Interleukin-1 Trap to Treat Autoinflammatory Diseases

NCT00094900 | Completed Phase 2 Results

• 2 other identifiers: 05001405-AR-0014
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Inflammation; Familial Mediterranean Fever; Still's Disease, Adult-Onset

Keywords

Muckle Wells Syndrome; NOMID; Adult Stills Disease; Familial Mediterranean; Treatment Trial/Fever; Autoinflammatory Disease

Outcome Measures

Primary Outcomes (5)

• Mean Change in Daily Scores

  Daily scores change from baseline to 10 days. The clinical daily diary scores (a composite score that included fever, rash, and arthritis/arthralgia, with each of the 3 symptoms scored from 0 \[no symptom\] to 4 \[worst symptom\], with an overall range score of 0-12).

  10 days for 4 patient, 6 days for 1 patient

• Mean Change in ESR

  ESR change from baseline to 10 days.The Erythrocyte Sedimentation Rate (ESR) is an acute phase reactant measured to evaluate lab parameters of inflammation

  10 days for 4 patient, 6 days for 1 patient

• Mean Change in hsCRP

  hsCRP change from baseline to 10 days.The high sensitivity C-reactive protein (hsCRP) is an acute phase reactant measured to evaluate lab parameters of inflammation

  10 days for 4 patient, 6 days for 1 patient

• Mean Change in SAA

  SAA change from baseline to 10 days.The serum Amyloid A (SAA) is an acute phase reactant measured to evaluate lab parameters of inflammation

  10 days for 4 patient, 6 days for 1 patient

• Response to Treatment (ACR20) in Patients With Adult Onset Still's Disease

  At the 24 month post-dose visit, an ACR20 responder was defined as someone who achieved at least 20% improvement in the tender and the swollen 28-joint count, and 20% improvement in at least 3 of the following 5 measures: Patient's pain assessment, Patient's global assessment of disease activity, Physician's global assessment of disease activity, Patient self-assessed disability, Acute phase reactant.

  24 months

Secondary Outcomes (92)

• Mean Change in Patient's Global Assessment, by VAS

  3 months

• Mean Change in Patient's Global Assessment, by VAS

  6 months

• Mean Change in Patient's Global Assessment, by VAS

  9 months

• Mean Change in Patient's Global Assessment, by VAS

  12 months

• Mean Change in Patient's Global Assessment, by VAS

  16 months

Study Arms (1)

IL-1 Trap

EXPERIMENTAL

Drug: IL-1 Trap

Interventions

IL-1 Trap DRUG

IL-1 Trap

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT, Hofmann SR, Stein L, Russo R, Goldsmith D, Dent P, Rosenberg HF, Austin F, Remmers EF, Balow JE Jr, Rosenzweig S, Komarow H, Shoham NG, Wood G, Jones J, Mangra N, Carrero H, Adams BS, Moore TL, Schikler K, Hoffman H, Lovell DJ, Lipnick R, Barron K, O'Shea JJ, Kastner DL, Goldbach-Mansky R. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002 Dec;46(12):3340-8. doi: 10.1002/art.10688.

  PMID: 12483741 BACKGROUND

• Chae JJ, Komarow HD, Cheng J, Wood G, Raben N, Liu PP, Kastner DL. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell. 2003 Mar;11(3):591-604. doi: 10.1016/s1097-2765(03)00056-x.

  PMID: 12667444 BACKGROUND

• De Benedetti F, Pignatti P, Massa M, Sartirana P, Ravelli A, Martini A. Circulating levels of interleukin 1 beta and of interleukin 1 receptor antagonist in systemic juvenile chronic arthritis. Clin Exp Rheumatol. 1995 Nov-Dec;13(6):779-84.

  PMID: 8835254 BACKGROUND

• Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH, Weinstein SP, Mellis SJ, Kastner DL. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008 Aug;58(8):2432-42. doi: 10.1002/art.23620.

  PMID: 18668591 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Inflammation; Familial Mediterranean Fever; Still's Disease, Adult-Onset; Cryopyrin-Associated Periodic Syndromes; Fever

Interventions

rilonacept

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hereditary Autoinflammatory Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Arthritis, Rheumatoid; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Skin Diseases, Genetic; Skin Diseases; Chronic Inducible Urticaria; Chronic Urticaria; Urticaria; Skin Diseases, Vascular; Cold Urticaria; Hypersensitivity, Immediate; Hypersensitivity; Chronic Disease; Disease Attributes; Body Temperature Changes; Signs and Symptoms

Limitations and Caveats

Secondary outcome analyses will be stratified based on primary outcome results - responders and non-responders. 1 subject with Familial Mediterranean Fever (FMF) was recruited but outcomes were not collected due to insufficient accrual of FMF cases.

Results Point of Contact

• Title: Raphaela Goldbach-Mansky, MD
• Organization: National Inst of Arthritis and Musculoskeletal and Skin Diseases

goldbacr@mail.nih.gov

13014356243

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2004
• First Posted: October 28, 2004
• Study Start: October 1, 2004
• Primary Completion: September 1, 2010
• Study Completion: December 1, 2010
• Last Updated: March 4, 2014
• Results First Posted: July 10, 2013

Record last verified: 2014-01

Locations

US (1)