Open-label Study of Anakinra in MPS III

Study Overview
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Brief Summary
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Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a disorder of metabolism, associated with insufficient production of a lysosomal enzyme needed for normal cell function. As a consequence of the cellular dysfunction, patients with this disorder develop progressive, irreversible neurodegeneration. Sadly, to date no evidence-based treatments are available. Inflammation has been connected with disease pathogenesis in the MPS disorders. Therapies aimed at decreasing inflammation are currently being studied in many MPS disorders and benefits in both brain and other parts of the body have been reported.Decreasing interleukin-1 (IL-1) in an animal model of MPS III showed benefits in brain disease and behavior. Thus, we think that anakinra (Kineret), which decreases IL-1 levels in the body, will improve behavioral and other problems in children with MPS III. Anakinra is approved by the FDA for treatment of rheumatoid arthritis (RA) and neonatal-onset multisystem inflammatory disease (NOMID). It is not approved for any MPS disorder. The design of this study is an open-label, single center, pilot study of 20 participants with MPS III. There will be an initial screening visit, followed by an 8-week observational period, then a 36-week treatment period, and finally another 8-week observational period to determine any effects of withdrawal from the treatment. During visits the participants will undergo a medical history, a physical examination, and anthropometric measurements. Blood, urine, and stool will be collected for biomarker levels and safety laboratory studies. Questionnaires will be completed with questions related to behavior, stooling, sleep, and activities of daily living. Seizure and movement disorders will be monitored as well. The most common risks of receiving anakinra, based on RA and NOMID experience, include local injection site reactions, headache, nausea, vomiting, arthralgia, and flu-like symptoms. The most serious potential risk is a serious infection and neutropenia. However, because so few people with MPS have been treated with anakinra, all the risks related to MPS patients receiving anakinra are not currently known. Additional risks related to taking part in the study include some pain, bruising, and/or bleeding due to blood draws/peripheral IV placement, and discomfort with completing some of the questionnaires. The expected potential direct benefits include, but are not limited to, improved behavior, sleep, stooling, communication, mood, and gait; as well as decreased seizure frequency, disordered movement and fatigue. However, there is no guarantee that participants will get any benefit from being in this study.

Official Title
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Open-label Pilot Study of the Effects of Anakinra in Mucopolysaccharidosis (MPS) III

Conditions
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Mucopolysaccharidosis III

Intervention / Treatment
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* Biological: anakinra


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MPS III ≥ 4 years of age Patient or parent/legal guardian is able and willing to provide informed consent. For patients 7 to 17 years of age, assent must also be provided when cognitively possible. If on Genistein, must have been on a stable dose for 6 months prior to enrollment If on melatonin or other sleep medications, must have been on stable doses for the past 3 months Exclusion Criteria: Currently enrolled in another ongoing clinical treatment trial Previous or current treatment with anakinra, canakinumab or any other IL-1 inhibitor. Use of the following therapies prior to enrollment: Narcotic analgesics within 24 hours prior to enrollment. Tocilizumab, dapsone or mycophenolate mofetil within 3 weeks prior to enrollment. Etanercept, leflunomide, thalidomide, or cyclosporine or intraarticular, intramuscular, intravenous, or oral administration of glucocorticoids within 4 weeks prior to enrollment. Intravenous immunoglobulin (IVIG), adalimumab, or methotrexate within 8 weeks prior to enrollment. Infliximab, 6-mercaptopurine, azathioprine, cyclophosphamide or chlorambucil within 12 weeks prior to enrollment. Rituximab within 26 weeks prior to enrollment Live vaccines within 1 month prior to enrollment. Known presence or suspicion of active, chronic or recurrent serious bacterial, fungal or viral infections, including tuberculosis, HIV infection or hepatitis B or C infection. Clinical evidence of liver disease or liver injury as indicated by presence of abnormal liver tests: AST or ALT > 5 x ULN, or AST or ALT > 3 x ULN accompanied by elevated bilirubin >2 x ULN. Presence of severe renal function impairment (estimated creatinine clearance < 30 mL/min/1.73m2). Presence of neutropenia. History of malignancy. Known hypersensitivity to E coli-derived proteins, or any components of Kineret® (anakinra). Pregnant or lactating women. Current active infection; History of serious opportunistic infection (e.g., bacterial [Legionella and Listeria]; tuberculosis [TB]; invasive fungal infections; or viral, parasitic, and other opportunistic infections); Positive TB skin test, positive Quantiferon-TB Gold TB test, positive chest X-ray, or a recent exposure to TB Requirement for live vaccine exposure that would be expected to occur during the time frame of the study

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment<br>anakinra 100 mg subcutaneous once daily | Biological: anakinra<br>* anakinra single-use prefilled glass syringes<br>* Other names: Kineret;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| multi-domain responder index (MDRI) - composite outcome | MDRI composite outcome comprised of the Sanfilippo Behavior Rating Scale, Children's Sleep Health Questionnaire, Autism Parent Stress Index, PROMIS fatigue survey, seizure log, movement disorder log, and Non-communicating Children's Pain Checklist - Revised. MDRI will be calculated as the sum of scores from the components. Subjects will receive a score for each component of the MDRI listed above. A score of 0 will be given for a change in score less than the Minimal Clinically Important Difference (MCID). A score of +1 (improvement) or -1 (worsening) will be given for a change in score of ≥ 1 MCID and < 2 times MCID. A score of +2 (improvement) or -2 (worsening) will be given for a change in score of ≥ 2 and <3 times MCID. A score of +3 (improvement) or -3 (worsening) will be given for a change in score of ≥ 3 times MCID. | up to 8 weeks |