An Extension Study to Determine Safety and Efficacy for Pediatric Patients With MPS Type IIIA Disease Who Participated in Study HGT-SAN-093.

Study Overview
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Brief Summary
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This extension study will allow participants to continue receiving treatment with HGT-1410 and to initiate treatment in patients who received no-treatment in Study HGT-SAN-093, and will evaluate the long-term safety and efficacy of the study drug.

Official Title
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An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and Efficacy Study of HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration Via an Intrathecal Drug Delivery Device in Pediatric Patients With Mucopolysaccharidosis Type IIIA Disease

Conditions
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Sanfilippo Syndrome, Mucopolysaccharidosis (MPS)

Intervention / Treatment
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* Drug: HGT-1410


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following criteria to be considered eligible for enrollment: Patient has completed through at least the Week 48 visit of Study HGT-SAN-093 The patient's parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board- (IRB-)/ Independent Ethics Committee- (IEC-) approved informed consent form after all relevant aspects of the study have been explained and discussed. Consent of the patient's parent(s) or legally authorized guardian(s) and the patient's assent, as relevant, must be obtained Exclusion Criteria: Patients will be excluded from the study if any of the following criteria are met: The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a decline of more than 20 points in the BSID-III cognitive DQ score between Baseline and the Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by the Investigator, has been deemed a treatment failure* The patient has experienced, in the opinion of the Investigator, a safety or medical issue that contraindicates treatment with HGT-1410, including but not limited to clinically relevant intracranial hypertension, severe infusion-related reactions after treatment with HGT-1410, uncontrollable seizure disorder The patient has a known hypersensitivity to any of the components of HGT-1410 The patient is enrolled in another clinical study, other than HGT-SAN-093, that involves clinical investigations or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions The patient has a condition that is contraindicated as described in the SOPH-A-PORT® Mini S IDDD Instructions for Use, including: The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT ® Mini S device The patient's body size is too small to support the size of the SOPH-A-PORT ® Mini S Access Port, as judged by the Investigator The patient's drug therapy requires substances known to be incompatible with the materials of construction The patient has a known or suspected local or general infection The patient is at risk of abnormal bleeding due to a medical condition or therapy The patient has one or more spinal abnormalities that could complicate safe implantation or fixation The patient has a functioning CSF shunt device The patient has shown an intolerance to an implanted device The patient is unable to comply with the protocol (eg, is unable to return for safety evaluations, or is otherwise unlikely to complete the study) as determined by the Investigator All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in the BSID-III DQ score is observed, then the patient may proceed into the Study SHP-610-201 without further evaluation. If a decline from Baseline of more than 20 points in DQ score is observed, then an individual evaluation by the Investigator will occur to determine if the patient is a treatment failure. This individual evaluation will take into account the DQ scores, VABS-II score, physical status, and any other information available for that patient at that time. If the Investigator deems the patient to be a treatment failure, then the patient may not enter the Study SHP-610-201

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: HGT-1410 Q2W in Study HGT-SAN-093 randomized to HGT-1410 Q2W<br>Patients in Group 1 will continue HGT-1410 treatment at a dose of 45 mg administered every 2 weeks (Q2W) starting at Week 50, with a cumulative treatment period of up to 42 months (168 weeks) . HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). HGT-SAN-093 = NCT02060526 | Drug: HGT-1410<br>* HGT-1410 administered according to Patient Group assignment.<br>* Other names: Recombinant Human Heparan N Sulfatase;|
| Active Comparator: HGT-1410 Q4W in Study HGT-SAN-093 randomized to HGT-1410 Q4W<br>Patients in Group 2 will continue HGT-1410 treatment at a dose of 45 mg administered every 4 weeks (Q4W) starting at Week 52, with a cumulative treatment period of up to 42 months (168 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). | Drug: HGT-1410<br>* HGT-1410 administered according to Patient Group assignment.<br>* Other names: Recombinant Human Heparan N Sulfatase;|
| Active Comparator: no-treatment in Study HGT-SAN-093 randomized to HGT-1410 Q2W<br>Patients in Group 3A will receive an IDDD following informed consent and will be randomized in a 1:1 allocation ratio to begin HGT-1410 treatment at a dose of 45 mg administered every 2 weeks (Q2W) starting at Week 0 of the extension study, with a cumulative treatment period of up to 30 months (120 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). | Drug: HGT-1410<br>* HGT-1410 administered according to Patient Group assignment.<br>* Other names: Recombinant Human Heparan N Sulfatase;|
| Active Comparator: no-treatment in Study HGT-SAN-093 randomized to HGT-1410 Q4W<br>Patients in Group 3B will receive an IDDD following informed consent and will be randomized in a 1:1 allocation ratio to begin HGT-1410 treatment at a dose of 45 mg administered every 4 weeks (Q4W) starting at Week 0 of the extension study, with a cumulative treatment period of up to 30 months (120 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). | Drug: HGT-1410<br>* HGT-1410 administered according to Patient Group assignment.<br>* Other names: Recombinant Human Heparan N Sulfatase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Type, Severity and Relationship to Treatment Drug | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. TEAEs was defined as all AEs from the time of initial IDDD implantation (or first dose if earlier) in either Study NCT02060526 (HGT-SAN-093) or Study NCT02350816 (SHP-610-210) to the data cutoff date (28 Jun 2017), or 30 days after the date of the last dose or 2 weeks after the date of device explant (whichever was later) if early termination occurred. Treatment-emergent AEs were summarized by type (serious, life-threatening), severity (mild, moderate, severe) and degree of relationship to investigational product (Intrathecal Drug Delivery Device (IDDD), device surgical procedure, or intraThecal administration of HGT-1410). | From start of study drug administration up to follow-up (Week 276) | 
| Number of Participants With Positive Anti-Recombinant Human Heparan N-Sulfatase (rhHNS) Antibody Status in Serum | Number of participants with positive anti-rhHNS antibody status in serum were reported. | Up to 120 weeks | 
| Area Under Curve (AUC) of Recombinant Human Heparan N-Sulfatase (rhHNS) Concentration in Cerebro Spinal Fluid (CSF) | No sufficient pharmacokinetic (PK) samples were collected and analyzed due to early termination of the study. | Week 0 and 48 | 
| Area Under Curve (AUC) of Recombinant Human Heparan N-Sulfatase (rhHNS) Concentration in Serum | No sufficient PK samples were collected and analyzed due to early termination of the study. | Week 0, 48 and 96 | 
| Levels of Glycosaminoglycan (GAG) Concentration in Cerebro Spinal Fluid (CSF) | Levels of GAG concentration in CSF was reported. Last measurable data was presented for respective participant up to their last observed time point. | Up to Week 120 | 
| Levels of Glycosaminoglycan (GAG) Concentration in Urine | Levels of GAG concentration in Urine were reported. Last measurable data was presented for respective participant up to their last available time point. | Up to Week 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Vineland Adaptive Behavior Scales Second Edition (VABS-II) | VABS-II measured adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. It was an instrument that supports the diagnosis of intellectual and developmental disabilities in participants. This test measured 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite ((a composite of the other four domains). Scoring was 'Usually' = 2, 'Sometimes'/Partially' = 1 or 'Never' = 0. The raw scores was converted to domain standard scores (mean 100, SD 15). Higher scores indicate undesirable behavior. Due to the premature termination of the treatment period, efficacy data were not analyzed and no efficacy conclusions were drawn. | Baseline, Week 120 | 
| Change From Baseline in the Developmental Quotient (DQ) Assessed by Neurocognitive Tests | The development quotient (DQ) was 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). Higher scores are indicative of decreased development. Neurocognitive tests included Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), Kaufman Assessment Battery for Children, Second Edition (KABC-II), Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Due to the premature termination of the treatment period, efficacy data were not analyzed and no efficacy conclusions were drawn. | Baseline, Week 120 | 
| Change From Baseline in Total Cortical Grey Matter Volume | The total cortical grey matter volume was assessed by volumetric magnetic resonance imaging (MRI) of the brain. Due to the premature termination of the treatment period, efficacy data were not analyzed and no efficacy conclusions were drawn. | Baseline, Week 120 |