Clinical Trial: 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 Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: 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 Pediat

Brief Summary:

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 Summary:

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.

Current Primary Outcome: Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) [ Time Frame: Baseline (Week 0) up to Week 48 ]

Original Primary Outcome: A maximum decline in DQ (Developmental Quotient) of 10 points over 48 weeks, assessed by neurocognitive testing [ Time Frame: Baseline to week 48 ]

Current Secondary Outcome:

• Number of Participants With Serious Adverse Events (SAE) [ Time Frame: Baseline (Week 0) up to Week 52 ]
  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.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Baseline (Week 0) up to Week 52 ]
  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).
• Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48 [ Time Frame: Baseline (Week 0) up to 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.
• Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48 [ Time Frame: Baseline (Week 0), 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.
• Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48 [ Time Frame: Baseline (Week 0), 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.
• Change From Baseline in Total Cortical Grey Matter Volume at Week 48 [ Time Frame: Baseline (Week 0), Week 48 ]
  The change from baseline in grey matter volume at Week 48 was assessed by magnetic resonance imaging (MRI).
• Change From Baseline in Concentration of Glycosaminoglycan (GAG) in Cerebrospinal Fluid (CSF) at Week 48 [ Time Frame: Baseline (Week 0), Week 48 ]
  Change from baseline in concentration of GAG in CSF at Week 48 was reported.
• Change From Baseline in Concentration of GAG in Urine at Week 48 [ Time Frame: Baseline (Week 0), 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.
• Concentration of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Cerebrospinal Fluid (CSF) [ Time Frame: Pre-dose, 4, 48 hours on Week 0 and Week 48 ]
  Concentration of rhHNS in CSF was assessed using validated enzyme-linked immunosorbent assay (ELISA) method.
• Maximum Observed Drug Concentration (Cmax) of Recombinant Human Heparan-N-Sulfatase (rhHNS) in Serum [ Time Frame: 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 ]
  Cmax of rhHNS in serum was evaluated using enzyme-linked immunosorbent assay (ELISA) method and liquid chromatography tandem mass spectrometry (LC-MS) method.

Original Secondary Outcome:

• Number of serious adverse events (SAE) [ Time Frame: Baseline to week 48 ]
• Number of treatment emergent adverse events (TEAE) [ Time Frame: Baseline to week 48 ]
• Anti-rhHNS Antibody Status in serum [ Time Frame: Baseline to week 48 ]
• The change from baseline in adaptive behavioral function, assessed by neurocognitive tests [ Time Frame: Baseline to week 48 ]
• The change from baseline in the DQ assessed by neurocognitive tests [ Time Frame: Baseline to Week 48 ]
• The change from baseline in total cortical grey matter volume [ Time Frame: Baseline to Week 48 ]
• The change from baseline in concentration of GAG in CSF [ Time Frame: Baseline to week 48 ]
• The change from baseline in concentration of GAG in urine [ Time Frame: Baseline to week 48 ]
• The concentration of rhHNS in CSF [ Time Frame: Baseline to week 48 ]
• The concentration of rhHNS in serum [ Time Frame: Baseline to week 48 ]

Dates:
Date Received: February 10, 2014
Date Started: February 2014
Date Completion:
Last Updated: April 10, 2017
Last Verified: July 2016