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Anakinra to Treat Patients With Neonatal Onset Multisystem Inflammatory Disease

This study has been terminated.
(data submitted for Food and Drug Administration (FDA) approval)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) )
ClinicalTrials.gov Identifier:
NCT00069329
First received: September 22, 2003
Last updated: October 7, 2016
Last verified: October 2016
  Purpose
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.

Condition Intervention Phase
Nervous System Malformations
Arthropathy, Neurogenic
Urticaria
Papilledema
Drug: anakinra
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    "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."

  • Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    "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."

  • Diary Symptom Sum Score (DSSS) (Fever, Rash, Joint Pain, Vomiting, and Headaches) [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    "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."

  • Patient / Parent Global Score of Overall Disease Activity [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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).

  • Patient / Parent Global Score of Overall Disease Activity [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    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).

  • Patient / Parent Global Score of Overall Disease Activity [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    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).

  • Parent /Patient Pain Rating [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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).

  • Parent /Patient Pain Rating [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    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).

  • Parent /Patient Pain Rating [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    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).

  • Childhood Health Assessment Questionnaire (CHAQ) [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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).

  • Childhood Health Assessment Questionnaire (CHAQ) [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    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).

  • Childhood Health Assessment Questionnaire (CHAQ) [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    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).

  • Serum Amyloid A (SAA) Measurement [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.

  • Serum Amyloid A (SAA) Measurement [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.

  • Serum Amyloid A (SAA) Measurement [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    Serum Amyloid A is an inflammatory marker for NOMID measured using Rapid Automated Enzyme Immunoassay. Normal SAA values were defined as ≤ 10 mg/liter.

  • C-reactive Protein (CRP) Measurement [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • C-reactive Protein (CRP) Measurement [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    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.

  • C-reactive Protein (CRP) Measurement [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    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.

  • Erythrocyte Sedimentation Rate (ESR) Measurement [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Erythrocyte Sedimentation Rate (ESR) Measurement [ Time Frame: 36 months ] [ Designated as safety issue: No ]
    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.

  • Erythrocyte Sedimentation Rate (ESR) Measurement [ Time Frame: 60 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 43
Study Start Date: September 2003
Study Completion Date: April 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Kineret

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.
  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00069329

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
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)
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
ClinicalTrials.gov Identifier: NCT00069329     History of Changes
Other Study ID Numbers: 030298  ZIAAR041138-08  03-AR-0298 
Study First Received: September 22, 2003
Results First Received: May 6, 2016
Last Updated: October 7, 2016
Health Authority: United States: Federal Government
United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: with Swedish Orphan Biovitrum Inc (SOBI)

Keywords provided by National Institutes of Health Clinical Center (CC):
Central Nervous System
Abnormalities
Arthropathy
Urticaria
Papilledema
Auto-Inflammation
Inflammatory Disease
Neonatal Onset Multisystem Inflammatory Disease
NOMID
CINCA Syndrome

Additional relevant MeSH terms:
Congenital Abnormalities
Urticaria
Joint Diseases
Papilledema
Cryopyrin-Associated Periodic Syndromes
Nervous System Malformations
Arthropathy, Neurogenic
Skin Diseases, Vascular
Skin Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Musculoskeletal Diseases
Optic Nerve Diseases
Cranial Nerve Diseases
Nervous System Diseases
Eye Diseases
Hereditary Autoinflammatory Diseases
Genetic Diseases, Inborn
Skin Diseases, Genetic
Interleukin 1 Receptor Antagonist Protein
Antirheumatic Agents

ClinicalTrials.gov processed this record on December 06, 2016