Research study to determine the effects of an investigational drug, SHP611 on patients with with Late Infantile Metachromatic Leukodystrophy (MLD) specially the gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with MLD.

Phase 1

Conditions: ate Metachromatic Leukodystrophy (MLD)
MedDRA version: 20.0 Level: PT Classification code 10067609 Term: Metachromatic leukodystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Registration Number: EUCTR2018-003291-12-ES

Lead Sponsor: Shire Human Genetic Therapies, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Not specified

Target Recruitment: 35

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/representative(s) must have the ability to comply with the clinical protocol

6. Subject's parent or legally authorized representative(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
Are the trial subjects under 18? yes
Number of subjects for this age range: 35
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

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)

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main 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 Objective: 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.;Primary end point(s): The primary efficacy endpoint is response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), evaluated as no greater than 2 levels decline from baseline in GMFC-MLD;Timepoint(s) of evaluation of this end point: 2 years

Secondary Outcome Measures

Name	Time	Method
<br> Secondary end point(s): The key secondary efficacy endpoint is response in Group A, defined as maintenance of gross motor function at 2 years (Week 106), defined as a GMFM-88 total score >40.<br><br> - To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFC-MLD<br> - To evaluate the effects of IT administration of SHP611 on the time course of declining gross motor function using GMFM-88<br> - To evaluate the effects of IT administration of SHP611 on expressive language using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD)<br> - To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) biomarker (ie, sulfatides)<br> - To evaluate the effects of IT administration of SHP611 on proton magnetic resonance spectroscopy<br> ;Timepoint(s) of evaluation of this end point: 2 years

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