Rilonacept for Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)

Phase 2

Completed

Conditions: DIRA

Interventions: Drug: Rilonacept

Registration Number: NCT01801449

Lead Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Brief Summary: Background:

- Deficiency of the IL-1 receptor antagonist (DIRA) is a condition that causes repeated episodes of inflammation. People with DIRA can have rashes, fever, and joint pain. Most treatments for DIRA are intended to control the immune system to stop these inflammations. There are drugs that can treat DIRA, but they have to be given daily as injections. Researchers want to try another drug, rilonacept, as a treatment for DIRA. It needs to be given only once a week. Rilonacept will be given to individuals who are at least 3 months old and who have DIRA.

Objectives:

- To test the safety and effectiveness of rilonacept for children and adults with DIRA.

Eligibility:

- Individuals at least 3 months old who have DIRA.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Other tests to study pain and movement will be given. Imaging studies such as bone density scans and x-rays may also be taken.

* Participants will have a minimum of four to five study visits over 12 months. Those who are on different anti-inflammatory drugs (such as anakinra) will stop taking them before beginning the study visits.

* Participants will have rilonacept injections weekly while on this study. The dose will be adjusted as needed to help treat the DIRA symptoms. Participants will keep a diary to monitor their symptoms and any side effects.

* Treatment with rilonacept will be given for 1 year. Participants will have study visits to monitor the treatment. They will provide blood samples and have other tests at these study visits.

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 specific cytokine pathways are dysregulated. Monogenic defects in the IL-1 pathway cause cryopyrin associated periodic syndromes (CAPS) and deficiency of the IL-1 receptor antagonist (DIRA), the latter is caused by mutations affecting the IL-1-receptor antagonist gene (IL1RN). Both disorders respond with complete resolution of the inflammatory response to treatment with the short acting IL-1 blocking agent anakinra. This exploratory study aims to examine the utility of the long acting IL-1 inhibitor rilonacept (rilonacept; Regeneron Pharmaceuticals, Inc.)

This pilot study is designed to address: 1) the utility and dosage of rilonacept needed to achieve inflammatory remission in children with DIRA who have shown a response to treatment with anakinra \[Kineret\[registered\]\]; and 2) to evaluate the safety and pharmacokinetics in young children on rilonacept.

Rilonacept is a recombinant fusion protein with picomolar affinity for IL-1 and a half-life of approximately 7.5 days in humans. It is approved by the Food and Drug Administration (FDA) for the treatment of adults and children 12 years of age and older with Cryopyrin-Associated Periodic Syndromes (CAPS), and was tested in the clinically milder forms of CAPS including Familial Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

In this study, clinical, and laboratory parameters will initially be measured at baseline following a withdrawal of anakinra for 24 hours. Subjects will receive a course of therapy with rilonacept that is predicted to induce inflammatory remission. Clinical and laboratory measures of inflammation will be assessed; rilonacept dose escalation will be implemented as necessary to achieve clinical and laboratory remission. Subjects will remain on study for 12 months and primary end point will be evaluated at 6 months.

Those subjects who complete the 1-year treatment period and maintain improved clinical and laboratory parameters compared to baseline values, may continue to receive study medication at their current dose. Principal investigator will help to obtain insurance coverage for rilonacept for their continued treatment, and will discuss with Regeneron Pharmaceuticals, Inc. for additional supplies of rilonacept for these subjects.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 6

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Rilonacept Treatment	Rilonacept	Rilonacept loading dose of 4.4 mg/kg/week followed by maintenance dose of 2.2 mg/kg/week. Total duration of the study 24 months. Maintenance dose could be escalated to 4.4 mg/kg/week or further to 6.6 mg/kg/week for 3 months only.

Primary Outcome Measures

Name	Time	Method
Number of Subjects Who Maintained Inflammatory Remission With Rilonacept	6 months	Inflammatory remission criteria remission criteria were defined as meeting all of the following criteria: a diary score of \<0.5 (reflecting no fever, skin rash or bone pain), normal acute phase reactants (C-reactive protein (CRP) \<0.5 mg/dL), no objective skin rash or radiological evidence of active bone lesions on x-ray.

Secondary Outcome Measures

Name	Time	Method
Height	Baseline	Antropometric measurements - Height z-score
Dual-energy X-ray Absorptiometry (DEXA) Scores	Baseline	Mean z-scores of anteroposterior lumbar (AP) spine were used for comparisons
Childhood Health Assessment Questionnaire (CHAQ)	Baseline	The Childhood Health Assessment Questionnaire (CHAQ) is a patient self-assessment (or parent assessment) tool 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). The scores are summed and divided by the number of total categories answered to arrive at a final value.
Pediatric Quality of Life Inventory (PedsQL)	Baseline	Pediatric Quality of Life Inventory (PedsQL)-assess functional impairment and change in treatment and health-related quality of life respectively. Responses on this scale are transformed into a 0-100 scale, with 0 being the worst value for health-related quality of life and 100 being the best possible value for health-related quality of life.
Weight	Baseline	Antropometric measurements - Weight z-score