Interleukin-1 Trap to Treat Autoinflammatory Diseases
- Conditions
- Still's Disease, Adult-OnsetInflammationFamilial Mediterranean Fever
- Interventions
- Registration Number
- NCT00094900
- Lead Sponsor
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
- 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.
- Detailed Description
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 MEFV encoding Pyrin. NOMID, MWS and FCAS are associated with mutations in CIAS1-encoding cryopyrin.
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. Our result of the FCAS/MWS part of this study and a multi center phase III study in patients with FCAS/MWS provided the basis for the FDA approval of IL-Trap for the treatment of patients with the CAPS.
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.
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/MWS and Still's disease, however only patients with Still's disease will be newly enrolled from this point on, enrollment for the FCAS/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. Those Adults Still's patients, who complete the extension phase, and maintain improved clinical and laboratory parameters compared to baseline values, may continue to receive study medication at their current dose. These individuals will have their medication supplied by the manufacturing company, Regeneron, until June 2010. At that time the subjects' health insurance companies will begin to pay for their medication supply or the subjects will begin treatment with Anakinra, another IL-1 blocker. Our follow-up plans for all patients who discontinue IL-1 Trap usage will be to monitor for any medication side effects or toxicities and collect adverse event data for 3 months post discontinuation. We will help our subjects to obtain insurance coverage for IL-1Trap.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 11
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description IL-1 Trap IL-1 Trap -
- Primary Outcome Measures
Name Time Method Mean Change in Daily Scores 10 days for 4 patient, 6 days for 1 patient 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).
Mean Change in ESR 10 days for 4 patient, 6 days for 1 patient ESR change from baseline to 10 days.The Erythrocyte Sedimentation Rate (ESR) is an acute phase reactant measured to evaluate lab parameters of inflammation
Mean Change in hsCRP 10 days for 4 patient, 6 days for 1 patient 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
Mean Change in SAA 10 days for 4 patient, 6 days for 1 patient SAA change from baseline to 10 days.The serum Amyloid A (SAA) is an acute phase reactant measured to evaluate lab parameters of inflammation
Response to Treatment (ACR20) in Patients With Adult Onset Still's Disease 24 months 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.
- Secondary Outcome Measures
Name Time Method Mean Change in SF-36 Mental Component Score 24 months Short Form 36 health survey (range 0-100 for each component score), mental component score, taken by patient from baseline to 24 months. Lower scores indicate feeling depressed, anxious all the time, while higher scores indicate a state of happiness and peacefulness. (Reference: Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form health survey (SF-36). I. Conceptual framework and item selection.Med Care 1992;30:473-83.)
Mean Change in WBCs 24 months White Blood Cell count change from baseline to 24 months
Mean Change in Serum Amyloid A 24 months Mean Change in Prednisone Dose 24 months Mean Change in Ferritin 24 months Ferritin level change from baseline to 24 months
Mean Change in Tender Joint Count 24 months Count of tender joints in patient from baseline to 24 months. 68 tender joints were assessed manually in a standardized fashion. (Reference: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727.-35)
Mean Change in Tender Joint Count. 6 months Count of tender joints in patient from baseline to 6 months. 68 tender joints were assessed manually in a standardized fashion. (Reference: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727.-35)
Mean Change in C-Reactive Protein 24 months Mean Change in Erythrocyte Sedimentation Rate 24 months Mean Change in Patient's Global Assessment, by VAS in AOSD Subjects 24 months Patient's global assessment change by visual analog scale from baseline to 24 months. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The VAS had a range of 0-10 cm, with 0 as none and 10 being the worst.
Mean Change in Tender Joint Count in AOSD Subjects 24 months Count of tender joints in patient from baseline to 24 months. 68 tender joints were assessed manually in a standardized fashion. (Reference: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727.-35)
Mean Change in Swollen Joint Count in AOSD Subjects 24 months Count of swollen joints in patient from baseline to 24 months. 68 swollen joints were assessed manually in a standardized fashion. (Reference: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727.-35)
Mean Change in Patient's Global Assessment, by VAS 24 months Patient's global assessment change by visual analog scale from baseline to 24 months. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The VAS had a range of 0-10 cm, with 0 as none and 10 being the worst.
Mean Change in Physician's Global Assessment, by VAS 24 months Physician's global assessment change by visual analog scale from baseline to 24 months. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The VAS had a range of 0-10 cm, with 0 as none and 10 being the worst.
Mean Change in Patient's Assessment of Pain, by VAS 24 months Patient's global assessment of pain by visual analog scale from baseline to 24 months. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The VAS had a range of 0-10 cm, with 0 as none and 10 being the worst.
Mean Change in Patient's Assessment of Fatigue, by VAS 24 months Patient's assessment of fatigue by visual analog scale from baseline to 24 months. A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured. The VAS had a range of 0-10 cm, with 0 as none and 10 being the worst.
Mean Change in Swollen Joint Count 24 months Count of swollen joints in patient from baseline to 24 months. 68 swollen joints were assessed manually in a standardized fashion. (Reference: Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727.-35)
Mean Change in SF-36 Physical Component Score 24 months Short Form 36 health survey (range 0-100 for each component score), physical component score, taken by patient from baseline to 24 months. Lower scores indicate limited physical function, while higher scores indicate higher physical function. (Reference: Ware JE Jr, Sherbourne CD. The MOS 36-item Short-Form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-83.)
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States