:  15

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.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA
Male or female subjects with inflammatory disease greater than or equal to 18 years of age.
Participation in NIH study #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 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 mg/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 x ULN 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 x ULN).
-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 x ULN, 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 as these abnormalities may 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.

Maryland
      National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  050014; 05-AR-0014
Record last reviewed:  October 15, 2004
Last Updated:  January 28, 2005
Record first received:  October 28, 2004
ClinicalTrials.gov Identifier:  NCT00094900
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08