Canakinumab to Treat Neonatal-Onset Multisystem Inflammatory Disease

NCT00770601 | Terminated Phase 3 Results

• 2 other identifiers: CACZ885D220109-AR-0006
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine whether a medicine called canakinumab is safe and effective for treating patients with neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome. This disease can cause rash, joint deformities, brain inflammation, problems with the eyes and learning difficulties. Canakinumab is an experimental drug that inhibits the action of a protein produced by the body called human IL-1beta, which is responsible for the symptoms in NOMID and also contributes to many other kinds of inflammatory diseases. Patients 2 years of age and older with NOMID / CINCA may be eligible for this study. Participants undergo the following procedures: Screening Phase

• Medical history and review of medical records
• Blood tests
• Daily diary of symptoms and medicines take Washout/Lead-in Phase
• Discontinuation of anakinra or other medications, a 6 to 48-hour run-in period (only for patients who discontinued anakinra or other IL-1 blocking therapy). Treatment Phase
• Injection of canakinumab under the skin every 8 weeks for 6 months
• Monitoring and evaluations during treatment, including:
• Quality-of-life questionnaires and daily diary
• Vital signs measurements (heartbeat, blood pressure, temperature)
• Blood tests
• Electrocardiogram
• Tuberculosis skin test
• Neurological, eye and skin examinations at beginning and end of study
• Cognitive evaluation at beginning and end of study
• Lumbar puncture (spinal tap) at the beginning of the study, 2 weeks after the second dosing of canakinumab and at the end of the study
• X-rays and bone density scan at beginning and end of study
• Magnetic resonance imaging (MRI) of the head at beginning and end of study Follow-up Phase
• Monthly clinic visits after the last dose of canakinumab for a minimum of 60 days End-of-Study Evaluation
• Series of tests 8 weeks after last dose of canakinumab to evaluate treatment response and side effects

Conditions

NOMID; CINCA Syndrome

Keywords

NOMID; CINCA Syndrome; Canakinumab

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Complete Remission and Relapse After 6 Months of Canakinumab Treatment.

  The primary endpoint of the study was the percentage of participants experiencing a relapse Central nervous system (CNS) relapse and/or inflammatory relapse) during 6-month open label administration of canakinumab in participant with NOMID/Chronic Infantile Neurological, Cutaneous, Articular Syndrome (CINCA). Complete remission consisted of inflammatory remission and CNS remission. 1 Inflammatory (systemic) remission was defined as follows (all criteria to be fulfilled): -Serum C-reactive protein (CRP) AND serum amyloid A (SAA) ≤ 10 milligrams/litre AND -daily diary score (mean score/week) ≤ 2. 2) CNS remission was defined as follows: Headache score (from the daily diary, mean score/week) \< 0.5 AND, when a lumbar puncture was performed: Normal values of white cell count (WBC) (≤15 cells/mm3) in CSF.

  6 months

Study Arms (1)

Canakinumab

EXPERIMENTAL

Participants received body-weight stratified dosage of canakinumab treatment at 300 milligrams (mg) (for participants weighing more than 40 kilograms (kg)) and at 2 mg/kg (for participants weight less than or equal to 40 kg) subcutaneously every 4-8 weeks as per investigator discretion for a treatment period of 6 months. The first 3 Neonatal-Onset Multisystem Inflammatory Disease (NOMID) participants enrolled received a dose of 150 mg (\>40 kg) and 2 mg/kg for children \<40 kg. Since this dose was insufficient to fully control the symptoms of the disease the 300 mg / 4mg/kg dose was introduced by Protocol Amendment 2.

Drug: Canakinumab

Interventions

Canakinumab DRUG

Canakinumab

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Male and female patients of greater than or equal to 2 years of age at the time of the screening visit.
• Patient's informed consent (for greater than or equal to 18 years of age), or in pediatric patients, parents' or legal guardian's informed consent and patient's assent to the protocol whenever possible.
• Females of childbearing potential (young women who have had at least one menstrual period regardless of age) and/or aged greater than or equal to 8 years must have a negative serum pregnancy test at screening and a negative urine pregnancy test at each 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, must agree to use a form of effective method of contraception (e.g. birth control pills, abstinence, double-barrier contraception, etc.) during the study (from the date of screening) and for at least 3 months following the last dose. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Presence, or history (prior to anakinra treatment), of at least 2 of the following clinical manifestations:
• Typical NOMID urticarial rash.
• Central nervous system (CNS) involvement: increased intracranial pressure (greater than 180 mm water), papilledema, cerebral spinal fluid pleocytosis (white cell count greater than 6 cells/mm(3)), stroke, seizures, and/or sensorineural hearing loss.
• Typical arthropathic changes on X-rays: epiphysial and/or patellar overgrowth.
• Onset of NOMID/CINCA before or at 6 months of age.
• Patients requiring oral steroids, NSAIDs and/or disease-modifying antirheumatic drugs (DMARDs) can be enrolled if they are on a stable dose (oral steroids: less than 20 mg/day or less than or equal to 0.4 mg/kg prednisone or prednisone equivalent, whichever applies) for at least 4 weeks prior to the screening visit. Steroid therapy may be tapered during treatment with canakinumab after the first canakinumab treatment period / cycle, at the discretion of the investigator.
• Negative tuberculin skin test reaction (PPD 5 tuberculin units or as according to local standard practice) (less than 5mm induration) at 48 to 72 hours after administration at the screening visit or within 2 months prior to the screening visit, according to national guidelines. Patients who have a positive PPD skin test with a documentation of BCG vaccination, who are at low environmental risk for tuberculosis (TB) infection or reactivation, and have a negative chest X-ray can be included. A positive PPD test will be defined using the MMWR 2000 guidance, summarized as criteria for tuberculin positivity by risk group.
• Able to comply with the requirements of the study.

You may not qualify if:

• Subjects meeting any of the following criteria will be excluded from entry into or continuation in the study unless sponsor approval is obtained:
• Pregnant or breastfeeding women.
• Participation in any clinical trial investigation within 4 weeks prior to dosing or longer if required by local regulation, with the exception of trials with anakinra and/or canakinumab.
• In case of previous treatment with biologic agents or DMARDs, an appropriate washout period (as according to the recognized duration of effect and half lives) will be required for such patients to be eligible to participate in the trial, e.g.:
• Previous treatment and required washout period prior to baseline and thereafter:
• Rituximab, 26 weeks
• Infliximab, 12 weeks
• Adalimumab, 8 weeks
• Etanercept, 4 weeks
• Anakinra, 1 day
• Any other investigational biologics, 8 weeks
• Leflunomide, 4 weeks
• Thalidomide, 4 weeks
• Cyclosporine, 4 weeks
• i.v. immunoglobulin (i.v. Ig), 8 weeks

Sponsors & Collaborators

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

Study Sites (1)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 9

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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 BACKGROUND

• Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum. 2004 Feb;50(2):607-12. doi: 10.1002/art.20033.

  PMID: 14872505 BACKGROUND

• Hirsch E, Irikura VM, Paul SM, Hirsh D. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11008-13. doi: 10.1073/pnas.93.20.11008.

  PMID: 8855299 BACKGROUND

• Sibley CH, Chioato A, Felix S, Colin L, Chakraborty A, Plass N, Rodriguez-Smith J, Brewer C, King K, Zalewski C, Kim HJ, Bishop R, Abrams K, Stone D, Chapelle D, Kost B, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2015 Sep;74(9):1714-9. doi: 10.1136/annrheumdis-2013-204877. Epub 2014 Jun 6.

  PMID: 24906637 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page
• link to the results on Novartis results database

MeSH Terms

Conditions

Cryopyrin-Associated Periodic Syndromes

Interventions

canakinumab

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

Study was terminated prematurely due to multiple protocol amendments for change in study design; limited number of participants; availability of sufficient clinical data for higher doses of drug and lack of severe NOMID subjects for further evaluation.

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

[email protected]

+1 (862) 778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2008
• First Posted: October 10, 2008
• Study Start: January 26, 2009
• Primary Completion: February 17, 2011
• Study Completion: February 17, 2011
• Last Updated: June 10, 2021
• Results First Posted: June 10, 2021

Record last verified: 2021-06

Locations

US (1)