Anakinra to Treat Patients With Neonatal Onset Multisystem Inflammatory Disease

A Long-Term Outcome Study With the IL-1 Receptor Antagonist Anakinra/Kineret in Patients With Neonatal Onset Multisystem Inflammatory Disease (NOMID/CINCA Syndrome) A Therapeutic Approach to Study the Pathogenesis of This Disease

This study will evaluate the safety and effectiveness of anakinra (Kineret) for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. This disease can cause rash, joint deformities, brain inflammation, eye problems, and learning difficulties. Immune suppressing medicines commonly used to treat other pediatric rheumatologic diseases do not suppress NOMID symptoms and, if used long-term and in high doses, can cause harmful side effects. Anakinra, approved by The Food and Drug Administration for treating rheumatoid arthritis in adults, blocks a substance called IL-1 that may be an important factor in causing the inflammation in NOMID.

Study Overview

• Status: Terminated
• Conditions: Nervous System Malformations; Urticaria; Papilledema; Arthropathy, Neurogenic
• Intervention / Treatment: Drug: anakinra

Detailed Description

This study uses the IL-1 receptor antagonist anakinra to treat children and adults with Neonatal-Onset Multisystem Inflammatory Disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. NOMID/CINCA syndrome is a rare genetic systemic auto-inflammatory disease that is characterized by a triad of symptoms, including a persistent urticaria-like skin rash, an arthropathy associated with patellar and epiphyseal osseous overgrowth, and neurological manifestations, including chronic aseptic meningitis, optic disc edema, high frequency hearing loss, and mental retardation. Spontaneous genetic mutations in the NACHT domain of CIAS1, a gene located on chromosome 1 have been recently identified in about half of the patients with NOMID/CINCA syndrome. CIAS1 encodes a protein, cryopyrin that is associated with up-regulation of IL-1 production in vitro, which has formed the rationale to target the IL-1 pathway in children with NOMID. During an up to 3- week enrollment period before initiating therapy, we will collect self/parent reported daily diary data and serological samples on up to 3 occasions one week apart, to determine baseline disease activity. These data may be gathered by collaborating centers. At the end of the observation period, patients will be admitted to the NIH for a standardized clinical evaluation and initiation of treatment with anakinra administered at 1 mg/kg/day by regular daily subcutaneous injections. If patients do not fulfill improvement criteria at 1 month, the dose will be escalated between 0.5 and 1 mg/kg/day increments to obtain inflammatory remission. An initial withdrawal study in a subset of 11 patients was performed. The clinical improvement at 3-4 months and the change in serum amyloid A levels (SAA) (a sensitive inflammatory marker) from before treatment to 3-4 months post treatment, and drug safety are the primary clinical outcomes of this study. To assess long-term safety and efficacy, all patients will be observed during an open ended extension phase of the study. Clinical and laboratory parameters will be used to assess safety and efficacy throughout the trial. All patients will be seen every 6 months and annually (as calculated from initiation of anakinra treatment) to further evaluate safety and long term outcomes. During the open ended extension phase of the study, patients who have residual clinical or laboratory evidence of active inflammation may have their dose increased between 0.5 and 1 mg/kg/day increments to a maximum dose of 10 mg/kg/per day to achieve clinical remission. In addition, since no data on the pharmacokinetics (PK) of anakinra in pediatric patients is available with doses exceeding 2 mg/kg/day, we plan to determine the PK of anakinra with each dose escalation.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

-INCLUSION CRITERIA:

1. There is no age limitation.

2. Patients fulfill at least 2 of the following 3 clinical manifestations:

   • Typical NOMID rash
   • CNS involvement (papilledema, CSF pleocytosis, sensorineural hearing loss)
   • Typical arthropathic changes on radiograph (epiphyseal and/or patellar overgrowth.
3. Onset of manifestations of NOMID/CINCA at less than or equal to 6 months of age.
4. Stable dose of steroids, NSAIDs, DMARDs for 4 weeks prior to enrollment visit.
5. Washout period for biologics: 6 half-lives before anakinra administration for all drugs with anti TNF properties. For etanercept (6 half-lives=24 days) this calculates to drug discontinuation 3 days before enrollment into the observation period, for infliximab and adalimumab (6 half-lives=48 days) drug will be discontinued 27 before the observation period, and for thalidomide (6 half-lives=3 days) drug will be discontinued for 3 days prior to anakinra administration.
6. Patient's or legal guardian's ability and willingness to give informed consent.
7. 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 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, will be asked to use a form of effective birth control, including abstinence.
8. Negative PPD test using 5 T.U. intradermal testing per CDC guidelines with exception of inclusion criteria #9 below.
9. Patients with latent TB (positive PPD test) must have adequate therapy for TB initiated prior to first dose of study medication as recommended in published guidelines.

EXCLUSION CRITERIA:

1. Having received live virus vaccine during 3 months prior to baseline visit (1st visit to NIH).
2. Patients with active infections or a history of pulmonary TB infection with or without documented adequate therapy, Patients with current active TB, or recent close exposure to an individual with active TB are excluded from the study.
3. Positive testing for HIV, Hepatitis B or C known or documented at screening, enrollment or baseline visit.
4. Have a history of or concomitant diagnosis of congestive heart failure.
5. History of malignancy.
6. Recent use of IL-1 antagonist within the last three months or prior use of anti CD4 antibody.
7. Known hypersensitivity to E. coli derived products or any components of anakinra.
8. Presence of any other rheumatic disease or major chronic infectious/inflammatory/immunologic disease (e.g. inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, SLE in addition to NOMID/CINCA).
9. Presence of the following at enrollment visit: ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories values, creatinine greater than 1.5 xULN, WBC less than 3.6x10(9)/l; platelet count less than 150,000 mm(3).
10. Enrollment in any other investigational clinical study or receiving an investigational agent, or has not yet completed at least 4 weeks since ending another investigational device or drug trial.
11. Subjects for whom there is concern about compliance with the protocol procedures by subject and/or parent/s and legally acceptable representative/s.
12. Lactating females or pregnant females.
13. Patients with asthma will only be included after evaluation by a pulmonary and infectious disease consultation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NOMID treatment arm; All patients enrolled received daily doses of subcutaneous injection of increased doses of anakinra starting at 0.5mg/kg/day up to a maximum 10mg/kg/day to achieve disease remission.	Drug: anakinra; daily injection of subcutaneous injection; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches)	"The severity of the main symptoms of the disease were scored on a scale from 0 (no symptoms) to 4 (highest severity) on a daily basis using a diary. Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting. Each of the diary variables was evaluated as a mean value for a period preceding the visits. The baseline value was the mean value of the 5-30 last days before the first dose of Kineret. For the subsequent visits, the mean value of the last 30 days with data before each visit was used as the response variable."	Baseline
Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches)	"The severity of the main symptoms of the disease were scored on a scale from 0 (no symptoms) to 4 (highest severity) on a daily basis using a diary. Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting. Each of the diary variables was evaluated as a mean value for a period preceding the visits. The baseline value was the mean value of the 5-30 last days before the first dose of Kineret. For the subsequent visits, the mean value of the last 30 days with data before each visit was used as the response variable."	36 months
Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches)	"The severity of the main symptoms of the disease were scored on a scale from 0 (no symptoms) to 4 (highest severity) on a daily basis using a diary. Five key symptoms were included in the primary variable DSSS: fever, headache, rash, joint pain, and vomiting. Each of the diary variables was evaluated as a mean value for a period preceding the visits. The baseline value was the mean value of the 5-30 last days before the first dose of Kineret. For the subsequent visits, the mean value of the last 30 days with data before each visit was used as the response variable."	60 months
Patient / Parent Global Score of Overall Disease Activity	Visual analog assessment of how arthritis affects the patient as rated by the patient themselves or parent. Measured on scale from very well (0 mm) to very poor (100 mm).	Baseline
Patient / Parent Global Score of Overall Disease Activity	Visual analog assessment of how arthritis affects the patient as rated by the patient themselves or parent. Measured on scale from very well (0 mm) to very poor (100 mm).	36 months
Patient / Parent Global Score of Overall Disease Activity	Visual analog assessment of how arthritis affects the patient as rated by the patient themselves or parent. Measured on scale from very well (0 mm) to very poor (100 mm).	60 months
Parent /Patient Pain Rating	Visual analog assessment of how much pain the patient experienced in past week due to illness as rated by the patient themselves or parent. Measured on scale from no pain (0 mm) to very severe pain (100 mm).	Baseline
Parent /Patient Pain Rating	Visual analog assessment of how much pain the patient experienced in past week due to illness as rated by the patient themselves or parent. Measured on scale from no pain (0 mm) to very severe pain (100 mm).	36 months
Parent /Patient Pain Rating	Visual Analog assessment of how much pain the patient experienced in past week due to illness as rated by the patient themselves or parent. Measured on scale from no pain (0 mm) to very severe pain (100 mm).	60 months
Childhood Health Assessment Questionnaire (CHAQ)	Patient self-assessment (or parent assessment) for how illness affects ability to function in daily life. Includes overall score, overall pain rating, overall global evaluation, subcategories for dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. Measured on scale of 0-3 from 'Without any difficulty' (0) to 'Unable to do' (3).	Baseline
Childhood Health Assessment Questionnaire (CHAQ)	Patient self-assessment (or parent assessment) for how illness affects ability to function in daily life. Includes overall score, overall pain rating, overall global evaluation, subcategories for dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.Measured on scale of 0-3 from 'Without any difficulty' (0) to 'Unable to do' (3).	36 months
Childhood Health Assessment Questionnaire (CHAQ)	Patient self-assessment (or parent assessment) for how illness affects ability to function in daily life. Includes overall score, overall pain rating, overall global evaluation, subcategories for dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. Measured on scale of 0-3 from 'Without any difficulty' (0) to 'Unable to do' (3).	60 months
Serum Amyloid A (SAA) Measurement	Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.	Baseline
Serum Amyloid A (SAA) Measurement	Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.	36 months
Serum Amyloid A (SAA) Measurement	Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.	60 months
C-reactive Protein (CRP) Measurement	C-reactive protein (CRP) is an inflammatory marker for NOMID. Systemic inflammatory remission was defined as a normal CRP level (≤0.5mg/dl). Analyzed at the NIH Clinical Center Laboratory.	Baseline
C-reactive Protein (CRP) Measurement	C-reactive protein (CRP) is an inflammatory marker for NOMID. Systemic inflammatory remission was defined as a normal CRP level (≤0.5mg/dl). Analyzed at the NIH Clinical Center Laboratory.	36 months
C-reactive Protein (CRP) Measurement	C-reactive protein (CRP) is an inflammatory marker for NOMID. Systemic inflammatory remission was defined as a normal CRP level (≤0.5mg/dl). Analyzed at the NIH Clinical Center Laboratory.	60 months
Erythrocyte Sedimentation Rate (ESR) Measurement	Erythrocyte Sedimentation Rate (ESR) is an inflammatory marker for NOMID. Normal ESR values are defined as ≤ 25 mm/hour. Analyzed at the NIH Clinical Center Laboratory.	Baseline
Erythrocyte Sedimentation Rate (ESR) Measurement	Erythrocyte Sedimentation Rate (ESR) is an inflammatory marker for NOMID. Normal ESR values are defined as ≤ 25 mm/hour. Analyzed at the NIH Clinical Center Laboratory.	36 months
Erythrocyte Sedimentation Rate (ESR) Measurement	Erythrocyte Sedimentation Rate (ESR) is an inflammatory marker for NOMID. Normal ESR values are defined as ≤ 25 mm/hour. Analyzed at the NIH Clinical Center Laboratory.	60 months

Collaborators and Investigators

• Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Raphaela T Goldbach-Mansky, M.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Publications and helpful links

General Publications

• Rodriguez-Smith J, Lin YC, Tsai WL, Kim H, Montealegre-Sanchez G, Chapelle D, Huang Y, Sibley CH, Gadina M, Wesley R, Bielekova B, Goldbach-Mansky R. Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation. Arthritis Rheumatol. 2017 Jun;69(6):1325-1336. doi: 10.1002/art.40055. Epub 2017 May 10.
• Chang Z, Spong CY, Jesus AA, Davis MA, Plass N, Stone DL, Chapelle D, Hoffmann P, Kastner DL, Barron K, Goldbach-Mansky RT, Stratton P. Anakinra use during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis Rheumatol. 2014 Nov;66(11):3227-32. doi: 10.1002/art.38811.
• Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint Basile G. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002 Jul;71(1):198-203. doi: 10.1086/341357. Epub 2002 May 24.
• Hashkes PJ, Lovell DJ. Recognition of infantile-onset multisystem inflammatory disease as a unique entity. J Pediatr. 1997 Apr;130(4):513-5. No abstract available.
• Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. doi: 10.1038/ng756.
• Kullenberg T, Lofqvist M, Leinonen M, Goldbach-Mansky R, Olivecrona H. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford). 2016 Aug;55(8):1499-506. doi: 10.1093/rheumatology/kew208. Epub 2016 May 3.
• Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, Zalewski C, Kim HJ, Bishop R, Hill S, Paul SM, Kicker P, Phillips Z, Dolan JG, Widemann B, Jayaprakash N, Pucino F, Stone DL, Chapelle D, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012 Jul;64(7):2375-86. doi: 10.1002/art.34409.
• Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006 Aug 10;355(6):581-92. doi: 10.1056/NEJMoa055137.

Study record dates

Study Major Dates

• Study Start: September 1, 2003
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: September 22, 2003
• First Submitted That Met QC Criteria: September 22, 2003
• First Posted (Estimate): September 23, 2003

Study Record Updates

• Last Update Posted (Estimate): December 1, 2016
• Last Update Submitted That Met QC Criteria: October 7, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Urticaria; Central Nervous System; Arthropathy; Papilledema; Inflammatory Disease; NOMID; Neonatal Onset Multisystem Inflammatory Disease; CINCA Syndrome; Abnormalities; Auto-Inflammation
• Additional Relevant MeSH Terms: Nervous System Diseases; Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Eye Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Hereditary Autoinflammatory Diseases; Skin Diseases, Genetic; Skin Diseases, Vascular; Hypersensitivity; Optic Nerve Diseases; Cranial Nerve Diseases; Joint Diseases; Urticaria; Cryopyrin-Associated Periodic Syndromes; Arthropathy, Neurogenic; Papilledema; Nervous System Malformations; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: 030298; ZIAAR041138-08 (U.S. NIH Grant/Contract); NCT00069329 (Other Identifier: National Institutes of Health); 03-AR-0298 (Other Identifier: NIHCC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: with Swedish Orphan Biovitrum Inc (SOBI)