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Safety, Tolerability, Ascending Dose and Dose Frequency Study of rhHNS Via an IDDD in MPS IIIA Patients

Descriptive Information
Brief Title † Safety, Tolerability, Ascending Dose and Dose Frequency Study of rhHNS Via an IDDD in MPS IIIA Patients
Official Title † A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
Brief Summary Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA. In these patients abnormal behaviors include, but are not limited to, aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average. The purpose of this study is to determine the safety and tolerability of rhHNS via ascending doses administered via an a surgically implanted intrathecal drug delivery device (IDDD) intrathecal (IT) route once monthly for 6 months in patients with MPS IIIA.
Detailed Description Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, intermediates of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser accumulation outside the brain. MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. Patients present a wide spectrum and severity of clinical symptoms. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average. No effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease. Shire Human Genetic Therapies (Shire HGT) is developing a sulfamidase enzyme replacement therapy (ERT)rhHNS for patients with MPS IIIA. rhHNS is being administered into the cerebrospinal fluid (CSF) via an surgically implanted intrathecal drug delivery device (IDDD), because when administered intravenously (IV) it does not cross the blood brain barrier (BBB). This study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (10mg,45mg and 90mg monthly for 6 months) of rhHNS administered via an IDDD in patients with Sanfilippo syndrome Type A ages greater than or equal to 3 years of age. Patients who have completed all study requirements in this study will be invited to participate in an open-label extension study that will be designed to evaluate long term safety and clinical outcomes of intrathecal administration of rhHNS.
Study Phase 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
Primary Outcome Measure † Safety
Secondary Outcome Measure † To determine (by dose group) the effects of IT administration of rhHNS, as measured by (1) change from baseline values, and (2) comparison to values obtained in a natural history study of untreated patients with MPS IIIA Surrogate Endpoint Trial
Condition † Sanfilippo Syndrome Type A (MPS IIIA)
Intervention † BiologicalRecombinant human heparan N-sulfatase
Study Arms / Comparison Groups Recombinant human heparan N-sulfatase rhHNS, HGT-1410
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Biological
Estimated Enrollment † 12
Start Date † June 2010
Completion Date September 2012
Primary Completion Date September 2012
Eligibility Criteria † Inclusion Criteria: Each patient must meet the following criteria to be enrolled in this study: - A documented deficiency in sulfamidase enzyme activity of greater than or equal to 10% of the lower limit of the normal range AND either - a normal enzyme activity level of at least 1 other sulfatase or 2 documented mutations •At least 3 years of age and have a developmental age above 1 year - Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family. - The patient's parent(s) or legal guardian must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study: - Significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments - MPS IIIA behavioral-related issues, as determined by the Investigator, that would preclude performance of study neurocognitive and developmental testing procedures. - Patient is pregnant, breast feeding, or is a female patient of childbearing potential who will not or cannot comply with the use of an acceptable method of birth control - The patient is blind and/or deaf. - The patient has any known or suspected hypersensitivity to anesthesia or is thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions. - The patient or the patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns. - Complications resulting from prior lumbar punctures. - CNS shunt - Skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD. - History of poorly controlled seizure disorder. - Patient is currently receiving psychotropic or other medications - The patient cannot sustain absence from aspirin, non-steroidal medications, or medications that affect blood clotting within 1 week prior to a relevant study-related procedure or has ingested such medications within 1 week before any procedures in which any change in clotting activity would be deleterious. - The patient has received treatment with any investigational drug or a device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently enrolled in another study that involves an investigational drug or device (screening through safety follow-up contact). - The patient has received a hematopoietic stem cell or bone marrow transplant. - The patient's parent(s), or patient's legal guardian(s) is/are unable to provide consent or the patient cannot provide assent
Gender Both
Ages 3 Years - N/A
Accepts Healthy Volunteers No
Contacts ††
Location Countries † Netherlands
Administrative Information
NCT ID † NCT01155778
Organization ID HGT-SAN-055
Secondary IDs †† 2009-015984-15
Responsible Party Sponsor
Study Sponsor † Shire Human Genetic Therapies, Inc.
Collaborators ††
Investigators † Study Director: Patrick Haslett, M.D., Shire Human Genetic Therapies, Inc.
Information Provided By
Verification Date September 2012
First Received Date † June 24, 2010
Last Updated Date September 28, 2012
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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