Principal Investigator: Joshua Bonkowsky
Keywords: Pediatric , Late Infantile Metachromatic Leukodystrophy , SHP611 , MLD Department: Pediatric Administration
IRB Number: 00119869
Specialty: Pediatric Neurology, Pediatric Neurology
Sub Specialties: Developmental Disabilities,
Recruitment Status: Recruiting

Contact Information

John Doyle
john.doyle@hsc.utah.edu
801-587-7400

Brief Summary

OBJECTIVES AND ENDPOINTS
Study Objectives
Primary Objective

The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of SHP611 on gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with MLD.

Secondary Objectives
Key secondary: The key secondary objective of this study is to evaluate the effects of IT administration of SHP611 on gross motor function, using the Gross Motor Function Measure 88 (GMFM-88) total score compared with matched historical control data in children with MLD.
 

Secondary:

  • To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFC-MLD
  • To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFM-88
  • To evaluate the effects of IT administration of SHP611 on expressive language using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD)
  • To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) biomarker (ie, sulfatides)
  • To evaluate the effects of IT administration of SHP611 on proton magnetic resonance spectroscopy (MRS) of the brain, specifically N-acetylaspartate/Creatine (NAA/Cr) in white matter

Pharmacokinetics:
To assess concentrations and PK profile of SHP611 in CSF and serum following single and repeat IT dosing of SHP611

Safety:
To determine the safety and tolerability of IT SHP611 based on:

  • Occurrence of treatment-emergent adverse events (TEAEs)
  • Clinical laboratory testing (serum chemistry, hematology, and urinalysis) and vital signs
  • Physical examination including documentation of signs and symptoms of MLD and a Developmental Questionnaire
  • 12-lead electrocardiogram (ECG)
  • CSF laboratory parameters (chemistries and cell counts)
  • Development of anti-SHP611 antibodies in CSF and serum
  • SOPH-A-PORT® Mini S device in subjects with MLD

Exploratory:
To evaluate the effects of administration of IT SHP611 on:

  • Serum and urine biomarkers (ie, sulfatides)
  • Severity score as measured by magnetic resonance imaging (MRI) of the brain
  • Volumetric analysis based on MRI of the brain
  • Ability to swallow as assessed by the Fiberoptic Endoscopic Evaluation of Swallowing (FEES)
  • Nerve conduction by electroneurography (ENG)
  • Communication and Cognition using the Battelle Developmental Inventory (BDI-2NU)
  • Caregiver burden and subject's health-related quality of life impact in children with MLD by evaluating:
    • Caregiver burden as assessed by the Caregiver Impact Questionnaire (CIQ)
    • Health Related Quality of Life (HRQOL) as assessed by the Infant Toddler Quality of
    • Life Questionnaire – 97 items (ITQOL-97)
  • Healthcare Utilization Questionnaire (HCUQ)

This study device has been approved for intrathecal delivery of Shire’s enzyme replacement therapies in the EU, but has not been approved for clinical use (it is investigational) in the rest of the world. The drug and device are both investigational and are being studies under a combination IND (FDA allowing both to be study under same IND).

Inclusion Criteria

Inclusion criteria: Patients must meet all of the following criteria to be considered eligible for inclusion as a subject in the study:

1. The subject must have a documented diagnosis of MLD (Groups A-D) a. Low ASA activity in leukocytes AND b. Elevated sulfatides in urine

2. The subject must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by a pediatric neurologist or medical geneticist by 30 months of age (Groups A-C) or presymptomatic (Group D)

3. The subject’s age at the time of informed consent, must be:

  • Group A: 18 to 48 months of age
  • Group B: 18 to 72 months of age
  • Group C: 18 to 72 months of age
  • Group D: <18 months of age

4. The subject’s GMFC-MLD level at screening must be:

  • Group A: GMFC-MLD level of 1 or 2
  • Group B: GMFC-MLD level of 3
  • Group C: GMFC-MLD level of 4
  • Group D: presymptomatic, are younger siblings of enrolled subjects, and have the same ASA allelic constitution

5. The subject and his/her parent/legal guardian(s) must have the ability to comply with the clinical protocol

6. Subject's parent or legal guardian(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the subject

Inclusion criteria for matched historical controls
Subjects must meet all of the following criteria to be considered eligible for inclusion as a matched historical control:
1. The subject must have a documented diagnosis of MLD a. Low ASA activity in leukocytes AND  b. Elevated sulfatides in urine

2. Subjects must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented at baseline

3. Subjects must have at least 2 motor assessments by GMFC-MLD with the second assessment occurring at approximately 106 (±6) weeks after the first assessment or else a second assessment measured before Week 100 with a GMFC-MLD level 5 or 6. Subjects with GMFC-MLD data (pro or retrospectively determined) must have the earliest observation of level 1 or 2 (walking with support) in the data source-verified medical record

4. Subjects must be 18 to 48 months of age at the earliest assessment

Exclusion Criteria

Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met.
Exclusion Criteria:
1. Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory’s normal range)

2. History of hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study

3. Initial presentation of behavioral or cognitive symptoms of MLD (per investigator’s clinical judgment)

4. The subject has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise

5. Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study

6. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days prior to study enrollment or at any time during the study

7. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use (IFU)

Exclusion criteria for matched historical controls
1. History of hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study

2. Initial presentation of behavioral or cognitive symptoms of MLD (per investigator’s clinical judgment)

3. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device)