Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of rhHNS Administration Via an IDDD in Pediatric Patients With Early Stage MPS IIIA Disease

Study Overview
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Brief Summary
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Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade. The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A Disease.

Detailed Description
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No effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease. Shire Human Genetic Therapies (Shire HGT) is developing an enzyme replacement therapy (ERT) recombinant human heparan-N-sulfatase (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 will evaluate the effect of 48 weeks of rhHNS treatment on the clinical course of MPS IIIA, using cognitive function as the primary outcome measure. The trial will evaluate 2 dosing regimens of rhHNS administered via an IDDD in comparison with a no treatment control group. Patients will be randomized 1:1:1 to either of the treatment groups or the no treatment group. Treatment will be administered in an open-label manner. The safety and tolerability profile of rhHNS will continue to be evaluated in this study.

Official Title
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A Randomized, Controlled, Open-label, Multicenter, Phase IIb Safety and Efficacy Study of rhHNS (Recombinant Human Heparan N Sulfatase) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Early Stage Mucopolysaccharidosis Type IIIA Disease

Conditions
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Sanfilippo Syndrome

Intervention / Treatment
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* Drug: Recombinant human heparan N-sulfatase [rhHNS]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must meet the following criteria to be enrolled in this study. Documented MPS IIIA diagnosis Age ≥12 months and ≤48 months The patient has a DQ score ≥60% The patient is medically stable, in the opinion of the Investigator, and able 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 legally authorized representative(s) must have voluntarily signed and dated an Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's parent(s), or legally authorized representative(s). Consent of the patient's parent(s) or legally authorized representative(s) must be obtained prior to the start of any study procedures. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. The presence of significant non-MPS IIIA related CNS impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator. The presence of at least one S298P mutation in SGSH, associated with attenuated disease OR there is documentation of the S298P mutation in a sibling affected by MPS IIIA, provided parental consent is obtained to use this information. The presence of relatively attenuated MPS IIIA disease in an older sibling, defined as preservation of any speech beyond the age of 10 years. Visual or hearing impairment sufficient, in the clinical judgment of the investigator, to preclude cooperation with neurodevelopmental testing. Use of hearing aids is permitted. In the opinion of the Investigator, the patient is assessed as having an unacceptably high risk for anesthesia due to airway compromise, drug hypersensitivity, or other conditions (such as neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns). The patient has a history of poorly controlled seizure disorder. The patient is currently receiving psychotropic or other medications, which in the Investigator's opinion would be likely to substantially confound test results. The patient has a history of bleeding disorder or is unable to abstain from medications that, in the opinion of the investigator, place them at risk of bleeding following surgery or LP. The patient participated in a clinical trial of another investigational medicinal product, within the 30 days prior to the study (or within 5 elimination half lives of the investigational product), or is currently enrolled in another study that involves an investigational drug or device. NOTE: Nutritional supplements, including genistein are permitted if they are taken or administered outside the context of a formal investigation. The patient has received a hematopoietic stem cell or bone marrow transplant, or gene therapy. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S-IDDD The patient's parent(s) or patient's legally authorized representative(s) is/are unable to understand the nature, scope, and possible consequences of the study, or do/does not agree to comply with the protocol defined schedule of assessments. The patient is unable to comply with the protocol (eg, has a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, or otherwise unlikely to complete the study) or is, in the opinion of the Investigator, otherwise unsuited for the study. The patient has any item (braces, tattoos, etc.) which would exclude the patient from being able to undergo MRI according to local Institutional Policy, or the patient has any other situation that would exclude the patient from undergoing any other procedure required in this study.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 48 Months

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 45 mg Q2W<br>rhHNS 45 mg administered intrathecally Q2W (once every 2 weeks ie, every 14 days), for 48 weeks via the surgically implanted IDDD (or LP) | Drug: Recombinant human heparan N-sulfatase [rhHNS]<br>* Recombinant human heparan N-sulfatase [rhHNS]<br>|
| Active Comparator: 45 mg Q4W<br>rhHNS 45 mg administered intrathecally Q4W (once every 4 weeks ie, every 28 days), for 48 weeks via the surgically implanted IDDD (or LP) | Drug: Recombinant human heparan N-sulfatase [rhHNS]<br>* Recombinant human heparan N-sulfatase [rhHNS]<br>|
| Placebo Comparator: Placebo<br>The comparator group will receive no treatment with rhHNS. | Drug: Recombinant human heparan N-sulfatase [rhHNS]<br>* Recombinant human heparan N-sulfatase [rhHNS]<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) | The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the DQ of 10 points or less over 48 weeks. Number of participants with the overall response were reported here. | Baseline (Week 0) up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events (SAE) | An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. | Baseline (Week 0) up to Week 52 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product related. This included an exacerbation of a pre-existing condition. TEAEs were defined as AE occurring on or after the time of first IDDD implantation or LP procedure to the end of study (EOS) visit (+30 days). | Baseline (Week 0) up to Week 52 | 
| Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 | A participant was considered positive if they had at least 1 positive result during the study. Once a participant reported antibody positive, they were considered positive for the remainder of the study. | Baseline (Week 0) up to Week 48 | 
| Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 | The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition. | Baseline (Week 0), Week 48 | 
| Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 | The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The DQ is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing ([age-equivalent score/chronological age] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. | Baseline (Week 0), Week 48 | 
| Change From Baseline in Total Cortical Grey Matter Volume at Week 48 | The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI). | Baseline (Week 0), Week 48 | 
| Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 | Change from baseline in concentration of GAG in CSF at Week 48 was reported. | Baseline (Week 0), Week 48 | 
| Change From Baseline in Concentration of GAG in Urine at Week 48 | The concentration of GAG in urine was normalized to the urine creatinine value and reported as milligram (mg) GAG per millimole (mmol) creatinine. | Baseline (Week 0), Week 48 | 
| Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) | Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method. | Pre-dose, 4, 48 hours on Week 0 and Week 48 | 
| Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum | Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method. | Predose, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h post-dose on Week 0 and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sulfoglucosamine sulfohydrolase (SGSH), recombinant human heparan N-sulfatase (rhHNS), Hunter's Syndrome, Shire HGT, Lysosomal Storage Disease (LSD), Sanfilippo Syndrome Type A (Sanfilippo A), enzyme replacement therapy (ERT)