Anakinra to Treat Patients With Neonatal Onset Multisystem Inflammatory Disease

NCT00069329 | Terminated Phase 1 Results

• 4 other identifiers: 030298ZIAAR041138-08NCT0006932903-AR-0298
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Nervous System Malformations; Arthropathy, Neurogenic; Urticaria; Papilledema

Keywords

Central Nervous System; Abnormalities; Arthropathy; Urticaria; Papilledema; Auto-Inflammation; Inflammatory Disease; Neonatal Onset Multisystem Inflammatory Disease; NOMID; CINCA Syndrome

Outcome Measures

Primary Outcomes (21)

• 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

Study Arms (1)

NOMID treatment arm

EXPERIMENTAL

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

Interventions

anakinra DRUG

daily injection of subcutaneous injection

Also known as: Kineret

NOMID treatment arm

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• There is no age limitation.
• 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.
• Onset of manifestations of NOMID/CINCA at less than or equal to 6 months of age.
• Stable dose of steroids, NSAIDs, DMARDs for 4 weeks prior to enrollment visit.
• 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.
• Patient's or legal guardian's ability and willingness to give informed consent.
• 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.
• 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.

You may not qualify if:

• Having received live virus vaccine during 3 months prior to baseline visit (1st visit to NIH).
• 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.
• Positive testing for HIV, Hepatitis B or C known or documented at screening, enrollment or baseline visit.
• Have a history of or concomitant diagnosis of congestive heart failure.
• History of malignancy.
• Recent use of IL-1 antagonist within the last three months or prior use of anti CD4 antibody.
• Known hypersensitivity to E. coli derived products or any components of anakinra.
• 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).
• 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).
• 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.
• Subjects for whom there is concern about compliance with the protocol procedures by subject and/or parent/s and legally acceptable representative/s.
• Lactating females or pregnant females.
• Patients with asthma will only be included after evaluation by a pulmonary and infectious disease consultation.

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 (8)

• 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.

  PMID: 12032915 BACKGROUND

• 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.

  PMID: 9108844 BACKGROUND

• 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.

  PMID: 11687797 BACKGROUND

• 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.

  PMID: 28118536 DERIVED

• 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.

  PMID: 27143789 DERIVED

• 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.

  PMID: 25223501 DERIVED

• 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.

  PMID: 22294344 DERIVED

• 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.

  PMID: 16899778 DERIVED

MeSH Terms

Conditions

Nervous System Malformations; Arthropathy, Neurogenic; Urticaria; Papilledema; Congenital Abnormalities; Joint Diseases; Cryopyrin-Associated Periodic Syndromes

Interventions

Interleukin 1 Receptor Antagonist Protein

Condition Hierarchy (Ancestors)

Nervous System Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Musculoskeletal Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Eye Diseases; Hereditary Autoinflammatory Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Chronic Inducible Urticaria; Chronic Urticaria; Cold Urticaria; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Limitations and Caveats

Data reported is on 26 patients who completed their 3 year assessment and 20 of these patients also completed their 5 year assessment.

Results Point of Contact

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

goldbacr@mail.nih.gov

+1 301 435 6243

Study Officials

• Raphaela T Goldbach-Mansky, M.D.

  National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2003
• First Posted: September 23, 2003
• Study Start: September 1, 2003
• Primary Completion: April 1, 2010
• Study Completion: April 1, 2010
• Last Updated: December 1, 2016
• Results First Posted: December 1, 2016

Record last verified: 2016-10

Data Sharing

• IPD Sharing: Will share

Locations

US (1)