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

A Pilot Open-Label Study of Rilonacept (Arcalyst) in the Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)

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.

Study Overview

• Status: Completed
• Conditions: DIRA
• Intervention / Treatment: Drug: Rilonacept

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

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: 3 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA

  1. Male or female pediatric and adult subjects with mutation positive IL1RN indicating DIRA. For the first five patients enrolled, they must have been on a stable dose of anakinra during the 2-week period prior to screening visit. If the subject is on other medications such as NSAIDs, methotrexate and/or oral steroids, it is a requirement that these doses have been stable during the 2-week period prior to screening visit.
  2. Subjects greater or equal to 3 months of age (however the first 5 patients enrolled will be over 2 years of age). Subjects 3 months old or older will be enrolled after SMC data review of the first 5 enrolled patients.
  3. Participation in NIH study #03-AR-0173 ( Studies of the Natural History, Pathogenesis and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CRMO, Still s Disease, Behcet s Disease, and other Undifferentiated Autoinflammatory Diseases )
  4. Subjects currently treated with anakinra may be enrolled in this study even though their DIRA may be quiescent. For these subjects, a history of active DIRA prior to treatment with anakinra will be sufficient. Subjects will not take anakinra 24 hours before initiation of drug treatment. Treatment naive patients will also be enrolled after SMC data review of the first 5 enrolled patients.
  5. Females of childbearing potential (young women who have had at least one menstrual period regardless of age) must have a negative serum pregnancy test at screening and a urine pregnancy test prior to administration of study medication.
  6. Females of childbearing age and men able to father a child and who are sexually active, who agree to use two forms of effective birth control, including abstinence.

  7. Negative Purified Protein Derivative (PPD) test using 5 T.U. intradermal testing or the QuantiFERON(SqrRoot) - TB Gold test per the Centers for Disease Control and Prevention (CDC) guidelines, and no evidence of active tuberculosis (TB) on chest X-ray.

     Subjects with latent TB (positive PPD or QuantiFERON - TB Gold test) currently treated with adequate therapy for at least one month prior to first dose of study medication may be included. Full prophylaxis regimens will be continued while on the study.

     Subjects who have had active TB in the past with documentation of adequate treatment may be included with strict clinical and radiological follow-up as per current guidelines.

     The Infectious diseases service will be consulted regarding all patients with evidence of TB infection (latent or active, current or history) prior to enrollment, and as appropriate during the study.

     Subjects who have been BCG-vaccinated will also be tested. Interpretation of PPD and QuantiFERON - TB Gold test in BCG recipients will be the same as for subjects who have not received BCG vaccine.

     Guardian/parent able to understand, and complete study-related questionnaires.

     Guardian/parent able and willing to give informed consent and abide with the study procedures.

     EXCLUSION CRITERIA

  1. Treatment receiving a live virus vaccine (such as the measles, mumps, and rubella vaccine) during the 3 months prior to baseline visit. No live vaccines will be allowed throughout the course of this study.
  2. Presence of active infections or a history of pulmonary TB infection without documented adequate therapy. Subjects with current active TB, or recent close exposure to an individual with active TB, are excluded from the study. Exceptions include patients with latent TB treated with adequate therapy for at least one month prior to the first dose of study medication, and patients with history of TB with documentation of adequate treatment.
  3. Positive test for, or prior history of, HIV, or Hepatitis B or C.
  4. History of malignancy. Subjects deemed cured of superficial malignancies such as cutaneous basal or squamous cell carcinomas, or in situ cervical cancer may be enrolled.
  5. Known hypersensitivity to Chinese Hamster Ovary cell-derived biological or any components of rilonacept.
  6. Presence of any additional rheumatic disease or significant systemic disease. For example, major chronic infectious/ inflammatory/ immunologic disease (such as inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, SLE in addition to autoinflammatory disease).

  7. Presence of any of the following laboratory abnormalities at enrollment visit:

     creatinine greater than 1.5xULN

     WBC less than 3.0x103/mm3

     ANC less than 800 cells/mL

     platelet count less than 150,000 mm3

     ALT or AST greater than 2.0x ULN.

  8. Lactating, breastfeeding or pregnant females.
  9. Enrollment in any other investigational treatment study or use of an investigational agent, or has not yet completed at least 4 weeks or 5 half-lives, whichever is longer, since ending another investigational device or drug trial.
  10. Subjects for whom there is concern about compliance with the protocol procedures.
  11. Presence of other severe acute or chronic medical or psychiatric condition, or significant laboratory abnormality requiring further investigation that may cause undue risk for the subject s safety, inhibit protocol participation, or interfere with interpretation of study results, and in the judgment of the Investigator would make the subject inappropriate for entry into this study.
  12. Subjects who have received a DMARDs (except methotrexate) and or TNFblocking agent within 4 half-lives prior to study entry.
  13. Men able to father a child and who are sexually active, who do not agree to use 2 form of effective birth control, including abstinence during the duration of the study an for at least 28 days following the last dose of rilonacept.
  14. Females of childbearing potential (woman greater than 12 or who have had at least 1 menstrual period regardless of age) who are sexually active and who do not agree to use 2 effective methods of birth control, including abstinence during the duration of the study an for at least 28 days following the last dose of rilonacept.

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: Rilonacept Treatment; 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.	Drug: Rilonacept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Who Maintained Inflammatory Remission With Rilonacept	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.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Height	Antropometric measurements - Height z-score	24 months after rilonacept initiation
Height	Antropometric measurements - Height z-score	Baseline
Weight	Antropometric measurements - Weight z-score	24 months after rilonacept initiation
Weight	Antropometric measurements - Weight z-score	Baseline
Childhood Health Assessment Questionnaire (CHAQ)	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.	24 months after rilonacept initiation
Childhood Health Assessment Questionnaire (CHAQ)	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.	Baseline
Dual-energy X-ray Absorptiometry (DEXA) Scores	Mean z-scores of anteroposterior lumbar (AP) spine were used for comparisons	12 months after rilonacept initiation
Dual-energy X-ray Absorptiometry (DEXA) Scores	Mean z-scores of anteroposterior lumbar (AP) spine were used for comparisons	Baseline
Pediatric Quality of Life Inventory (PedsQL)	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.	24 months after rilonacept initiation
Pediatric Quality of Life Inventory (PedsQL)	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.	Baseline

Collaborators and Investigators

• Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Collaborators: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Gina A Montealegre, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009 Jun 4;360(23):2426-37. doi: 10.1056/NEJMoa0807865.
• Garg M, de Jesus AA, Chapelle D, Dancey P, Herzog R, Rivas-Chacon R, Muskardin TLW, Reed A, Reynolds JC, Goldbach-Mansky R, Sanchez GAM. Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. JCI Insight. 2017 Aug 17;2(16):e94838. doi: 10.1172/jci.insight.94838. eCollection 2017 Aug 17.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: February 12, 2013
• Primary Completion (Actual): April 28, 2016
• Study Completion (Actual): April 28, 2016

Study Registration Dates

• First Submitted: February 27, 2013
• First Submitted That Met QC Criteria: February 27, 2013
• First Posted (Estimate): February 28, 2013

Study Record Updates

• Last Update Posted (Actual): October 16, 2017
• Last Update Submitted That Met QC Criteria: September 13, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: Clinical Trial; Rilonacept; DIRA; IL-1; Autoinflammatory Syndrome
• Additional Relevant MeSH Terms: Anti-Inflammatory Agents; Rilonacept
• Other Study ID Numbers: 130086; 13-AR-0086 (Other Identifier: The National Institutes of Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: NIH Biomedical Translational Research Information System

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No