Extension of Study HGT-SAN-055 Evaluating Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Study Overview
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Brief Summary
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Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 9 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 to 15 years of age on average. The purpose of this study is to collect long term safety and tolerability data in patients with MPS IIIA who previously received rhHNS in study HGT-SAN-055 (NCT01155778).

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 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 is a multicenter study designed to collect long-term safety and tolerability data in patients with Sanfilippo Syndrome Type A (MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy.Patients will continue in the treatment group as they participated in the HGT-SAN-055 study (rhHNS administered by IT injection 10 mg once per month, 45 mg once per month or 90 mg once per month. The study duration will be a maximum duration of 8 years of rhHNS treatment or until rhHNS is commercially available, the patient discontinues from the study, the Sponsor stops the study, or the Sponsor discontinues the development of rhHNS.

Official Title
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An Open-Label Extension of Study HGT-SAN-055 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Conditions
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Sanfilippo Syndrome

Intervention / Treatment
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* Biological: rhHNS-10 mg
* Biological: rhHNS-45 mg
* Biological: rhHNS-90 mg


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: The patient must have completed Study HGT SAN 055 and the opinion of the investigator, has no safety or medical issues that contraindicate participation. The patient, patient's parent(s), or legally authorized representative(s) has voluntarily signed an Institutional Review Board / Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's, the patient's, patient's parents or legally authorized representative's consent and patient's assent, as appropriate, must be obtained prior to any study specific procedures. The patient has received at least 5 of the 6 planned infusions of rhHNS in the HGT-SAN-055 study. Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery (if necessary for replacement purposes), without placing an undue burden on the patient/patient's family. Exclusion Criteria: Subjects will be excluded from the study if there is evidence of any of the following criteria at screening or at anytime during the study: The patient has experienced an adverse reaction to study drug in Study HGT-SAN-55 that contraindicates further treatment with rhHNS. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS drug product. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator. The patient has significant MPS IIIA behavioral-related issues, as determined by the Investigator, which would preclude performance of study neurocognitive and developmental testing procedures. The 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, such as condoms, barrier method, oral contraception, etc. 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 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 and the dose and regimen of which cannot be kept constant throughout the study. 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 (eg, device re-implantation if applicable), 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 (other than rhHNS) 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.

Ages Eligible for Study
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Minimum Age: 3 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhHNS-10 mg<br>Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years | Biological: rhHNS-10 mg<br>* Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years<br>* Other names: Recombinant human heparan N-sulfatase;|
| Experimental: rhHNS-45 mg<br>Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years | Biological: rhHNS-45 mg<br>* Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years<br>* Other names: Recombinant human heparan N-sulfatase;|
| Experimental: rhHNS-90 mg<br>Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years | Biological: rhHNS-90 mg<br>* Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years<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) And Treatment Emergent Serious Adverse Events (TESAEs) | 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 study drug related. Treatment-emergent Adverse events (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (NCT01155778) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. TEAEs included participants with any AE, any drug-related AE, any surgery-related AE, any IDDD-related AE, and any IT administration process-related AE, any SAE, any serious drug-related AE. | From start of study drug administration up to follow-up (Month 103) | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity | 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 study drug related. TEAEs were defined as all AEs from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (NCT01155778) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. Severity of an AE is determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities; Severe: Inability to carry out usual activities. | From start of study drug administration up to follow-up (Month 103) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) | Clinical laboratory assessments include hematology, serum chemistry including liver function tests, coagulation urinalysis and cerebrospinal fluid (CSF) were reported. | From start of study drug administration up to follow-up (Month 103) | 
| Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as Treatment Emergent Adverse Events (TEAEs) | Any change in ECG assessments which were deemed to be clinically significant findings and abnormalities were recorded as TEAEs. | From start of study drug administration up to follow-up (Month 103) | 
| Number of Participants With Postive Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS) | Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Participants with positive Anti-rhHNS antibody status in serum were reported. | Month 103 | 
| Number of Participants With Positive Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS) | Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Participants with positive anti-rhHNS antibody in CSF were reported | Month 103 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID-III) at Month 103 | BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers aged 0-42 months and consisted of a series of developmental play tasks. Score ranges: Cognitive scale 0-91, Receptive communication 0-49, Expressive communication 0-48, Fine motor 0-66 and Gross motor 0-72. Higher values denote stronger skills and abilities in the domain, indicating better outcomes. | Baseline, Month 103 | 
| Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID-III)/Kaufman Assessment Battery for Children Second Edition (KABC-II) Age-Equivalent Scores at Month 103 | BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers aged 0-42 months and consisted of a series of developmental play tasks. KABC-II was an individually administered measure of the processing and reasoning abilities of children and adolescents between the ages of 3 and 18 years and an alternative to BSID-III. Raw scores were converted to age--equivalent scores to measure ability, skill, and knowledge, expressed as the age at which most individuals reach the same level (age norm; range: 0, unbound ). A positive value indicates improvement. The BSID--III and KABC--II age--equivalent scores were based on the cognitive domain and average non-verbal age-equivalent score, respectively. | Baseline, Month 103 | 
| Change From Baseline in Developmental Quotient (DQ) Using Bayley Scales of Infant Development Third Edition (BSID-III) and Kaufman Assessment Battery for Children Second Edition (KABC-II) at Month 103 | BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers aged 0-42 months and consisted of a series of developmental play tasks. KABC-II was an individually administered measure of the processing and reasoning abilities of children and adolescents between the ages of 3 and 18 years and an alternative to BSID-III. Raw scores of successfully completed items are converted to scale scores and to composite scores. The mean composite score is 100 and the standard deviation (SD) is 15. The DQ was 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). A positive value indicates improvement in health and cognition. | Baseline, Month 103 | 
| Change From Baseline in Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Month 103 | 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 is 'Usually' = 2, 'Sometimes'/Partially' = 1 or 'Never' = 0. The standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning, communication, daily living skills, socialization and motor skills domains were reported here. The range for individual standard scores is 20-160. | Baseline, Month 103 | 
| Change From Baseline in Cerebrospinal Fluid (CSF) Total Heparan Sulfate Levels at Month 103 | Change from baseline in CSF total heparan sulfate at month 103 was recorded. | Baseline, Month 103 | 
| Change From Baseline in Urine Glycosaminoglycan (GAG) Levels at Month 103 | Change from baseline in Urine GAG at month 103 was recorded. | Baseline, Month 103 | 
| Change From Baseline in Brain Magnetic Resonance Imaging (MRI) at Month 103 | Brain MRI parameters include grey matter volume (GMV), white matter volume (WMV) and Intracranial cerebrospinal fluid Volume (ICSFV). Change from baseline in brain MRI at Month 103 was reported. | Baseline, Month 103 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Human Heparan N-Sulfatase (rhHNS), Sanfilippo Syndrome Type A (MPS IIIA), Lysosomal storage disease (LSD), Mucopolysaccharidosis (MPS) III