A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in Subjects With Late Infantile Metachromatic Leukodystrophy
Phase: PHASE2
Conditions: Metachromatic Leukodystrophy (MLD)
Sponsor: Shire

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PROTOCOL: SHP611-201
TITLE:
A Global, Multicenter, Single-arm, Matched External Control Study of 
Intrathecal SHP611 in Subjects with Late Infantile Metachromatic 
Leukodystrophy
SHORT TITLE:
A Single-arm Study of Intrathecal SHP611 in Subjects with 
Metachromatic Leukodystrophy
STUDY PHASE:
Phase 2
ACRONYM:
EMBOLDEN
DRUG:
SHP611 (HGT-1110, TAK-611, recombinant human arylsulfatase A 
[rhASA]); INN/USAN: cebsulfase alfa
IND NUMBER:
PIND 110798
EUDRACT 
NUMBER:
2018-003291-12
SPONSOR:
Shire Human Genetic Therapies, Inc., a wholly owned subsidiary of 
Takeda Pharmaceutical Company Limited
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
Multicenter
PROTOCOL 
HISTORY:
Protocol Amendment 5: 12 Oct 2022
Protocol Amendment 4: 16 Sep 2020
Protocol Amendment 3.2: 02 Dec 2019 (Germany)
Protocol Amendment 3.1: 18 Nov 2019 (Site 001, United States)
Protocol Amendment 3: 21 Jun 2019
Protocol Amendment 2: 04 Apr 2019
Protocol Amendment 1: 10 Oct 2018
Original Protocol 1.0: 23 Aug 2018
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda.
For non-commercial use only

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CONFIDENTIAL
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
This includes any instances wherein the quality or performance of a Takeda product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, wrong product such that the label and contents are different products); or a 
product deficiency that relates to identity, quality, durability, reliability, safety and performance 
of the product but did not result in an AE, which include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product causing it 
to malfunction or to present a hazard or fail to meet label claims
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
Please use the information below as applicable to report the Product Quality Complaint or 
Non-Medical Complaint:
Origin of Product Quality Complaint
E-mail Address
Global
PQC@takeda.com
Telephone number (provided for reference if needed):
Takeda, Lexington, MA (USA)
1-800-828-2088
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
EMERGENCY CONTACT INFORMATION..............................................................................12
PRODUCT QUALITY COMPLAINTS........................................................................................13
TABLE OF CONTENTS...............................................................................................................14
LIST OF TABLES.........................................................................................................................19
LIST OF FIGURES .......................................................................................................................19
1.
PROTOCOL SUMMARY......................................................................................................20
1.1
Synopsis ...................................................................................................................20
1.2
Schema .....................................................................................................................31
1.3
Schedule of Activities ..............................................................................................32
2.
INTRODUCTION..................................................................................................................42
2.1
Indication and Current Treatment Options...............................................................42
2.2
Product Background and Clinical Information ........................................................43
2.3
Study Rationale ........................................................................................................43
2.4
Benefit/Risk Assessment..........................................................................................44
2.5
Compliance Statement..............................................................................................44
3.
OBJECTIVES AND ENDPOINTS........................................................................................45
3.1
Study Objectives ......................................................................................................45
3.1.1
Primary Objective..................................................................................................45
3.1.2
Secondary Objectives.............................................................................................45
3.2
Study Endpoints .......................................................................................................47
4.
STUDY DESIGN ...................................................................................................................51
4.1
Overall Design..........................................................................................................51
4.2
Scientific Rationale for Study Design......................................................................54
4.3
Justification for Dose ...............................................................................................55
4.4
Duration of Subject Participation and Study Completion Definition ......................56
4.5
Sites and Regions .....................................................................................................56
5.
STUDY POPULATION.........................................................................................................57
5.1
Inclusion Criteria......................................................................................................57
5.2
Exclusion Criteria.....................................................................................................58
5.3
Restrictions...............................................................................................................59
5.4
Reproductive Potential .............................................................................................59
5.4.1
Female Contraception............................................................................................59
5.4.2
Male Contraception................................................................................................59
6.
STUDY INTERVENTION ....................................................................................................60
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6.1
Investigational Product.............................................................................................60
6.1.1
Identity of Investigational Product.........................................................................60
6.1.2
SOPH-A-PORT Mini S IDDD ..............................................................................60
6.1.3
Blinding the Treatment Assignment......................................................................62
6.2
Administration of Investigational Product ...............................................................62
6.2.1
Allocation of Subjects to Treatment ......................................................................62
6.2.2
Dosing....................................................................................................................62
6.2.3
Unblinding the Treatment Assignment..................................................................62
6.2.4
Dose Modification .................................................................................................62
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product.................63
6.3.1
Labeling .................................................................................................................63
6.3.2
Packaging...............................................................................................................63
6.3.3
Storage ...................................................................................................................63
6.3.4
Special Handling....................................................................................................64
6.4
Drug and Device Accountability..............................................................................64
6.5
Treatment Compliance .............................................................................................65
6.6
Prior and Concomitant Treatment............................................................................66
6.6.1
Prior Treatment ......................................................................................................66
6.6.2
Concomitant Treatment .........................................................................................66
6.6.3
Permitted Treatment...............................................................................................66
6.6.4
Prohibited Treatment .............................................................................................66
7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL..........................................................................67
7.1
Discontinuation of Study Treatment ........................................................................67
7.2
Reasons for Discontinuation ....................................................................................67
7.3
Withdrawal from the Study......................................................................................68
7.4
Temporary Hold of Dosing ......................................................................................69
7.5
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..............................69
8.
STUDY ASSESSMENTS AND PROCEDURES..................................................................70
8.1
Study Periods............................................................................................................70
8.1.1
Screening Period....................................................................................................71
8.1.2
Surgical Implantation of IDDD, Day -10 to 28 .....................................................71
8.1.3
Baseline Assessments (prior to first administration of SHP611; Day -1 to 0) ......72
8.1.4
Treatment Period....................................................................................................72
8.1.4.1
Treatment Period - Study Week 0..........................................................72
8.1.4.2
Treatment Period – Remaining Study Visits..........................................72
8.1.5
Final Visit End of Study (EOS) .............................................................................73
8.1.6
Safety Follow-up....................................................................................................73
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8.1.7
Additional Care of Subjects after the Study ..........................................................73
8.2
Study Assessments ...................................................................................................73
8.2.1
Demographic and Other Baseline Characteristics .................................................73
8.2.1.1
Medical and Medication History............................................................73
8.2.1.2
MLD Diagnosis......................................................................................74
8.2.1.3
Cross Reacting Immunologic Material (CRIM).....................................74
8.2.2
Efficacy..................................................................................................................74
8.2.2.1
Gross Motor Function Classification in MLD .......................................74
8.2.2.2
Gross Motor Function Measure-88 ........................................................75
8.2.2.3
Global Impression of Motor Function Change and Severity .................76
8.2.2.4
Alberta Infant Motor Scale (Group D only)...........................................76
8.2.2.5
Note Documenting Current Motor Function..........................................76
8.2.2.6
Expressive Language Function Classification in MLD (ELFC-MLD)..76
8.2.2.7
The Eating and Drinking Ability Classification System (EDACS) .......76
8.2.2.8
Anesthesia ..............................................................................................77
8.2.2.9
Magnetic Resonance Imaging and Brain Magnetic Resonance 
Spectroscopy ..........................................................................................77
8.2.3
Safety .....................................................................................................................78
8.2.3.1
Physical Examination.............................................................................78
8.2.3.2
Adverse Events.......................................................................................78
8.2.3.3
Vital Signs..............................................................................................78
8.2.3.4
Clinical Laboratory Tests.......................................................................79
8.2.3.5
Immunoassay for Anti-SHP611 Antibodies...........................................79
8.2.3.6
Electrocardiogram ..................................................................................79
8.2.4
Intrathecal Drug Delivery Device Considerations.................................................79
8.2.4.1
Intrathecal Drug Delivery Device Implantation, Replacement, or 
Revision..................................................................................................79
8.2.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement......80
8.2.4.3
SOPH-A-PORT Mini S Assessments in CSF and Serum......................80
8.2.4.4
Cerebrospinal Fluid Sampling Procedure ..............................................80
8.2.4.5
Intrathecal Drug Delivery Device Removal...........................................80
8.2.4.6
Pharmacokinetics ...................................................................................81
8.2.4.7
Sulfatide/Lysosulfatide Biomarker Assessments...................................82
8.2.4.8
Additional Biomarker Assessments .......................................................82
8.2.4.9
Genetics..................................................................................................83
8.2.4.10
Health-related Quality of Life (QoL) and Other Assessments...............83
9.
STATISTICAL CONSIDERATIONS ...................................................................................86
9.1
Statistical Analysis Process......................................................................................86
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9.2
Planned Analysis, Adaptive Design, and Data Monitoring Committee...................86
9.3
Sample Size and Power Considerations...................................................................86
9.4
Statistical Analysis Set(s).........................................................................................87
9.5
Efficacy Analyses.....................................................................................................88
9.5.1
Matched External Control......................................................................................88
9.5.2
Multiplicity Adjustments .......................................................................................88
9.5.3
Missing Data Imputations......................................................................................88
9.5.4
Primary Efficacy Endpoint ....................................................................................89
9.5.4.1
Primary Efficacy Endpoint.....................................................................89
9.5.4.2
Sensitivity Analysis................................................................................89
9.5.5
Analyses of Secondary and Exploratory Efficacy Endpoints................................89
9.6
Safety Analyses........................................................................................................90
9.7
Other Analyses .........................................................................................................91
9.7.1
Pharmacokinetic Analyses.....................................................................................91
9.7.2
Extension Period....................................................................................................92
10. APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.........................................................................................................93
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations.....................93
Appendix 1.1
Regulatory and Ethical Considerations..................................................93
Appendix 1.2
Sponsor’s Responsibilities .....................................................................93
Appendix 1.3
Investigator’s Responsibilities ...............................................................94
Appendix 1.4
Data Management Considerations .........................................................97
Appendix 1.5
Ethical Considerations............................................................................98
Appendix 2
Clinical Laboratory Tests.....................................................................101
Appendix 3
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ..................................................................102
Appendix 3.1
Adverse Event Definitions ...................................................................102
Appendix 3.2
Collection of Adverse Events...............................................................105
Appendix 3.3
Assessment of Adverse Events ............................................................105
Appendix 3.4
Safety Reporting...................................................................................106
Appendix 3.5
Serious Adverse Event Collection Time Frame...................................107
Appendix 3.6
Serious Adverse Event Onset and Resolution Dates............................108
Appendix 3.7
Fatal Outcome ......................................................................................108
Appendix 3.8
Pregnancy.............................................................................................108
Appendix 3.9
Abuse, Misuse, Overdose and Medication Error .................................108
Appendix 3.10
Urgent Safety Measures .......................................................................109
Appendix 3.11
Device-associated Definitions..............................................................110
Appendix 3.12
Expected Adverse Device Effects........................................................110
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Appendix 3.13
Regulatory Agency, Institutional Review Board, Ethics 
Committee and Site Reporting ...............................................................................112
Appendix 4
Genetics................................................................................................113
Appendix 5
Scales and Assessments .......................................................................115
Appendix 6
Bioanalysis ...........................................................................................116
Appendix 7
Normal Ranges for Pulse, Systolic & Diastolic Blood Pressure, 
and ECG Parameters by Age..................................................................................117
Appendix 8
Premature Closure of the Study ...........................................................119
Appendix 9
Abbreviations .......................................................................................120
Appendix 10
Protocol History ...................................................................................124
11. REFERENCES .....................................................................................................................140
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LIST OF TABLES
Table 1
Schedule of Activities: Part 1 (Screening through Week 53)........................32
Table 2
Schedule of Activities: Part 2 (Week 54 through Week 106) .......................36
Table 3
Schedule of Activities: Extended Treatment Period through Safety 
Follow-up ......................................................................................................39
Table 4
Objectives and Endpoints..............................................................................47
Table 5
Gross Motor Function Classification in MLD...............................................75
Table 6
Expressive Language Function Classification-MLD ....................................76
Table 7
The Eating and Drinking Ability Classification System ...............................77
LIST OF FIGURES
Figure 1.
Study Schematic Diagram: Primary and Extension Treatment Periods........31
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1.
PROTOCOL SUMMARY
1.1
Synopsis
Protocol number: SHP611-201
Drug: SHP611 (also known as TAK-611; recombinant human 
arylsulfatase A [rhASA]); INN/USAN: cebsulfase alfa
Title of the study: A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in 
Subjects with Late Infantile Metachromatic Leukodystrophy
Short title: A Single-arm Study of Intrathecal SHP611 in Subjects with Metachromatic Leukodystrophy
Study phase: Phase 2
Number of subjects (total and per subject group): 
The study was planned to enroll a total of up to 42 subjects. Six subject groups are defined based on subject age 
and degree of motor dysfunction at screening.

Group A (GMFC-MLD category 1 or 2):
Approximately 16 subjects who are 18 to 48 months of 
age with a Gross Motor Function Classification in 
Metachromatic Leukodystrophy (GMFC-MLD) 
category of 1 or 2

Group B (GMFC-MLD category 3):
Up to 8 subjects who are 18 to 72 months of age with a 
GMFC-MLD category of 3

Group C (GMFC-MLD category 4):
Up to 8 subjects who are 18 to 72 months of age with a 
GMFC-MLD category of 4

Group D (minimally symptomatic): 
Up to 3 subjects who are ≥6 to <18 months of age, with 
the same ASA allelic constitution as an older sibling 
with confirmed late infantile or juvenile onset MLD

Group E (GMFC-MLD category 1 or 2, 
<18 months of age):
Up to 3 subjects ≥12 to <18 months of age, with 
documented diagnosis of MLD per inclusion criteria 1 
and 2 with a history of achieving stable walking 
(defined as at least 1 month of independent walking) and 
a GMFC-MLD category of 1 or 2

Group F (GMFC-MLD category 5 or 6):
Up to 4 subjects who are 18 to 72 months of age with a 
GMFC-MLD category of 5 or 6
Subjects in Groups A, B, C, and F must have an initial onset of gait disorder due to spastic ataxia or weakness 
and documented by a primary care physician or a specialist physician by 30 months of age. Subjects in Group E 
must have neurological symptoms documented by either a primary care physician or a specialist physician.
It is planned that all subjects who participated in this study through Week 106 may be included in the extension 
period of the study for long-term safety and efficacy follow-up. 
Investigator(s): Multicenter
Site(s) and Region(s): 
Investigational sites may be located in North America, Europe, Middle East, Latin America, and Japan
Study period (planned): 2019-2025
Clinical phase:
2
Objectives:
Primary: The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of 
SHP611 (also known as TAK-611) on the time to loss of locomotion, as indicated by category 5 or higher in the
Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched 
external control group data in children with late infantile MLD.
 
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Secondary:

To evaluate the effects of IT administration of SHP611 on subjects who experience decline in gross motor 
function as indicated by GMFC-MLD category 5 or higher, compared with matched external control group
data in children with MLD

To evaluate the effects of IT administration of SHP611 on the decline in gross motor function, as measured 
by an unreversed decline in GMFC-MLD of more than 2 categories compared with matched external
control group data in children with MLD, time course of declining gross motor function using the 
GMFC-MLD, and change from baseline of gross motor function, using the GMFC-MLD

To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) sulfatides
(pharmacodynamic [PD] biomarker)

To evaluate the effects of IT administration of SHP611 on gross motor function, using the Gross Motor 
Function Measure 88 (GMFM-88) total score in children with MLD

To evaluate the effects of IT administration of SHP611 on the time course of decline in gross motor 
function using GMFM-88, as measured by
o
an unreversed decline from baseline in GMFM-88 total score of >20 points or unreversed 
decline to <40 points, whichever occurs first, 
o
change from baseline of gross motor function, using the GMFM-88 total score, and 
o
GMFM-88 total score decline of no more than 20 points from baseline and a total score that is 
≥40

To evaluate the effects of IT administration of SHP611 on expressive language using the Expressive 
Language Function Classification (ELFC-MLD)
Pharmacokinetics:

To evaluate the concentrations of SHP611 in CSF following single and repeat IT dosing of SHP611

To evaluate the concentrations and pharmacokinetic (PK) parameters of SHP611 in 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:

CSF, serum and urine biomarkers

Proton magnetic resonance spectroscopy (MRS) of the brain, specifically N-acetylaspartate/Creatine 
(NAA/Cr) in white matter

Eichler MLD MRI severity score

Severity score as measured by magnetic resonance imaging (MRI) of the brain
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
Volumetric analysis based on MRI of the brain

Global impression of motor function – change (GIMF-C)

Global impression of motor function– severity (GIMF-S)

Caregiver burden and subject’s health-related quality of life impact in children with MLD by evaluating:
o
Caregiver burden as assessed by the Caregiver Impact Questionnaire (CIQ)
o
Health Related Quality of Life (HRQOL) as assessed by the Infant Toddler Quality of Life 
Questionnaire-97 items (ITQOL-97)

Healthcare Utilization as measured by the Health Care Utilization Questionnaire (HCUQ)

Caregiver work productivity and activity impairment as assessed using the Work Productivity and Activity 
Impairment Questionnaire (WPAI): Specific Health Problem V2.0

Ability to eat and drink as assessed using the Eating and Drinking Ability Classification System (EDACS) 
assessments
Rationale: 
Deficiency of the lysosomal enzyme arylsulfatase A in MLD leads to the accumulation of sulfated 
glycosphingolipids, known collectively as sulfatides. These accumulate in, and are toxic to, the cells which 
maintain the myelin insulation sheath of axons both centrally and peripherally. It is hypothesized that IT 
administration of recombinant human arylsulfatase A (SHP611) would be sufficient to hydrolyze accumulated 
sulfatides in cells of the nervous system and could slow or prevent further accumulation, which should translate 
into motor system benefits. There are currently very limited approved therapies for MLD.
Administration of SHP611 via an implanted intrathecal drug delivery device (IDDD) was well tolerated in 
Phase 1/2 studies in pediatric subjects with MLD and the device appeared to have an acceptable safety profile. In 
these studies, the higher dose appeared to show a signal of stabilized motor function in 4 of 12 subjects who 
received the 100 mg every-other-week (EOW) dose. This Phase 2 study will investigate the potential of IT 
SHP611 at a higher dose of 150 mg once weekly to stabilize or slow progression of motor dysfunction in 
pediatric subjects with late infantile MLD. The extension period of the study will evaluate long-term safety and 
efficacy outcomes of treatment with IT SHP611 in subjects who have participated in the study through Week 106.
Investigational product, dose, and mode of administration:
SHP611 (formerly designated as HGT-1110), recombinant human arylsulfatase A (rhASA).
Subjects weighing ≥7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly for 105 weeks. Subjects weighing 
≥5 kg (11.0 lbs) to <7 kg will receive 100 mg IT SHP611 weekly; however, when the subjects weigh more than 
7 kg they will begin dosing with 150 mg IT SHP611 weekly for the remainder of the study.
SHP611 administration will be via an implanted SOPH-A-PORT Mini S IDDD. If the device becomes 
nonfunctional at any time during the study, it will be removed and may be replaced or revised as appropriate. If 
use of the IDDD is not possible, a lumbar puncture (LP) may be utilized to obtain CSF samples and/or to deliver 
investigational drug product. It is anticipated that LP may have to be performed with anesthesia support at the 
discretion of the investigator. After 12 consecutive LPs, the feasibility of further use of LPs for that subject will 
be determined at the discretion of the investigator and the Takeda medical monitor and documented in a note to 
file.
Methodology:
SHP611-201 is a single-arm, matched external control, global, multicenter, Phase 2 trial. The study was planned 
to enroll up to 42 subjects with late infantile MLD who have an initial onset of neurological symptoms 
documented prior to 30 months of age (Groups A, B, C, and F), or who are minimally symptomatic and ≥6 to 
<18 months of age (Group D), or who are early symptomatic and ≥12 to <18 months of age (Group E). Minimally 
symptomatic is defined as being without clear symptoms of late infantile MLD or only showing mild symptoms 
(such as weakness) that do not meet the criteria for a GMFC-MLD category of >0 (NB: no subjects were enrolled 
in Groups D or E). The rate and severity of disease progression is well documented in late infantile MLD. A 
distinguishing feature of the definition of late infantile MLD is the early age at disease symptom onset with a 
majority of patients with late infantile MLD showing first motor dysfunction before the age of 18 months. Six 
subject groups are defined for this study based on age and motor dysfunction at screening:
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
Group A (GMFC-MLD category 1 or 
2):
18 to 48 months of age with a GMFC-MLD category of 1 or 
2

Group B (GMFC-MLD category 3):
18 to 72 months of age with a GMFC-MLD category of 3

Group C (GMFC-MLD category 4):
18 to 72 months of age with a GMFC-MLD category of 4

Group D (minimally symptomatic): 
≥6 to <18 months of age with the same ASA allelic 
constitution as an older sibling with confirmed late infantile 
or juvenile onset MLD

Group E (GMFC-MLD category 1 or
2)
≥12 to <18 months of age, with documented diagnosis of 
MLD per inclusion criteria 1 and 2 with a history of 
achieving stable walking (defined as at least 1 month of 
independent walking) and a GMFC-MLD category of 1 or 2

Group F (GMFC-MLD category 5 or 
6):
18 to 72 months of age with a GMFC-MLD category of 5 or 
6
Subjects weighing ≥7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly. It is anticipated that the majority of 
subjects will receive 150 mg IT weekly for a total treatment duration of 105 weeks; however, subjects weighing 
≥5 kg (11.0 lbs) to <7 kg (15.4 lbs) will receive 100 mg IT SHP611 weekly until they weigh ≥7 kg, at which time 
they will begin dosing with 150 mg IT SHP611 weekly.
The study will evaluate safety and efficacy of the treatment regimen on gross motor function using the 
GMFC-MLD and GMFM-88 total score to measure disease progression (Groups A, B, C, E, and F). Subjects in 
Group D will be assessed with the Alberta Infant Motor Scale (AIMS) and the GMFM-88 until they are 
ambulating or 18 months of age, whichever comes first. Once the AIMS is no longer being used, the 
GMFC-MLD and GMFM-88 will be used to measure motor function in this group.
The primary efficacy endpoint is time to loss of locomotion, measured by progression to GMFC-MLD category
5 or higher, or death, whichever occurs first, up to Week 106, evaluated on subjects in Group A. A secondary 
efficacy endpoint is response in Group A, defined as maintenance of gross motor function at Week 106, evaluated
as subjects who do not experience any event within Week 106, where event is defined as a decline in 
GMFC-MLD to category 5 or higher, or death.
The efficacy of SHP611 will be evaluated by comparison of SHP611-201 enrolled subjects in Group A with a
matched external control group. The data from these untreated MLD subjects (ie, subjects who have received no 
investigational product or therapy) will come from the ongoing Global Leukodystrophy Initiative (GLIA-MLD) 
natural history study. 
The matched external control group must have data for at least baseline gross motor function evaluation. The
filtering criteria for these external control subjects will be very similar to the inclusion/exclusion criteria for 
enrolled subjects in Group A of this present study.
Subjects will be implanted with the SOPH-A-PORT Mini S IDDD. Procedures for implantation are detailed in 
the device’s Instructions for Use (IFU) manual. Standard hospital procedures for surgery will be followed and the 
subject may be under anesthesia for this procedure. Prior to implantation, individual neurosurgeons may order 
additional imaging to estimate the canal size and spinal cord conus location in younger patients. After 
implantation, a leak test is performed by the neurosurgeon to ensure a sealed system is in place. X-rays may be 
performed as needed, particularly for younger subjects, throughout the study to confirm placement of the device 
and/or evaluate a nonworking catheter. In order to facilitate healing, subjects should remain under observation in 
the hospital setting until deemed clinically stable by the investigator and should limit activity for 24 hours after 
IDDD implantation. To allow for healing, a waiting period of 3 to 5 days after device implantation must be 
observed before the first administration of SHP611 may occur. If the device becomes nonfunctional at any time 
during the study, it may be removed, replaced, or revised as appropriate. After IDDD replacement or revision, a 
waiting period of 3-5 days must be observed before IT SHP611 dosing may resume. Examination of both the port 
and catheter track will be performed before each IT injection, which includes aspiration of CSF via the port.
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During the treatment period, subjects will undergo assessments of gross motor function, brain imaging, and 
health-related quality of life. Initial assessment of gross motor function using the GMFC-MLD scale will be 
conducted by local, trained healthcare professionals and video-recorded. Videos of GMFC-MLD assessments will 
be evaluated by central video reviewers for primary scoring of gross motor function on the instrument.
Safety will be assessed by collection of adverse events, physical examinations, vital signs, concomitant 
medications, ECG, clinical laboratory testing, and monitoring of anti-SHP611 antibodies. Periodic assessments 
will be performed before and after SHP611 administration at specific study visits (eg, serum/CSF PK sampling 
and CSF, serum, and urine biomarkers sampling and testing).
The study will consist of a screening period of up to 28 days. Implantation of the SOPH-A-PORT Mini S IDDD 
may occur during a period of up to 10 days prior to the first administration of IT SHP611 to 28 days after the first 
administration of IT SHP611. IT SHP611 administrations that occur prior to implantation of the IDDD will be 
administered via LP.
Subjects will be assessed according to the following schedule:

Screening (-28 to -1 days)

Surgical implantation of IDDD (-10 to 28 days)

Primary treatment period (Week 0 [baseline assessments prior to dosing ] through Week 105)

End of primary treatment period (Week 106)

Extension treatment period (from Week 106 administration of SHP611)

End of treatment (EOT) (last administration of SHP611)

End of study (EOS) (1 week after EOT)

Safety follow-up (2 weeks after EOS)
After the primary treatment period is completed at Week 106, subjects may participate in the extension period of 
the study where they may continue to receive treatment with SHP611 for an extended duration of time. 
Subjects will receive weekly treatment until they or their parents/guardians decide to discontinue treatment; the 
sponsor discontinues the study; the subject is discontinued from the study due to medical or safety concerns; or 
the product becomes commercially available in the subject’s country of residence, whichever comes first. During 
the extension period, main site assessments will be scheduled every 6 months. These assessments may be skipped 
for a visit at the discretion of the investigator and upon discussion of the investigator with the Medical Monitor if 
it is determined that the subject is unable to perform the assessments. At the EOT visit, subjects will receive their 
last administration of SHP611 and comprehensive assessments will be completed at the EOS visit.
If a subject discontinues from the study earlier than EOS, every effort should be made to complete assessments 
for the EOS and the safety follow-up visits. Subjects are to have the IDDD removed when they discontinue from 
the study, unless the subject is continuing to receive treatment with SHP611 through another mechanism (eg, 
commercially available) or the investigator determines that the IDDD should not be removed from the subject 
based upon a safety assessment and the IDDD (full or partial) should remain in the subject.
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Inclusion and Exclusion 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-F)
a.
Low ASA activity in leukocytes (compared to laboratory normal range)
AND
b.
Elevated sulfatides in urine
2.
The subject must have a gait disorder due to spastic ataxia or weakness attributable to MLD by the 
investigator and documented by a primary care physician or a specialist physician by 30 months of age 
(Groups A-C, and F), or be minimally symptomatic and ≥6 to <18 months of age (Group D); or be early 
symptomatic and ≥12 to <18 months of age (Group E). Subjects in Group E must have neurological 
symptoms documented by either a primary care physician or a specialist physician.
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: ≥6 to <18 months of age

Group E: ≥12 to <18 months of age

Group F: 18 to 72 months of age
4.
The subject’s GMFC-MLD category at screening must be: 

Group A: GMFC-MLD category of 1 or 2

Group B: GMFC-MLD category of 3

Group C: GMFC-MLD category of 4

Group D: minimally symptomatic, and has the same ASA allelic constitution as an older sibling with 
confirmed late infantile or juvenile onset MLD

Group E: GMFC-MLD category of 1 or 2 with a history of achieving stable walking (defined as at 
least 1 month of independent walking)

Group F: GMFC-MLD category of 5 or 6
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
Exclusion criteria:
1.
Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon 
the reference laboratory’s normal range) or a known genetic disorder other than MLD
2.
History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), or gene 
therapy; or undergoes BMT, HSCT, or gene therapy at any point during the study
3.
Primary presentation of MLD was behavioral or cognitive symptoms (per investigator’s clinical judgment); 
behavioral symptoms that are secondary to motor deficits (eg: tantrums in response to loss of motor skills) 
are not exclusionary.
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
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5.
Any other medical condition or serious comorbid illness that in the opinion of the investigator would 
preclude participation in the study
6.
Subjects with laboratory, ECG or vital sign abnormalities reflecting intercurrent illness that may 
compromise their safety during the trial should not be enrolled. Abnormal laboratory, vital sign and ECG 
results at screening should be reviewed with the Takeda medical monitor.
7.
The subject is enrolled in another clinical study that involves use of any investigational product (drug or 
device) within 30 days or 5 half-lives (whichever is longer) prior to study enrollment or at any time during 
the study
8.
The subject has had prior exposure to SHP611.
9.
Subjects weighing <5 kg
10. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD 
Instructions for Use
a.
The patient has had, or may have, an allergic reaction to the materials of construction 
b.
The patient has shown an intolerance to an implanted device
c.
The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access Port
d.
The patient’s drug therapy requires substances known to be incompatible with the materials of 
construction
e.
The patient has a known or suspected local or general infection
f.
The patient is at risk of abnormal bleeding due to a medical condition or therapy
g.
The patient has one or more spinal abnormalities that could complicate safe implantation or fixation
h.
The patient has a functioning CSF shunt device
Filtering criteria for the selection of the matched external control group will be provided in the Statistical 
Analysis Plan (SAP).
Maximum duration of subject participation in the study:
The primary treatment period is planned for 106 weeks with an extension period starting at Week 106 
administration of SHP611. The planned overall duration of each subject’s involvement in the study is 
approximately 26 months from screening to the last scheduled visit for the primary treatment period with the 
extension period planned to continue until Mar 2025, or product commercialization date, or until the program is 
discontinued. 
Subjects will continue treatment until they or their parents/guardians decide to discontinue treatment; the sponsor 
discontinues the study; the subject is discontinued from the study due to medical or safety concerns; or the 
product becomes commercially available in the subject’s country of residence, whichever comes first.
Statistical analysis:
Analysis populations

The Screened Set will consist of all subjects who have signed informed consent

The Safety Analysis Set will consist of all subjects from Study SHP611-201 (Groups A-F) who receive 
at least 1 dose of SHP611, or subjects who have undergone the IDDD implantation procedure

The Full Analysis Set (FAS) will consist of all subjects from the SHP611-201 Safety Analysis Set who
receive at least 1 dose of SHP611 and have at least a screening GMFC-MLD assessment

The modified Full Analysis Set (mFAS) will consist of all subjects from Group A in the FAS and the 
matched external control subjects for Group A from GLIA-MLD natural history study obtained after 
matching as described in the SAP

The PK Analyses Set will consist of all subjects from the SHP611-201 Safety Analysis Set who receive 
at least 1 dose of SHP611 and have at least 1 postdose measurable [ie, not below quantifiable limits 
(BQL)] concentration of SHP611 in serum or CSF
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
The Immunogenicity Analyses Set will consist of all subjects from the SHP611-201 Safety Analysis Set 
who receive at least 1 dose of SHP611 and have at least 1 anti-SHP611 antibody assessment with 
reportable result in serum or CSF
Extension period:
The same analysis populations, as in the primary treatment period, will be used for the extension period.
Device-related analyses will be conducted in the subset of subjects in the Safety Analysis Set who had the device 
implant procedure performed.
Primary efficacy endpoint
The primary efficacy endpoint is time to loss of locomotion, measured by progression to GMFC-MLD category 5 
or higher, or death, whichever occurs first, up to Week 106, evaluated on subjects in Group A.
Secondary efficacy endpoint(s)
The secondary efficacy endpoints of this study are:

Response in Group A, defined as maintenance of gross motor function at Week 106, evaluated as 
subjects who do not experience any event within Week 106, where event is defined as a decline in 
GMFC-MLD to category 5 or higher, or death

Decline in gross motor function using GMFC-MLD:
o
Change from baseline at Week 106 and EOS in gross motor function, using the GMFC-MLD
o
Subjects with unreversed decline from baseline in GMFC-MLD of more than 2 categories, defined 
as any decline of more than 2-categories that has not reverted to a 2-category decline (or better) at 
Week 106, evaluated on subjects in Group A
o
Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories, defined as any 
decline of more than 2-categories that has not reverted to a 2-category decline (or better) as of the 
last recorded observation

Change from baseline at Week 106 and EOS in CSF sulfatides levels

Response in Group A, defined as maintenance of gross motor function at Week 106, defined as a 
GMFM-88 total score ≥40

Decline in gross motor function using GMFM-88: 
o
Time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score decrease 
of >20 points or unreversed decline to a score <40 points, whichever occurs first
o
Change from baseline at Week 106 and EOS in gross motor function, using the GMFM-88 total 
score
o
Subjects in Group A with GMFM-88 total score decrease of ≤20 points from baseline and a total 
score that is ≥40 at Week 106 and EOS

Change from baseline at Week 106 and EOS in expressive language using the ELFC-MLD 
Pharmacokinetic endpoints

CSF parameters:
o
Predose concentrations (Ctrough) of SHP611 at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106
o
Postdose concentrations of SHP611 at 6 and 24 hours (Weeks 0 and 106)

Serum parameters:
o
PK parameters after the first dose (Week 0) and after repeated doses (Week 106) of SHP611 
determined by noncompartmental analysis will include but not limited to area under the 
concentration (AUC), maximum concentration (Cmax), and clearance after IT administration (CL/F)
o
Predose concentrations (Ctrough) of SHP611 at Weeks 0, 13, 26, 40, 53, 79, and 106
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Safety endpoints

Treatment-emergent adverse events (TEAEs)

Changes from baseline at Week 106 and EOS in clinical laboratory testing (serum chemistry, 
hematology, and urinalysis)

Change from baseline at Week 106 and EOS in physical examination including documentation of signs 
and symptoms of MLD (tone, reflexes, and vision)

Change from baseline at Week 106 and EOS in 12-lead electrocardiogram (ECG)

Change from baseline at Week 106 and EOS in CSF laboratory parameters (chemistries, cell counts)

Anti-SHP611 antibodies in CSF and serum at Week 106 and EOS

SOPH-A-PORT Mini S assessments will be evaluated using assessments of device implantation, device 
function, device longevity, and adverse events (AEs) associated with the implant surgery or device
Exploratory endpoints

Change in CSF, serum, and urine biomarkers over time

Change in MRS metabolite levels, specifically: N-acetylaspartate/Creatine over time

Change in Eichler MLD MRI severity score over time

Change in the total MLD severity score based on brain MRI over time

Change in volumetric analysis of the brain based on MRI over time

Change in global impression of motor function–change (GIMF-C) over time

Change in global impression of motor function–severity (GIMF-S) over time

Change in caregiver burden and subject’s health-related quality of life:
o
Descriptive statistics of the Caregiver Impact Questionnaire (CIQ) item responses over time to 
inform scoring
o
Change in each of the parent and infant/toddler concepts as assessed by the Infant Toddler Quality 
of Life Questionnaire – 97 items (ITQOL-97) over time

Change in incidence of hospitalizations, number of days in hospital, reason for admission, and frequency 
of selected MLD-related procedures (use of feeding tube, use of intubation, and type of respiratory 
support) over time; total number of additional hospitalizations during the 2-year follow-up

Change in caregiver work productivity and activity impairment as assessed using the Work Productivity 
and Activity Impairment Questionnaire (WPAI): Specific Health Problem V2.0 over time

Change in ability to eat and drink as assessed using the Eating and Drinking Ability Classification 
System (EDACS) assessments over time
Sample size calculation and power considerations
Per original Protocol, sample size was calculated based on the response in Group A, (ie, the maintenance of gross 
motor function at Week 106, evaluated as no greater than 2 categories decline from baseline in GMFC-MLD), 
and at least 12 paired completers is required to detect a treatment difference for a desired power of 90%, using 
McNemar’s test at a 2-sided significance level of 0.05, with the assumption that the response rates in Group A of 
current study and the matched external control group are 65% and 10% respectively. Furthermore, to adjust for 
potential unmatched and early discontinuation of subjects, a total of 16 subjects were originally planned to be 
enrolled into Group A of the current study. As the GLIA-MLD external control group for Group A cohort was 
expected to be large, efficient matching was plausible and incorporated in the assumptions.
Type I error and power were assessed for the time to event primary endpoint for sample sizes similar to that 
planned in the original protocol, through simulations using an interval censoring approach. Comparable 
assumptions were made on the response rates for the time to event primary endpoint in simulations. The response 
rates (ie, proportion of subjects not reaching GMFC-MLD category 5 or higher, or death) at Week 106 for 
Group A in the current study and the matched external control group are 65% and 10%, respectively. 
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The encounter structure from a subset of external control group for Group A subjects in the natural history study 
was considered. A simulated event time was randomly matched to a GLIA-MLD encounter schedule and was 
considered censored if it could not be observed within Week 106 under the matched schedule. The event time 
was assumed to follow a Weibull distribution, with a range of compatible shape parameters that allow 
approximation of the target response rates of 65% and 10% in the two groups, and a 25% censoring proportion 
for the GLIA-MLD control group. The type I error was preserved well. The power is assessed to be 
approximately between 71% to 82%. Matching efficiency is not assumed in the simulations.
Efficacy analysis
The efficacy of SHP611 in SHP611-201 Group A will be compared to matched external control group data from 
untreated MLD subjects in the Global Leukodystrophy Initiative natural history study (GLIA-MLD).
For Group A subjects in this study, the time to event (TTE) starting point is set at the Baseline visit where 
patients receive the first dose of SHP611. The external control group for Group A subjects will be selected from 
the GLIA-MLD database using appropriate filtering criteria. For each external control subject, a collection of 
“qualifying encounters” when the subject is in the appropriate age range for Group A and GMFC-MLD category 
of 1 or 2, will be identified and an appropriate TTE starting point will be defined. Details of this definition will be 
provided in the SAP. 
For this matched external control study, an appropriate matching process will be applied to balance the baseline 
observed characteristics between the treatment and matched external control groups. Matching diagnostics will be 
conducted. Further details will be provided in the SAP.
For the analysis of the primary efficacy endpoint, the time to event data for Group A and matched external
control group up to Week 106 will be compared using the stratified log-rank test, where the matching 
identification created from the matching process will be used as strata. Interval censoring methods will be used, 
with event assumed to have first happened between the last visit/encounter prior to the event observation, and the 
visit/encounter when the event is first observed. The null hypothesis of the stratified log-rank test will be 
evaluated at the 1-sided 0.025 level of significance. Kaplan-Meier (KM) survival curves suitable for interval 
censoring data will be presented.
As study drug dosing was affected by the COVID-19 pandemic, a sensitivity analysis will be conducted for 
Group A subjects who missed no more than two consecutive SHP611 doses due to COVID-19.
The details of the matching method and other sensitivity analyses, as well as the secondary and exploratory 
efficacy endpoints, will be specified in the SAP.
Safety analysis
Treatment-emergent adverse events (TEAEs) are defined as AEs that occurred at or after the first dose of 
investigational product or device implant surgery (whichever occurs first) and through the last follow-up date
plus 14 days (inclusive). Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 
The number of events and percentage of TEAEs will be calculated overall, by system organ class (SOC), by 
preferred term, and by subject groups (A-F). TEAEs will be further summarized by severity, relationship to 
investigational product, disease and outcomes, the IDDD, the IDDD surgical procedure, anesthesia, and IT 
administration process. Adverse events related to investigational product, AEs leading to withdrawal, serious 
adverse events (SAEs; all SAEs reported by the investigator, those SAEs considered as Related and those 
considered as Not Related by Takeda shall be collected), and deaths will be similarly summarized and listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by subject groups (A-F) and visit. 
Potentially clinically important findings will also be summarized and listed. Descriptive summaries will also be 
provided for 12-lead ECG, CSF laboratory parameters (chemistries, cell counts), anti-SHP611 antibodies in CSF 
and serum.
SOPH-A-PORT Mini S assessments
SOPH-A-PORT Mini S assessments will be evaluated using assessments of device implantation, device function, 
device longevity, and AEs associated with the implant surgery or device. These data will be collected on the 
subject’s electronic case report form (eCRF) from the time of implantation and continue throughout the study as 
long as the SOPH-A-PORT Mini S remains implanted.
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Pharmacokinetic analyses
All PK analyses will be performed using the PK Analysis Set.
Blood and CSF samples will be collected for determination of SHP611 levels after IT administration. SHP611 
concentrations in serum and CSF will be determined using the validated Enzyme-Linked Immunosorbent Assays
(ELISA) method which was used for the previous SHP611 clinical studies (HGT-MLD-070/HGT-MLD-071). 
SHP611 activity in CSF and serum will also be determined by validated Activity assays. The SHP611 Activity 
results will be used as surrogate marker for anti-SHP611 neutralizing antibodies and its impact on PK profile.
Details of the PK analysis including handling of PK data, parameters estimated, and presentation of PK data will 
be provided in the Clinical Pharmacology Analysis Plan (CPAP).
There will be no inferential statistical analysis of the PK data. Summary statistics (number of observations [N], 
mean, SD, coefficient of variation [CV%], median, maximum, minimum, geometric mean and geometric CV%) 
will be determined for all serum PK parameters and presented by bioanalytical method and visit for each group 
and for overall population. Serum and CSF concentrations at each nominal sampling time will also be 
summarized by bioanalytical method and visit for each group and for overall population using descriptive 
statistics. More details will be provided in the CPAP.
At the investigator’s discretion a blood sample for PK analysis may be collected at the time of occurrence of an 
SAE or AE of special interest.
The serum and CSF concentration data from this study may be pooled with the data from Studies HGT-MLD-070 
and HGT-MLD-071 in a population PK analysis. A population PK/PD and exposure-response analyses may be 
conducted using data from this study and reported separately.
Extension period
Summary statistics for continuous variables will include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. Categorical variables will be summarized using the number and percentage of 
subjects in each category, including a missing category if applicable.
Statistical inferences for the primary and selected secondary endpoints may be performed during the extension 
period.
The safety analyses will be performed using all data through Week 106 and the extension period up to EOS. 
Baseline will be defined as the same as that for the study (this baseline is clinically relevant for assessing the 
long-term safety and efficacy outcomes of extended treatment with IT SHP611).
The same analysis populations, as in the primary treatment period, will be used for the extension period.
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1.2
Schema
Figure 1
Study Schematic Diagram: Primary and Extension Treatment Periods
EOS=end of study; EOT=end of treatment; IT=intrathecal.
*Subjects may continue treatment in the study beyond Week 210. They will continue to follow the same schedule of assessments, 
ie, weekly dosing and main site visits every 6 months. Subjects will continue treatment until they or their parents/guardians 
decide to discontinue treatment; the sponsor discontinues the study; the subject is discontinued from the study due to medical or 
safety concerns; or the product becomes commercially available in the subject’s country of residence, whichever comes first.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.
INTRODUCTION
2.1
Indication and Current Treatment Options 
Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid 
metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA), 
which results in progressive accumulation of galactosylceramide-3-O-sulfate (cerebroside sulfate 
or sulfatide) and a cytotoxic metabolite of sulfatide (lysosulfatide or 
galactosylsphingosine-3-O-sulfate) (Hans et al. 2009; Sugiyama et al. 1990; Toda et al. 1990). 
Clinical manifestations are severe peripheral nerve damage, areflexic spasticity, and cognitive 
dysfunction (Kehrer et al. 2014; Wang et al. 2011). Approximately 200 ASA allele types have 
been reported in patients with MLD. The most frequently reported alleles (465 +1G>A, 
1283 C>T, and 542 T>G) account for 37% of the mutations (Barth et al. 1993a; 
Barth et al. 1993b; Cesani et al. 2016; Gieselmann et al. 1991; Lugowska et al. 2005; 
Luzi et al. 2013; Virgens et al. 2015; Zlotogora et al. 1995). The rapidity with which the disease 
progresses clinically correlates with the level of residual enzymatic activity in vitro within the 
lysosomes (Kroos et al. 2008; Schaefer et al. 2005; Scott et al. 1995); however, the phenotypic 
variability due to factors other than ASA gene mutations do not allow genotype to consistently 
predict the disease course (Gieselmann and Krageloh-Mann 2014).
MLD presents with various neurological signs and symptoms with more severe types of the 
disease presenting earlier in life (Alam et al. 2015; Costello et al. 2009; Fluharty 2014; 
Gulati et al. 2016). Usually 3 main clinical subtypes are differentiated based on age of onset: 
late infantile MLD (40%-60% of cases), juvenile MLD (20%-35%), and adult MLD (15%-25%) 
(Wang et al. 2011). While this grouping into types is useful clinically and for genetic counseling, 
MLD is a continuum of clinical severity and the typing is somewhat arbitrary with an overlap of 
these clinical subtypes in some cases.
The late infantile MLD type is the most frequent presentation of the disorder and is usually 
diagnosed in the second year of life (Kolodny and Fluharty 1995). Development in children with 
late infantile MLD appears normal until onset of the initial symptoms. The natural history of 
disease progression is well documented in late infantile MLD with median onset of first motor 
symptoms at 17 months (Kehrer et al. 2011b) and in most patients before the age of 30 months 
(van Rappard et al. 2015). The typical initial presentation is a gait disturbance that progresses 
rapidly to complete loss of motor capabilities (median time 15 months) (Kehrer et al. 2011b). 
The disease progresses rapidly with seizures, motor deficits, and significant peripheral nerve 
damage resulting in an inability to walk, stand, or sit; frequent crying and irritability due to 
painful contractures; swallowing difficulties resulting in an inability to eat with resultant weight 
loss requiring a feeding tube; respiratory difficulties; an inability to speak; and sometimes 
blindness. The child’s ability to respond to caretakers and engage in social interactions becomes 
increasingly limited with eventual nonresponsiveness due to progressive neurodegeneration 
(Gieselmann and Krageloh-Mann 2014). There is evidence of cognitive impairment and failure 
to achieve developmental milestones, which are also likely manifestations of a demyelinating 
process in the central and peripheral nervous systems (PNS) (í Dali et al. 2010; 
Kehrer et al. 2014). This demyelination likely results in axonal damage that is severe and 
possibly irreversible (Eichler et al. 2009; í Dali et al. 2015). 
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The visceral involvement in MLD may occasionally manifest as gallbladder disease; the lack of 
ASA in the kidney results in high excretion of urinary sulfatide. The disease is typically fatal, 
progressing to a decerebrate state with death occurring approximately 5 years after disease onset, 
generally due to complications from an infection (Eichler et al. 2016; Kehrer et al. 2014; Wang 
et al. 2011).
2.2
Product Background and Clinical Information
SHP611 (also known as TAK-611; formerly known as HGT-1110, with the INN/USAN 
cebsulfase alfa), is a recombinant human arylsulfatase A (rhASA) that is under development as 
an enzyme replacement therapy for the treatment of MLD. SHP611 (rhASA) is a multimeric 
glycoprotein produced using a genetically engineered human cell line (HT-1080) to secrete the 
human lysosomal enzyme, ASA. The glycans of SHP611 contain mannose-6-phosphate (M6P), 
which allows for target cell uptake and internalization into the lysosomal site of action via 
membrane-bound M6P receptors.
A particular challenge for lysosomal storage diseases, such as MLD, which affect the brain, is 
targeting enzyme replacement therapy to the central nervous system (CNS), as the blood brain 
barrier prevents passive diffusion of proteins from systemic circulation into the CNS 
(Vellodi 2005). This program attempts to overcome this physical challenge by administering 
directly into the CNS. In nonclinical studies, SHP611 administered via the IT route was taken up 
by the meninges, glial cells (oligodendrocytes), and neurons and deposited in the lysosomal 
compartment of target cells in cynomolgus monkeys, thus demonstrating that IT administration 
successfully delivers SHP611 to the site of action in the lysosomes of the oligodendrocytes. 
Furthermore, in a mouse model of MLD, IT administration of SHP611 reduced accumulation of 
sulfatides and LAMP-1, a lysosomal marker that is elevated in lysosomal storage diseases 
(Parkinson-Lawrence et al. 2005) in the brain and spinal cord of the affected animals indicating 
that SHP611 reached the tissues of interest in this model.
In subjects with MLD, SHP611 is administered directly to the CNS using a surgically implanted 
intrathecal drug delivery device (IDDD). The advantage of using an IDDD is that it obviates the 
need for multiple lumbar punctures (LPs) which would otherwise be required for drug delivery. 
The safety of SHP611 was evaluated in the first-in-human, multicenter, Phase 1/2 dose 
escalation study of SHP611 in children with MLD (HGT MLD-070, completed) and its 
extension study (HGT-MLD-071, ongoing). Intrathecal administration of SHP611 in children 
with MLD was well tolerated in these studies. Through 104 weeks, there appeared to be a signal 
of stabilization of motor function and magnetic resonance imaging (MRI) MLD severity.
Refer to the latest version of the SHP611 investigator’s brochure (IB) for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy, and safety of SHP611. 
2.3
Study Rationale
Currently there are very limited approved therapies for MLD, a progressive, ultimately fatal, 
genetic neurological disease. Children with MLD typically receive supportive care with 
palliative care later during the course of their disease. 
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Children may live for 5-10 years before they die and require complete care with feeding, 
diapering, clothing, and bathing as well as controls of pain and avoidance of complications of 
paralysis such as joint contractures and decubitus ulcers. The selection of supportive and 
palliative care is focused on management of the clinical symptoms (Kolodny and Fluharty 1995; 
van Rappard et al. 2015). Hematopoietic stem cell transplantation (HSCT) using bone marrow 
transplantation (BMT) or umbilical cord blood and gene therapy using lentiviral hemopoietic 
stem-cell therapy (Sessa et al. 2016) has been attempted for MLD with mixed results. A 
hematopoietic stem cell, lentiviral vector-based human ASA gene therapy, LIBMELDYTM
(Orchard Therapeutics) has received a marketing authorization in the European Union (EU). 
LIBMELDY is indicated for use in children with late infantile or early juvenile forms of MLD who 
have not yet developed symptoms, and in early juvenile MLD who have initial symptoms but can 
still walk independently and have not yet developed mental deterioration.
The unmet medical need extends to families, caregivers, and providers, with great cost and 
multidisciplinary provider management required. Novel disease-modifying approaches that hold 
the potential for altering the clinical course of disease progression are needed. Intrathecal 
administrations of SHP611 in subjects with MLD could potentially stabilize or slow progression 
of neurological dysfunction by restoring a level of CNS and PNS ASA enzymatic activity that 
would be sufficient to hydrolyze accumulated sulfatide and slow or prevent further substrate 
accumulation. This study has been designed to evaluate the safety and efficacy of IT 
administration of SHP611 in MLD.
2.4
Benefit/Risk Assessment 
MLD is a rapidly progressive neurological disorder that results in motor dysfunction and 
premature death, and for which there is no effective treatment. The initial clinical safety results 
in Phase 1/2 studies indicate a favorable benefit/risk profile for SHP611. The SOPH-A-PORT 
Mini S IDDD has been generally well tolerated in the HGT-MLD-070/071 clinical trials.
Always refer to the latest version of the IB for the overall benefit/risk assessment and the most 
accurate and current information regarding drug metabolism, pharmacokinetics, efficacy, and 
safety of SHP611
2.5
Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements. 
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1.
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3.
OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
3.1.1
Primary Objective
The primary objective of this study is to evaluate the effects of intrathecal (IT) administration of 
SHP611 on the time to loss of locomotion, as indicated by category 5 or higher in the Gross 
Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with 
matched external control group data in children with late infantile MLD.
3.1.2
Secondary Objectives
Secondary Objectives:

To evaluate the effects of IT administration of SHP611 on subjects who experience 
decline in gross motor function as indicated by GMFC-MLD category 5 or higher,
compared with matched external control group data in children with MLD

To evaluate the effects of IT administration of SHP611 on the decline in gross motor 
function, as measured by an unreversed decline in GMFC-MLD of more than 2 
categories compared with matched external control group data in children with MLD, 
time course of declining gross motor function using the GMFC-MLD, and change from 
baseline of gross motor function, using the GMFC-MLD

To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) 
sulfatides (pharmacodynamic [PD] biomarker)

To evaluate the effects of IT administration of SHP611 on gross motor function, using 
the Gross Motor Function Measure 88 (GMFM-88) total score in children with MLD

To evaluate the effects of IT administration of SHP611 on the time course of declining 
gross motor function using GMFM-88, as measured by
o
an unreversed decline from baseline in GMFM-88 total score of >20 points or 
unreversed decline to <40 points, whichever occurs first, 
o
change from baseline of gross motor function, using the GMFM-88 total score, and 
o
GMFM-88 total score decline of no more than 20 points from baseline and a total 
score that is ≥40

To evaluate the effects of IT administration of SHP611 on expressive language using the 
Expressive Language Function Classification in Metachromatic Leukodystrophy 
(ELFC-MLD) 
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Pharmacokinetics:

To evaluate the concentrations of SHP611 in CSF following single and repeat IT dosing 
of SHP611

To evaluate the concentrations and PK parameters of SHP611 in 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:

CSF, serum and urine biomarkers

Proton magnetic resonance spectroscopy (MRS) of the brain, specifically 
N-acetylaspartate/Creatine (NAA/Cr) in white matter

Eichler MLD MRI severity score

Severity score as measured by magnetic resonance imaging (MRI) of the brain

Volumetric analysis based on MRI of the brain

Global impression of motor function – change (GIMF-C)

Global impression of motor function– severity (GIMF-S)

Caregiver burden and subject’s health-related quality of life impact in children with MLD 
by evaluating:
o
Caregiver burden as assessed by the Caregiver Impact Questionnaire (CIQ)
o
Health Related Quality of Life (HRQOL) as assessed by the Infant Toddler Quality of 
Life Questionnaire – 97 items (ITQOL-97)
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
Healthcare Utilization as measured by the Health Care Utilization Questionnaire (HCUQ)

Caregiver work productivity and activity impairment as assessed using the Work 
Productivity and Activity Impairment Questionnaire (WPAI): Specific Health Problem 
V2.0

Ability to eat and drink as assessed using the Eating and Drinking Ability Classification 
System (EDACS) assessments
3.2
Study Endpoints
The study objectives and endpoints are summarized in Table 4. Refer to Section 9 for a detailed 
description of endpoints and the planned statistical analysis.
Table 4
Objectives and Endpoints
Objective
Endpoint(s)
Primary

The primary objective of this study is to evaluate the 
effects of intrathecal (IT) administration of SHP611 
on the time to loss of locomotion, as indicated by 
category 5 or higher in the Gross Motor Function 
Classification in Metachromatic Leukodystrophy 
(GMFC-MLD) compared with matched external
control group data in children with late infantile MLD

The primary efficacy endpoint is time to loss of 
locomotion, measured by progression to 
GMFC-MLD category 5 or higher, or death, 
whichever occurs first, up to Week 106, 
evaluated on subjects in Group A
Secondary

To evaluate the effects of IT administration of 
SHP611 on subjects who experience decline in gross 
motor function as indicated by GMFC-MLD category 
5 or higher, compared with matched external control 
group data in children with MLD

Response in Group A, defined as maintenance 
of gross motor function at Week 106, evaluated 
as subjects who do not experience any event 
within Week 106, where event is defined as a 
decline in GMFC-MLD to category 5 or higher, 
or death

To evaluate the effects of IT administration of 
SHP611 on the decline in gross motor function, as 
measured by an unreversed decline in GMFC-MLD 
of more than 2 categories compared with matched 
external control group data in children with MLD, 
time course of declining gross motor function using
the GMFC-MLD, and change from baseline of gross 
motor function, using the GMFC-MLD

Decline in gross motor function using 
GMFC-MLD: Change from baseline at Week 
106 and EOS in gross motor function, using the 
GMFC-MLD

To evaluate the effects of IT administration of 
SHP611 on the decline in gross motor function, as 
measured by an unreversed decline in GMFC-MLD 
of more than 2 categories compared with matched 
external control group data in children with MLD, 
time course of declining gross motor function using
the GMFC-MLD, and change from baseline of gross 
motor function, using the GMFC-MLD

Decline in gross motor function using 
GMFC-MLD: Subjects with unreversed decline 
from baseline in GMFC-MLD of more than 
2 categories, defined as any decline of more 
than 2-categories that has not reverted to a 
2-category decline (or better) at Week 106, 
evaluated on subjects in Group A
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Table 4
Objectives and Endpoints
Objective
Endpoint(s)

To evaluate the effects of IT administration of 
SHP611 on the decline in gross motor function, as 
measured by an unreversed decline in GMFC-MLD 
of more than 2 categories compared with matched 
external control group data in children with MLD, 
time course of declining gross motor function using 
the GMFC-MLD, and change from baseline of gross 
motor function, using the GMFC-MLD

Decline in gross motor function using 
GMFC-MLD: Time to unreversed decline from 
baseline in GMFC-MLD of more than 
2 categories, defined as any decline of more 
than 2 categories that has not reverted to a 
2-category decline (or better) as of the last 
recorded observation

To evaluate the effects of IT administration of 
SHP611 on CSF sulfatides (PD biomarker)

Change from baseline at Week 106 and EOS in 
CSF sulfatides levels

To evaluate the effects of IT administration of 
SHP611 on gross motor function, using the Gross 
Motor Function Measure 88 (GMFM-88) total score 
in children with MLD

Response in Group A, defined as maintenance 
of gross motor function at Week 106, defined as 
a GMFM-88 total score ≥40

To evaluate the effects of IT administration of 
SHP611 on the time course of declining gross motor 
function using GMFM-88, as measured by 
o
an unreversed decline from baseline in GMFM-
88 total score of >20 points or unreversed decline 
to <40 points, whichever occurs first, 
o
change from baseline of gross motor function, 
using the GMFM-88 total score, and 
o
GMFM-88 total score decline of no more than 
20 points from baseline and a total score that is 
≥40

Decline in gross motor function using 
GMFM-88: Time to unreversed decline from 
baseline at Week 106 and EOS in GMFM-88 
total score decrease of >20 points or unreversed 
decline to a score <40 points, whichever occurs 
first

Decline in gross motor function using 
GMFM-88: Change from baseline at Week 106 
and EOS in gross motor function, using the 
GMFM-88 total score

Decline in gross motor function using 
GMFM-88: Subjects in Group A with 
GMFM-88 total score decrease of ≤20 points 
from baseline and a total score that is ≥40 at 
Week 106 and EOS

To evaluate the effects of IT administration of 
SHP611 on expressive language using the Expressive 
Language Function Classification (ELFC-MLD)

Change from baseline at Week 106 and EOS in 
expressive language using the ELFC-MLD 
Pharmacokinetic

To evaluate the concentrations of SHP611 in CSF 
following single and repeat IT dosing of SHP611

CSF parameters:
o
Predose concentrations (Ctrough) of SHP611 
at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 
106
o
Postdose concentrations of SHP611 at 6 
and 24 hours (Weeks 0 and 106)
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Table 4
Objectives and Endpoints
Objective
Endpoint(s)

To evaluate the concentrations and PK parameters of 
SHP611 in serum following single and repeat IT 
dosing of SHP611

Serum parameters:
o
PK parameters after the first dose (Week 0) 
and after repeated doses (Week 106) of 
SHP611 determined by noncompartmental 
analysis will include but not limited to area 
under the concentration (AUC), maximum 
concentration (Cmax), and clearance after IT 
administration (CL/F)
o
Predose concentrations (Ctrough) of SHP611 
at Weeks 0, 13, 26, 40, 53, 79, and 106
Safety

Occurrence of treatment-emergent adverse events 
(TEAEs)

Treatment-emergent adverse events (TEAEs)

Clinical laboratory testing (serum chemistry, 
hematology, and urinalysis) and vital signs

Changes from baseline at Week 106 and EOS in 
clinical laboratory testing (serum chemistry, 
hematology, and urinalysis)

Physical examination including documentation of 
signs and symptoms of MLD and Developmental 
Questionnaire

Change from baseline at Week 106 and EOS in 
physical examination including documentation 
of signs and symptoms of MLD (tone, reflexes, 
and vision)

12-lead electrocardiogram (ECG)

Change from baseline at Week 106 and EOS in 
12-lead electrocardiogram (ECG)

CSF laboratory parameters (chemistries and cell 
counts)

Change from baseline at Week 106 and EOS in 
CSF laboratory parameters (chemistries, cell 
counts)

Development of anti-SHP611 antibodies in CSF and 
serum

Anti-SHP611 antibody responses in CSF and 
serum at Week 106 and EOS

SOPH-A-PORT® Mini S device in subjects with 
MLD

SOPH-A-PORT Mini S assessments will be 
evaluated using assessments of device 
implantation, device function, device longevity, 
and adverse events (AEs) associated with the 
implant surgery or device
Exploratory
To evaluate the effects of administration of IT 
SHP611 on:
Change in:

CSF, serum and urine biomarkers

CSF, serum, and urine biomarkers over time

Proton magnetic resonance spectroscopy (MRS) of 
the brain, specifically N-acetylaspartate/Creatine 
(NAA/Cr) in white matter

MRS metabolite levels specifically: 
N-acetylaspartate/Creatine over time

Eichler MLD MRI severity score

Eichler MLD MRI severity score over time

Severity score as measured by magnetic resonance 
imaging (MRI) of the brain

Total MLD severity score based on brain MRI 
over time 

Volumetric analysis based on MRI of the brain

Volumetric analysis of the brain based on MRI 
over time
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Table 4
Objectives and Endpoints
Objective
Endpoint(s)

Global impression of motor function – change 
(GIMF-C) 

GIMF-C over time

Global impression of motor function – severity 
(GIMF-S)

GIMF-S over time

Caregiver burden and subject’s health-related quality 
of life impact in children with MLD by evaluating:
o
Caregiver burden as assessed by the Caregiver 
Impact Questionnaire (CIQ)
o
Health Related Quality of Life (HRQOL) as 
assessed by the Infant Toddler Quality of Life 
Questionnaire – 97 items (ITQOL-97)

Caregiver burden and subject’s health-related 
quality of life: Descriptive statistics of the 
Caregiver Impact Questionnaire (CIQ) item 
responses over time to inform scoring

Caregiver burden and subject’s health-related 
quality of life: change in each of the parent and 
infant/toddler concepts as assessed by the 
Infant Toddler Quality of Life Questionnaire –
97 items (ITQOL-97) over time

Healthcare Utilization as measured by the Health 
Care Utilization Questionnaire (HCUQ)

Incidence of hospitalizations, number of days in 
hospital, reason for admission, and frequency of 
selected MLD-related procedures (use of 
feeding tube, use of intubation, and type of 
respiratory support) over time; total number of 
additional hospitalizations during the 2-year 
follow-up

Caregiver work productivity and activity impairment 
as assessed using the Work Productivity and Activity 
Impairment Questionnaire (WPAI): Specific Health 
Problem V2.0

Caregiver work productivity and activity 
impairment as assessed using the Work 
Productivity and Activity Impairment 
Questionnaire (WPAI): Specific Health 
Problem V2.0 over time

Ability to eat and drink as assessed using the Eating 
and Drinking Ability Classification System (EDACS) 
assessments

Change in ability to eat and drink as assessed 
using the Eating and Drinking Ability 
Classification System (EDACS) assessments
over time
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4.
STUDY DESIGN
4.1
Overall Design 
SHP611-201 is a single-arm, matched external control, global, multicenter, Phase 2 trial. The 
study was planned to enroll up to 42 subjects with late infantile MLD who have an initial onset 
of neurological symptoms documented prior to 30 months of age (Groups A, B, C, and F), or 
who are minimally symptomatic and ≥6 to <18 months of age (Group D), or who are early 
symptomatic and ≥12 to <18 months of age (Group E). Minimally symptomatic is defined as 
being without clear symptoms of MLD or only showing mild symptoms (such as weakness) that 
do not meet the criteria for a GMFC-MLD category of >0 (NB: no subjects were enrolled in 
Groups D or E). The rate and severity of disease progression is well documented in late infantile 
MLD (Kehrer et al. 2011b; Kehrer et al. 2011a). A distinguishing feature of the definition of late
infantile MLD is the early age at disease symptom onset with a majority of patients with late
infantile MLD showing first motor dysfunction before the age of 18 months. Six subject groups 
are defined for this study based on age and motor dysfunction at screening:

Group A (GMFC-MLD category 1 or 
2):
Approximately 16 subjects who are 18 to 
48 months of age with a GMFC-MLD 
category of 1 or 2

Group B (GMFC-MLD category 3):
Up to 8 subjects who are 18 to 72 months of 
age with a GMFC-MLD category of 3

Group C (GMFC-MLD category 4):
Up to 8 subjects who are 18 to 72 months of 
age with a GMFC-MLD category of 4

Group D (minimally symptomatic):
Up to 3 subjects who are ≥6 to <18 months 
of age, with the same ASA allelic 
constitution as an older sibling with
confirmed late infantile or juvenile onset 
MLD

Group E (GMFC-MLD category 1 or 2, 
<18 months of age):
Up to 3 subjects who are ≥12 to <18 months 
of age, with documented diagnosis of MLD 
per inclusion criteria 1 and 2 who have 
achieved stable walking (defined as at least 
1 month of independent walking) and who 
have a GMFC-MLD category of 1 or 2

Group F (GMFC-MLD category 5 or 
6):
Up to 4 subjects who are 18 to 72 months of 
age with a GMFC-MLD category of 5 or 6
Subjects weighing ≥7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly. It is anticipated that 
the majority of subjects will receive 150 mg IT weekly for a total treatment duration of 
105 weeks; however, subjects weighing ≥5 kg (11.0 lbs) to <7 kg (15.4 lbs) will receive 100 mg 
IT SHP611 weekly until they weigh ≥7 kg, at which time they will begin dosing with 150 mg IT 
SHP611 weekly.
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The study will evaluate safety and efficacy of the treatment regimen on gross motor function 
using the GMFC-MLD and GMFM-88 total score to measure disease progression (Groups A, B, 
C, E, and F). Subjects in Group D will be assessed with the Alberta Infant Motor Scale (AIMS) 
(Piper and Darrah 1994) and the GMFM-88 until they are able to walk or reach 18 months of 
age, whichever comes first. After this, motor function of subjects in Group D will be assessed 
using the GMFC-MLD and the GMFM-88.
The primary efficacy endpoint is time to loss of locomotion, measured by progression to 
GMFC-MLD category 5 or higher, or death, whichever occurs first, up to Week 106, evaluated 
on subjects in Group A. A secondary efficacy endpoint is response in Group A, defined as 
maintenance of gross motor function at Week 106, evaluated as subjects who do not experience 
any event within Week 106, where event is defined as a decline in GMFC-MLD to category 5 or 
higher, or death.
The efficacy of SHP611 will be evaluated by comparison of SHP611-201 enrolled subjects in 
Group A with matched external control group. The data from these untreated MLD subjects (ie, 
subjects who have received no investigational product or therapy) will come from the ongoing 
Global Leukodystrophy Initiative (GLIA-MLD) natural history study. The matched external
control group must have data for at least baseline gross motor function evaluation. The filtering 
criteria for these controls will be very similar to the inclusion/exclusion criteria for enrolled 
subjects in Group A of this present study.
Subjects will be implanted with the SOPH-A-PORT Mini S IDDD. Procedures for implantation 
are detailed in the device’s Instructions for Use (IFU) manual. Standard hospital procedures for 
surgery will be followed and the subject may be under anesthesia for this procedure. Prior to 
implantation, individual neurosurgeons may order additional imaging to estimate the canal size 
and spinal cord conus location in younger subjects. After implantation, a leak test is performed 
by the neurosurgeon to ensure a sealed system is in place. X-rays may be performed as needed, 
particularly for younger subjects, throughout the study to confirm placement of the device and/or 
evaluate a nonworking catheter. In order to facilitate healing, subjects should remain under 
observation in the hospital setting until deemed clinically stable by the investigator and should 
limit activity for 24 hours after IDDD implantation. To allow for healing, a waiting period of 3 to 
5 days after device implantation must be observed before the first administration of SHP611 may 
occur. If the device becomes nonfunctional at any time during the study, it may be removed, 
replaced or revised as appropriate. A 3-5 day waiting period should also be observed after IDDD 
revision or re-implantation prior to resumption of dosing. Examination of both the port and 
catheter track will be performed before each IT injection, which includes aspiration of CSF via 
the port. 
If use of the IDDD is not possible, a lumbar puncture (LP) may be utilized to obtain CSF 
samples and/or to deliver investigational drug product. It is anticipated that LP may have to be 
performed with anesthesia support at the discretion of the investigator. After 12 consecutive LPs, 
the feasibility of further use of LPs for that subject will be determined at the discretion of the 
investigator and the Takeda medical monitor and documented in a note to file.
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During the treatment period, subjects will undergo assessments of gross motor function, brain 
imaging, and quality of life. Initial assessment of gross motor function using the GMFC-MLD 
scale will be conducted by local, trained healthcare professionals and video-recorded. Videos of 
GMFC-MLD assessments will be evaluated by central video reviewers for primary scoring of 
gross motor function on the instrument.
Safety will be assessed by collection of adverse events (AEs), physical examinations, vital signs, 
concomitant medications, ECG, clinical laboratory testing, and monitoring of anti-SHP611 
antibodies. Periodic assessments will be performed before and after SHP611 administration at 
specific study visits (eg, serum/CSF PK sampling and CSF, serum, and urine biomarkers 
sampling and testing).
The study will consist of a screening period of up to 28 days. Surgical implantation of the 
SOPH-A-PORT Mini S IDDD may occur during a period of 10 days prior to the first 
administration of IT SHP611 to 28 days following the first administration of IT SHP611. IT 
SHP611 administered prior to IDDD implantation will be administered by LP.
Subjects will be assessed according to the following schedule:

Screening (-28 to -1 days)

Surgical implantation of IDDD (-10 to 28 days)

Primary treatment period (Week 0 [baseline assessments prior to dosing {-1 to 0 days}] 
through Week 105)

End of primary treatment period (Week 106)

Extension treatment period (from Week 106 administration of SHP611)

End of treatment (EOT) (last administration of SHP611)

End of study (EOS) (1 week after EOT)

Safety follow-up (2 weeks after EOS)
After the primary treatment period is completed at Week 106, subjects may continue in the 
extension period of the study where they may continue to receive treatment with SHP611 for an 
extended duration of time. 
Subjects will receive weekly treatment until they or their parents/guardians decide to discontinue 
treatment; the sponsor discontinues the study; the subject is discontinued from the study due to 
medical or safety concerns; or the product becomes commercially available in the subject’s 
country of residence, whichever comes first. During the extension period, main site assessments 
will be scheduled every 6 months. These assessments may be skipped for a visit at the discretion 
of the investigator and upon discussion of the investigator with the Medical Monitor if it is 
determined that the subject is unable to perform the assessments. At the EOT visit, subjects will 
receive their last administration of SHP611 and comprehensive assessments will be completed at 
the EOS visit.
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If a subject discontinues from the study earlier than EOS, every effort should be made to 
complete assessments for the EOS and the safety follow-up visits. Subjects are to have the IDDD 
removed when they discontinue from the study, unless the subject is continuing to receive 
treatment with SHP611 through another mechanism (eg, commercially available) or the
investigator determines that the IDDD should not be removed from the subject based upon a 
safety assessment and the IDDD (full or partial) should remain in the subject.
Sites will employ all efforts to see subjects for the clinical assessments; however, in unavoidable 
circumstances, such as the COVID-19 public health emergency, sites should use their judgment 
in conducting the study visits to maintain continuity of subject dosing and to collect as much data 
as possible while ensuring the protocol is being followed. Due to COVID-19 control measures, 
there may be unavoidable protocol deviations which will be documented in the study records 
using already established procedures. These data may be handled differently in the final data 
analysis, with this documented in the Statistical Analysis Plan.
4.2
Scientific Rationale for Study Design
Deficiency of the lysosomal enzyme ASA in MLD leads to the accumulation of sulfated 
glycosphingolipids, known collectively as sulfatides. These accumulate in, and are toxic to, the 
cells which maintain the myelin insulation sheath of axons both centrally and peripherally. It is 
hypothesized that IT administration of rhASA (SHP611) would be sufficient to hydrolyze 
accumulated sulfatides in cells of the nervous system and could slow or prevent further 
accumulation, which should translate into motor system benefits. There are currently very 
limited approved therapies for MLD.
Administration of SHP611 via an implanted IDDD was well tolerated in Phase 1/2 studies in 
pediatric subjects with MLD and the device appeared to have an acceptable safety profile. In 
these studies, the higher dose appeared to show a signal of stabilized motor function in 4 of 
12 subjects who received the 100 mg every-other-week (EOW) dose. This Phase 2 study will 
investigate the potential of IT SHP611 at a higher dose of 150 mg once weekly to stabilize or 
slow progression of motor dysfunction in pediatric subjects with late infantile MLD.
In the extension treatment period of the study, subjects who have participated in the primary 
treatment of the study may receive treatment with SHP611 for an extended duration of time to
evaluate long-term safety and efficacy outcomes of treatment with IT SHP611.
While a randomized concurrent double-blind placebo control is the preferred clinical trial design, 
there are no active-comparators for this life-threatening, rapidly progressive disease. Concurrent 
controls such as delayed start, no-treatment, and placebo controls have been evaluated and 
deemed infeasible due to challenges with enrollment and lack of support from parents of patients 
and investigators. Nonconcurrent, matched external control group will be used for this study as 
this is the only feasible and ethical option; other options would not be supported by families and 
investigators.
Both the GMFC-MLD (Kehrer et al. 2011b; Kehrer et al. 2011a) and the GMFM-88 
(Iannaccone and Hynan 2003; Linder-Lucht et al. 2007; Russell et al. 2013; Russell et al. 1989)
instruments will be used to measure gross motor function of study subjects.
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The GMFC-MLD instrument will be used for the primary endpoint as it was developed 
specifically for MLD patients, based on experiences with the GMFCS instrument used for 
cerebral palsy (Palisano et al. 1997). It has been reported to be an established and reliable tool 
for the standardized assessment of gross motor function in MLD that can be used to classify the 
stages of disease progression and for evaluation of therapeutic options for MLD. The 
GMFC-MLD covers clinically relevant gross motor stages occurring in patients with MLD and 
consists of 7 categories based primarily on locomotion, and in more advanced disease also 
includes sitting and other motions. The GMFC-MLD is applicable from the age of 18 months 
onwards, or in younger subjects if stable walking has been achieved (able to walk independently 
for at least a month) and can be assessed retrospectively based on medical records. The 
intra-rater reliability of the tool has been reported to be high, with kappa coefficient k=0.90 for 
overall rater agreement (95% CI 0.87-0.93).
The GMFM-88 instrument will be used as a secondary endpoint and is included as a supportive 
method of measuring clinical response to that used for the primary endpoint. The GMFM-88 has 
demonstrated valid and reliable measurement properties in several different patient populations, 
including cerebral palsy (from 5 months through 16 years old), by evaluation of a broad range of 
tasks that could be accomplished independently by a child of 5 years of age without any motor 
disability. The GMFM-88 assesses gross motor function across 5 dimensions: lying and rolling; 
sitting; kneeling and crawling; standing; and walking, running, and jumping. The GMFM-88 
instrument is administered by a trained physical therapist in about 45 to 60 minutes. It can be 
administered in a standardized, reliable, and reproducible manner to subjects.
Inclusion of subjects ≥6 to <18 months of age who are minimally symptomatic will be allowed in 
Group D as long as inclusion/exclusion criteria are satisfied. Subjects in Group D will have the 
same ASA allelic constitution as an older sibling with confirmed infantile or juvenile onset 
MLD. Subjects in Group E will be ≥12 to <18 months of age, with documented diagnosis of 
MLD per inclusion criteria 1 and 2 who have achieved stable walking (defined as at least 
1 month of independent walking) at some point prior to screening, and who are early 
symptomatic with a GMFC-MLD category of 1 or 2 at screening. Group E allows for enrollment 
of young subjects with MLD who are not necessarily siblings of enrolled subjects in the other 
groups. In addition to safety and biomarker data, this group will allow for assessment of IT 
SHP611 effect in a younger group who may be earlier in their disease progression.
As discussed above, this study design is limited by the lack of available concurrent controls.
4.3
Justification for Dose
Subjects weighing ≥7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly. It is anticipated that 
the majority of subjects will receive 150 mg IT weekly for a total treatment duration of 
105 weeks; however, subjects weighing ≥5 kg (11.0 lbs) to <7 kg (15 lbs) will receive 100 mg IT 
SHP611 weekly until they weigh ≥7 kg, at which time they will begin dosing with 150 mg IT 
SHP611 weekly for the remainder of the study for 105 weeks. For the extension period, dosing 
will be once weekly administration of IT SHP611 at 150 mg.
The dose of 150 mg to be investigated in this study (SHP611-201) is supported by the current 
Phase 1/2 clinical safety data as well as nonclinical studies.
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The 150 mg dose of SHP611 was selected based on safety, clinical activity, and PK data from 
the Phase 1/2 dose escalation study (HGT-MLD-070). Pharmacokinetic modeling and clinical 
activity of SHP611 in the Phase 1/2 program suggest that IT administration of SHP611 (150 mg 
once weekly) may produce a more rapid and sustained therapeutic benefit in a greater number of 
subjects with MLD. No clinical therapeutic effect was observed for lower doses evaluated 
previously in Takeda studies HGT-MLD-070/071.
As would be expected with both a larger dose amount and a greater frequency, a population 
PK/PD model simulation of the 150 mg weekly dose predicts higher peak Cmax and total 
concentrations of SHP611 in serum, CSF, and CNS compartments than the 100 mg dose EOW 
administered in studies HGT-MLD-070/071. The 150 mg regimen is expected to produce 50% 
higher SHP611 concentrations in the CSF and the CNS than the 100 mg regimen.
4.4
Duration of Subject Participation and Study Completion Definition
Once it has been confirmed that all eligibility criteria have been met, a subject will be considered 
enrolled in the study. Enrollment of subjects may occur prior to IDDD implantation of the first 
dose of SHP611. The subject’s duration of participation in the primary treatment period is 
expected to be approximately 106 weeks. Upon completion of the primary treatment period, 
subjects may participate in the extension period of the study.
If a subject discontinues from the study earlier than EOS, every effort should be made to 
complete assessments for the EOS and the safety follow-up visits. Refer to the Schedule of 
Activities: Extended Treatment Period through Safety Follow-up for details.
The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, 
whichever is later (refer to Section 8.1.6 for the defined follow-up period for this protocol).
4.5
Sites and Regions
This is a multicenter study. Investigational sites are planned in North America, Europe, Middle 
East, Latin America, and Japan.
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5.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
5.1
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-F)

Low ASA activity in leukocytes (compared to laboratory normal range)
AND

Elevated sulfatides in urine
2. The subject must have a gait disorder due to spastic ataxia or weakness attributable to MLD 
by the investigator and documented by a primary care physician or a specialist physician by 
30 months of age (Groups A-C, and F), or be minimally symptomatic and ≥6 to <18 months 
of age (Group D); or be early symptomatic and ≥12 to <18 months of age (Group E). 
Subjects in Group E must have neurological symptoms documented by either a primary care 
physician or a specialist physician.
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: ≥6 to <18 months of age

Group E: ≥12 to <18 months of age

Group F: 18 to 72 months of age
4. The subject’s GMFC-MLD category at screening must be:

Group A: GMFC-MLD category of 1 or 2

Group B: GMFC-MLD category of 3

Group C: GMFC-MLD category of 4

Group D: minimally symptomatic, ≥6 to <18 months of age, with the same ASA allelic 
constitution as an older sibling with confirmed late infantile or juvenile onset MLD 

Group E: early symptomatic, ≥12 to <18 months of age with a GMFC-MLD category of 
1 or 2, and with a history of achieving stable walking (defined as at least 1 month of 
independent walking)

Group F: GMFC-MLD category of 5 or 6
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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.
5.2
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) or a known genetic disorder other than 
MLD
2. History of bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), 
or gene therapy; or undergoes BMT, HSCT, or gene therapy at any point during the study
3. Primary presentation of MLD was behavioral or cognitive symptoms (per investigator’s 
clinical judgment); behavioral symptoms that are secondary to motor deficits (eg, tantrums in 
response to loss of motor skills) are not exclusionary
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. Subjects with laboratory, ECG, or vital sign abnormalities reflecting intercurrent illness that 
may compromise their safety during the trial should not be enrolled. Abnormal laboratory, 
vital sign and ECG results at screening should be reviewed with the Takeda medical monitor.
7. The subject is enrolled in another clinical study that involves use of any investigational 
product (drug or device) within 30 days or 5 half-lives (whichever is longer) prior to study 
enrollment or at any time during the study
8. The subject has had prior exposure to SHP611
9. The subject must weigh >11 lbs (5 kg)
10. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S 
IDDD Instructions for Use (IFU)
a.
The patient has had, or may have, an allergic reaction to the materials of construction 
b. The patient has shown an intolerance to an implanted device
c.
The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port
d. The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction
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e.
The patient has a known or suspected local or general infection
f.
The patient is at risk of abnormal bleeding due to a medical condition or therapy
g. The patient has one or more spinal abnormalities that could complicate safe implantation 
or fixation
h. The patient has a functioning CSF shunt device
Inclusion and exclusion criteria for the matched external control group will be provided in the 
Statistical Analysis Plan (SAP).
5.3
Restrictions 
The use of the IDDD will be restricted to SHP611-201 study-related activities and should not be 
accessed for any other purpose, including administration of concomitant medications. The safety 
of SHP611 IT in patients receiving other drugs intrathecally has not been assessed. Therefore, 
administration of intrathecal drugs other than SHP611 during study participation is 
contraindicated. In this setting, SHP611 will be discontinued for the subject. Subject activity 
restrictions may be imposed at the discretion of the investigator. 
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity restrictions 
for patients to be implanted with this device. Activities that may include sudden, excessive, or 
repetitive bending, twisting, bouncing, or stretching can damage or dislodge IDDD components 
and should be avoided.
5.4
Reproductive Potential
This study will not enroll subjects of child-bearing potential.
5.4.1
Female Contraception
Not applicable.
5.4.2
Male Contraception
Not applicable.
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6.
STUDY INTERVENTION
6.1
Investigational Product
6.1.1
Identity of Investigational Product
The investigational product is SHP611, which will be provided in vial form. Additional 
information is provided in the current SHP611 IB.
SHP611 drug product is a sterile solution of recombinant human arylsulfatase A (rhASA), 
30 mg/mL, in 154 mM sodium chloride (NaCl), at pH 6.0 with (vol/vol) 0.005% polysorbate 20. 
SHP611 drug product is packaged in ISOI 2R, Type I borosilicate glass vials with a butyl rubber 
stopper with a fluoro-resin coating. Vials are sealed with and aluminum overseal. Each vial 
contains 1.6 mL of drug product to deliver a minimum extractable volume of 1.3 mL per vial 
with minimal waste, and for handling convenience in the clinical setting.
Investigational drug product will be clearly labeled according to country specifications. This will 
include, but is not limited to, manufacturer’s name, protocol number, lot number, storage 
conditions, and expiration date.
See the Pharmacy Manual for additional details.
6.1.2
SOPH-A-PORT Mini S IDDD
After IDDD implantation, the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port. The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The Sophysa SOPH-A-PORT Mini-S is an intrathecal drug delivery device that has been used in 
all of Takeda’s intrathecal enzyme replacement programs (Sanfilippo Syndrome type A, Hunter 
Syndrome, and MLD). It is an implantable port access system designed to provide repeated 
access to the intrathecal space for drug delivery. This device is manufactured by Sophysa SA 
(Sophysa), Orsay, France. The development of the SOPH-A-PORT Mini S was based on a kit 
component modification of an existing CE-marked device in the EU. SOPH-A-PORT Mini S is 
approved in the EU exclusively for long-term intrathecal administration of Takeda’s enzyme 
replacement therapies per the medical device directives.
The SOPH-A-PORT line of products has been CE-marked in the EU since 1998 and was 
authorized for marketing in Japan in 2000. The SOPH-A-PORT Mini S has been characterized 
and tested through a series of development studies, eg, functional and performance testing and 
long-term biocompatibility. Functional, performance, and long-term biocompatibility test results 
have shown that the SOPH-A-PORT Mini S is suitable for its intended use. In the EU, the 
SOPH-A-PORT Mini S was added to the CE mark certificate for the SOPH-A-PORT Product 
Family, effective on 16 May 2013, and updated on 13 Oct 2013. The indication was expanded to 
include long-term intrathecal administration of Takeda’s enzyme replacement therapies on 
13 Mar 2019. The SOPH-A-PORT Mini S is an investigational device in all other non-EU 
countries. In the United States, the SOPH-A-PORT Mini S device is considered a device 
constituent part of the SHP611 combination product, per 21 CFR part 4. 
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Sophysa maintains the original Investigational Device Master File (I-MAF) MAF2173 to support 
the SOPH-A-PORT Mini S investigational presentation for use in clinical development of 
SHP611. Sophysa has submitted an Investigational Device Master File which includes 
information for an Investigational Device Exemption (IDE) application for a “significant risk” 
clinical investigation of a Class III device subject to Premarket Approval (PMA). Sophysa has 
issued letters of authorization to Takeda and to FDA accordingly. Sophysa submits amendments 
to the Investigational Master File for Devices as required for any changes to the SOPH-A-PORT 
Mini S investigational presentation. The current IDE equivalent MAF2173 has been maintained 
to provide on-going support of Takeda’s clinical trial efforts for Hunter Intrathecal (HIT) and 
Metachromatic Leukodystrophy (MLD) programs.
Takeda conducts internal quarterly safety reviews to discuss the safety profile of the device. As 
of 31 Aug 2018, there were 139 devices implanted in 106 subjects across all intrathecal programs 
at Takeda. Overall, 53 (50%) subjects needed no additional surgery, 38 (36%) subjects had 
failure of initial device, 22 (21%) subjects had adjustment of initial device without device failure, 
and 17 (14%) subjects ultimately had complete device removal without replacement. These 
medical safety review meetings have determined a positive benefit risk ratio and therefore all 
ongoing clinical trials will continue utilizing the device for enzyme replacement studies. 
The SOPH-A-PORT Mini S is comprised of the following components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector

One catheter passer
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with ethylene oxide. Instructions for Use are also included in the packaging.
Labels are provided on the outer carton on the SOPH-A-PORT Mini S box.
Further details are provided in the IFU.
The use of the IDDD will be restricted to SHP611-201 study-related activities and should not be 
accessed for any other purpose, including administration of concomitant medications. The safety 
of SHP611 IT in patients receiving other drugs intrathecally has not been assessed. Therefore, 
administration of intrathecal drugs other than SHP611 during study participation is 
contraindicated. In this setting, SHP611 will be discontinued for the subject.
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6.1.3
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment 
This is a single-arm study. 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If a unique identifier is allocated incorrectly, the clinical 
research associate (CRA)/study monitor must be notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from unique identifiers, may 
also be assigned to subjects for specific treatment assignment as dictated by the study. In these 
cases, the same investigational product packing identification number may not be assigned to 
more than 1 subject.
6.2.2
Dosing
Subjects weighing ≥7 kg (15.4 lbs) will receive 150 mg IT SHP611 weekly. It is anticipated that 
the majority of subjects will receive 150 mg IT weekly for a total treatment duration of 
105 weeks; however, subjects weighing ≥5 kg (11.0 lbs) to <7 kg (15.4 lbs) will receive 100 mg 
IT SHP611 weekly until they weigh ≥7 kg, at which time they will begin dosing with 150 mg IT 
SHP611 weekly for the remainder of the study. 
Dosing may only occur at an approved investigational site.
6.2.3
Unblinding the Treatment Assignment
Not applicable.
6.2.4
Dose Modification
The once weekly IT dose of SHP611 150 mg to be investigated in this study is supported by the 
current Phase 1/2 clinical safety data as well as nonclinical studies.
As with all clinical studies evaluating a new dose or dosing regimen, the sponsor will closely 
monitor the emerging safety profile to determine if the expected higher exposure from using a 
once weekly 150 mg dosing regimen alters the investigational product’s safety profile and 
benefit/risk ratio. Based on the observed safety profile of SHP611 with doses up to 100 mg
administered EOW to subjects for more than 5 years of treatment, and Takeda’s experience with 
other enzyme replacement therapies, a significant change in the overall safety profile of SHP611 
is not expected with the proposed dose and dosing regimen.
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The maximum administered dose will not exceed 150 mg once weekly.
6.3
Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
Investigational drug product will be clearly labeled according to country specifications. This will 
include, but is not limited to, drug name, protocol number, lot number, storage conditions, and 
expiration date. All packaging and labeling will be done in accordance with applicable regulatory 
requirements. 
See Pharmacy Manual for additional details. 
Space is allocated on the label so that the site representative can record a unique subject 
identifier.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label.

Obscure the clinical study label.

Identify the study subject by name.
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
CARTON 37x37x47 Millimeter white Crash-Lock
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier on the investigational product bottle/carton 
labels as they are distributed.
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Investigational product must be stored in accordance with labeled storage conditions, including 
refrigeration at 2 to 8ºC (36 to 46ºF). Temperature monitoring is required at the storage location 
to ensure that the investigational product is maintained within an established temperature range. 
The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such 
a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.3.4
Special Handling
Do not freeze. Avoid exposure to intense direct sunlight. Investigational drug product may not be 
used beyond the expiration date on the labeling.
6.4
Drug and Device Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
investigational product will be documented in the subject’s source and/or other investigational 
product record.
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No investigational product stock or returned inventory from a Takeda-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
With the written agreement of the sponsor, at the end of the study all unused stock, and 
empty/used investigational product packaging may be destroyed at the site or a local facility. In 
this case, destruction records identifying what was destroyed, when and how, must be obtained 
with copies provided to the sponsor. Destruction of investigational product must be in 
accordance with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
The disposition of all SOPH-A-PORT Mini S IDDDs delivered to the investigator must be 
recorded on a patient-by-patient basis by completing the accountability log. The date and time of 
administration of the investigational drug product and use of the SOPH-A-PORT Mini S device 
must be documented on the subject’s appropriate electronic case report form (eCRF). The 
investigator, Clinical Research Coordinator, or designee (eg, pharmacist) must ensure that all 
documentation regarding receipt, storage, dispensing, loss/damaged SOPH-A-PORT Mini S 
IDDDs and return of used/unused IDDDs) is complete, accurate, and ready for review at each 
monitoring visit and/or audit. The sites must ensure that the SOPH-A-PORT Mini S devices are 
available for the monitor to inventory and prepare for return shipment to the Sponsor or 
designee, if required. 
The SOPH-A-PORT Mini S and its components are sterile, single-use devices. Please refer to the 
IDDD Manual for device return instructions.
Drug accountability must be assessed at the container/packaging level for unused investigational 
product that is contained within the original tamper-evident sealed container (eg, bottles, trays, 
vials) or at the individual count level for opened containers/packaging. The 
pharmacist/nominated person will record details on the drug accountability form.
6.5
Treatment Compliance
Treatment with the investigational product will be administered via an IDDD (or LP) under the 
supervision of the investigator and in the controlled environment of a clinical center; therefore, 
full subject compliance with treatment is anticipated in this study.
The initial implantation and revision and/or explantation of the SOPH-A-PORT Mini S will be 
performed by pediatric or general neurosurgeons, anesthesiologists, or interventional radiologists 
who have experience in port and catheter implant procedures and intrathecal access procedures, 
and have completed training with the SOPH-A-PORT Mini S. Please refer to the IFU for further 
details.
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Investigational product administration will be performed in a clinical setting by appropriately 
trained and skilled healthcare providers (nurses or physicians) with knowledge of the subject’s 
drug regimen and experienced in accessing vascular or CNS ports or CNS infusion pumps.
Subjects and subjects’ families will not be directly using the device to administer drugs and will 
have limited direct interaction with the device as there is minimal care required both during the 
immediate postoperative period as the implant site heals, and at times of drug administration.
6.6
Prior and Concomitant Treatment
6.6.1
Prior Treatment
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 30 days prior to the screening visit (Day -28 to -1) (or pharmacokinetic equivalent of 
5 half-lives, whichever is longer) and through the final study contact (including protocol-defined 
follow-up period) must be recorded in the subject’s source document.
6.6.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of initial implantation of 
the IDDD or the first dose of investigational product, whichever occurs first, and the end of the 
follow-up period, inclusive. Concomitant treatment information must be recorded in the subject’s 
source document. Subjects must receive all other standard treatments for their condition and its 
complications, including treatment for decubitus ulcers, seizures, and spasticity.
6.6.3
Permitted Treatment
Medications not indicated as prohibited are permitted, including treatments for non-exclusionary 
medical conditions. In the event of an emergency, any needed medications may be prescribed 
without prior approval by the sponsor, but the medical monitor must be notified of the use of any 
prohibited medications immediately thereafter.
6.6.4
Prohibited Treatment
As noted in the Exclusion Criteria (Section 5.2), the use of any investigational therapy 
(drug/device, HSCT, gene therapy, bone marrow transplant) other than that received in study 
SHP611-201 is prohibited within 30 days prior to enrollment or at any time during the study.
Treatments not listed above are considered allowable. 
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7.
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Treatment
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
EOS, including a safety follow-up 2 weeks after EOS, will be performed as completely as 
possible. Comments (spontaneous or elicited) or complaints made by the subject must be 
recorded in the source documents. The reason for discontinuation, date of discontinuation of the 
investigational product, and the total amount of investigational product administered must be 
recorded in the source documents.
If subjects do not receive intercurrent disease modifying treatment (eg, gene therapy, BMT, 
HSCT), they may be asked to return to complete EOS assessments during the week that would 
have been EOS week for the subject if he/she had continued in the study.
Subjects who discontinue will not be replaced.
7.2
Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document, including unavoidable circumstances, such as the COVID-19 public 
health emergency. If a subject is discontinued for more than 1 reason, each reason should be 
documented in the source and the most clinically relevant reason should be indicated.
Reasons for discontinuation include, but are not limited to:

Adverse event 

Lost to follow-up 

Lack of efficacy

Withdrawal by subject

Other
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the eCRF. If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the eCRF. If a subject chooses to withdraw from study participation due to personal 
concerns related to the COVID-19 public health emergency (other than a COVID-19-related 
adverse event), this should be specified as the reason for subject withdrawal in the eCRF.
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Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue 
study treatment will remain in the study and must continue to be followed for protocol 
specified follow-up procedures. The only exception to this is when a participant 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by the participant to provide this information.

Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion of 
the investigator, indicates that continued participation in the study is not in the best 
interest of the participant

Termination of the study by Takeda

Loss of the ability of the parent/legal guardian to freely provide consent through 
imprisonment or involuntarily incarceration for treatment of either a psychiatric or 
physical (eg, infectious disease) illness

Inability to comply with protocol

Discretion of the investigator
7.3
Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
Reasons for withdrawal include but are not limited to:

Completed

Death (provide cause)

Adverse event (specify)

Lost to follow-up (specify)

Noncompliance with study drug

Noncompliance with study procedures (specify)

Other (specify)
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7.4
Temporary Hold of Dosing
Dosing may be held until safety information can be reviewed in the event that:

Two or more subjects experience the same severe adverse event that is considered related 
to SHP611

Review of the safety and tolerability data, or clinical judgment of the investigator, 
suggest the emergence of a new potentially serious safety signal related to SHP611.
Dosing may not be resumed until a thorough review of safety and tolerability data has been 
completed and the Takeda medical monitor, Takeda pharmacovigilance representative, and the 
investigators agree that it is safe to proceed.
Any subject for whom dosing is stopped permanently or who is otherwise removed from the 
study should enter the post-treatment follow-up phase of the study.
7.5
Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or telephone contact). 
At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt request) 
asking that the subject return to the site for final safety evaluations.
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8.
STUDY ASSESSMENTS AND PROCEDURES
8.1
Study Periods
The detailed study procedures/assessments to be performed throughout the study are outlined in 
the Schedule of Activities (see Table 1, Table 2, and Table 3); which must be referred to in 
conjunction with the instructions provided in this section and in the relevant study manuals. 
Study assessments are detailed in Section 8.2.
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject, subject’s 
parent(s), guardian, or legally authorized representative (as per local requirements) will provide 
written informed consent; the subject will provide verbal or written assent as appropriate. Refer 
to Appendix 1.5 for additional details.
All data collected are to be recorded on the appropriate eCRF. 
All efforts should be made to ensure subject comfort during study procedures. Procedures should 
be performed in an age appropriate setting (pediatric unit or clinic) with caregivers present where 
permitted by the local institution. Topical, local or general anesthetic agents, administered by 
appropriately trained personnel, should be deployed to minimize pain.
Additional details for study procedures, including sample collection, are described in the Study 
Manual of Operations or Laboratory Manual and other manuals as appropriate for this study.
In acknowledgement of hospital, local, state, or national government restrictions or other site 
related factors caused by unavoidable circumstances, such as the COVID-19 public health 
emergency, which may prevent investigators from conducting the study according to the 
Schedule of Activities at the clinical study site, investigators may seek approval from the 
medical monitor to continue patients in the study despite departure from the Schedule of 
Activities. Investigators are expected to evaluate the impact to the safety of the study participants 
and site personnel for patients to continue. In evaluating such requests, the medical monitor will 
give the highest priority to the safety and welfare of the subjects. For patients that are impacted 
any procedures not conducted per the original study plan will be documented in the study 
records.
When approval is given for a patient to miss an in-person study visit, a study site physician will 
speak directly with the parent(s)/LAR(s) of the patient by telephone or other medium (eg, a 
computer-based video communication) during each visit window to assess subject safety and 
overall clinical status. During this contact, the study site physician or other qualified site staff 
should conduct the following assessments: AE/SAE collection and concomitant medication 
documentation. Assessments that cannot be completed during the protocol specified window will 
be considered missing data and such departures will be recorded in the study records. 
Alternatively, sites may seek approval to extend the visit window in order to conduct an on-site 
visit.
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8.1.1
Screening Period 
Screening (-28 to -1 days) 
The Screening Period is from -28 to -1 days and assessments may take place across several days 
during this period to allow an appropriate time frame in which to complete all procedures and 
confirm study eligibility. Screening procedures beginning with informed consent will be 
performed as outlined in Table 1 and will be completed prior to enrollment. The Screening 
Period will allow for the determination of eligibility of each subject’s inclusion into the study. 
Subjects who meet all study entrance criteria will be enrolled in the study pending sponsor and 
investigator approval.
A screen failure is a subject who has given informed consent and failed to meet all of the 
inclusion criteria and/or has met at least 1 of the exclusion criteria. Patient eligibility according 
to the study inclusion and exclusion criteria will be assessed during the Screening period. Sites 
will be allowed one opportunity to rescreen any patient who fails initial screening or withdraws 
consent prior to device implantation. If the patient subsequently screen fails, the patient will no 
longer be considered for inclusion in the study.
All AEs occurring after completion of informed consent must be recorded in the source 
documents and eCRF. Any abnormal laboratory results at screening should be discussed with the 
medical monitor. Normal ranges for vital signs and key ECGs parameters are presented in 
Appendix 7.
8.1.2
Surgical Implantation of IDDD, Day -10 to 28
Procedures for implantation are detailed in the device’s IFU manual. Standard hospital 
procedures for surgery will be followed and the subject may be under anesthesia for this 
procedure. Prior to implantation, individual neurosurgeons may order additional imaging to 
estimate the canal size and spinal cord conus location in younger patients. After implantation, a 
leak test is performed by the neurosurgeon to ensure a sealed system is in place. X-rays may be 
performed as needed, particularly for younger subjects, throughout the study to confirm 
placement of the device and/or evaluate a nonworking catheter. In order to facilitate healing, 
subjects should remain under observation in the hospital setting until deemed clinically stable 
by the investigator and should limit activity for 24 hours after IDDD implantation. To allow 
for healing, a waiting period of 3 to 5 days after device implantation must be observed before 
the first administration of SHP611 may occur. This waiting period must also be observed after 
any subsequent re-implantation or revision of the IDDD. Examination of both the port and 
catheter track will be performed before each IT injection, which includes aspiration of CSF via 
the port. 
Surgical implantation of the IDDD is allowed from 10 days before to 28 days after the first dose 
of SHP611. If use of the IDDD is not possible a lumbar puncture (LP) may be utilized to obtain 
CSF samples and/or to deliver investigational drug product. As LP can be painful, it is 
anticipated that LP may have to be performed with anesthesia support at the discretion of the 
investigator. No more than two attempts of LP should be made for a single administration of 
study drug. Subjects undergoing LP should be monitored closely following the procedure for 
signs of infection or spinal fluid leakages. 
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After 12 consecutive LPs, the feasibility of further use of LPs for that subject will be determined 
at the discretion of the investigator and the Takeda medical monitor and documented in a note to 
file.
8.1.3
Baseline Assessments (prior to first administration of SHP611; Day -1 to 0)
Baseline assessments must be completed prior to the first administration of SHP611 at Week 0. 
Refer to Section 1.3 for details on which assessments are to be completed.
8.1.4
Treatment Period
8.1.4.1
Treatment Period - Study Week 0
SHP611 will be administered weekly, and the first administration of SHP611 will be considered 
Week 0. Examination of both the port and catheter track will be performed before each IT 
injection, which includes aspiration of CSF via the port. 
Please refer to the Manual of Operations for details regarding investigational drug product 
administration. 
Week 0 and other treatment period assessments (Table 1, Table 2, and Table 3) and collection of 
samples must be performed prior to the administration of anesthesia and SHP611.
8.1.4.2
Treatment Period – Remaining Study Visits
Table 1, Table 2, and Table 3 detail the Treatment Period assessments to be performed at each 
visit. Most assessments and collection of sampling should be performed prior to the 
administration of anesthesia and SHP611 with the exception of X-rays or assessments designated 
as post-administration.
Study Week Visits 0, 5, 9, 13, 26, 40, 53, 79, and 106 during the primary treatment period of the 
study must be conducted at the main site (shaded columns in the Schedule of Activities). For the 
extension period of the study, 6-month visits, EOT, EOS, and Safety Follow-up must be 
conducted at the Main Site (shaded columns in the Schedule of Activities).
Study Week Visits 1-4, 6-8, 10-12, 14-25, 27-39, 41-52, 54-78, and 80-105 may be conducted at 
local sites (unshaded columns in the Schedule of Activities) if subjects’ parent(s) or legally 
authorized representative(s) provide a separate written informed consent/assent to participate in 
study procedures to be conducted at local sites prior to the conduct of these procedures. For the 
extension period, Weekly Visits may be conducted at local sites (unshaded columns in the 
Schedule of Activities) if subjects’ parent(s), or legally authorized representative(s) provide a 
separate written informed consent/assent to participate in study procedures to be conducted at 
local sites prior to the conduct of these procedures. At the discretion of the investigator and upon 
discussion of the investigator with the Medical Monitor, if it is determined that the subject is 
unable to perform an efficacy outcome assessment, such as GMFC-MLD, GMFM-88, 
ELFC-MLD, GIMF-C and GIMF-S, CIQ, ITQOL, WPAI, and EDACS, these assessments may 
be skipped for a visit.
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8.1.5
Final Visit End of Study (EOS)
Table 3 details the comprehensive assessments that will be conducted at the EOS Visit.
Subjects may continue in the extension period of the study, where they may continue to receive 
treatment with SHP611 for an extended duration of time.
If a subject discontinues from the study earlier than EOS, every effort should be made to 
complete assessments for the EOS and the safety follow-up visits.
8.1.6
Safety Follow-up
The safety follow-up for this protocol is 14 days after EOS.
At the end of this study there will be a safety follow-up visit to conduct a symptom-directed 
physical exam and query for serious adverse events (SAEs), adverse events (AEs), and 
concomitant treatments. All AEs and SAEs that are not resolved at the time of this contact will 
be followed to closure (see Appendix 3.2). This visit is to occur for all subjects, regardless if 
administration of study drug is discontinued for any reason or the IDDD remains in the subject. 
No additional safety follow-up of such subjects will be required. 
8.1.7
Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.2
Study Assessments 
8.2.1
Demographic and Other Baseline Characteristics
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product.
Demographic information will be recorded for each subject and will include the following 
information: gender, age, race, and ethnic origin. MLD-related history will be recorded and will 
include age at onset of first MLD symptoms, age at MLD diagnosis, genotype, and family 
history of MLD. A copy of the subject’s medical record showing documentation of a gait 
disorder attributable to MLD by 30 months of age must be included in the source documentation. 
Medical records for family members of the subject may be requested.
8.2.1.1
Medical and Medication History
Medical and medication history will be collected and recorded in the subject’s source documents. 
The medical history must include history of non-pharmacologic treatments and history of any 
medication hypersensitivities, as well as document any gait disorder attributable to MLD by 
30 months of age.
Medical and surgical history will include the following systems: head, neck, eyes, mouth, ears, 
nose, throat, chest, lungs, cardiovascular, abdomen, gastrointestinal, genito-urinary, skin, 
musculoskeletal, neurological, and psychiatric system.
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8.2.1.2
MLD Diagnosis
Sample collection and assays for leukocyte ASA enzyme activity, urine sulfatide, and genotype 
determination will be performed to confirm the diagnosis of MLD. Abnormal ASA enzyme 
activity and urine sulfatide concentration consistent with a diagnosis of MLD is required for 
study eligibility, but genotype results are not. If ASA enzyme activity and urine sulfatide results 
from a reliable lab are available at screening, these lab results may be used for the eligibility 
criteria; however, samples for leukocyte ASA enzyme activity and urine sulfatides must still be 
collected at screening.
8.2.1.3
Cross Reacting Immunologic Material (CRIM)
A blood sample will be obtained from each subject at Screening and the leukocytes from it will 
be tested for the presence of ASA CRIM. In subjects weighing ≥11.5 kg, 10 cc will be collected 
for CRIM evaluation; 3 cc will be collected for CRIM evaluation in subjects weighing <11.5 kg.
The peripheral blood mononuclear cells (PBMC) will be isolated and the tests will be performed 
at a Takeda designated test facility.
8.2.2
Efficacy
For all assessments to be conducted in this study, refer to the relevant manual for detailed 
instructions.
8.2.2.1
Gross Motor Function Classification in MLD
The GMFC-MLD instrument was developed specifically for MLD patients, based on experiences 
with the GMFCS instrument used for cerebral palsy (Palisano et al. 1997). The GMFC-MLD is 
applicable from the age of 18 months onwards and can be assessed retrospectively based on 
medical records. It is an established and reliable tool for the standardized assessment of gross 
motor function in MLD which can be used to classify the stages of disease progression. The 
GMFC-MLD covers clinically relevant gross motor stages occurring in patients with MLD and 
consists of 7 categories based primarily on locomotion (see Table 5), and in more advanced 
disease also includes sitting and other motions. 
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Table 5
Gross Motor Function Classification in MLD
Category
Gross Motor Function
Category 0
Walking without support with quality of performance normal for age
Category 1
Walking without support but with reduced quality of performance, ie 
instability when standing or walking
Category 2
Walking with support. Walking without support not possible (fewer than five 
steps)
Category 3
Sitting without support and locomotion such as crawling or rolling. Walking 
with or without support not possible
Category 4
(a) Sitting without support but no locomotion or (b) Sitting without support 
not possible, but locomotion such as crawling or rolling
Category 5
No locomotion nor sitting without support, but head control is possible
Category 6
Loss of any locomotion as well as loss of any head and trunk control
Source: (Kehrer et al. 2011a). Note: The term ‘category’ is used as ‘level’ in the source.
Initial assessment of gross motor function using the GMFC-MLD scale will be conducted by 
local, trained healthcare professionals and video-recorded. Videos of GMFC-MLD assessments 
will be evaluated by central video reviewers for primary scoring of gross motor function on the 
instrument.
8.2.2.2
Gross Motor Function Measure-88
The GMFM-88 is a clinician-evaluated assessment of motor function across five dimensions: 
1) lying and rolling 2) sitting 3) kneeling and crawling 4) standing and 5) walking, running, and 
jumping. GMFM-88 will be performed by a trained physiotherapist. Scoring is based on the 
percentage of accomplished tasks within each of the dimensions, and a total score is calculated 
by averaging each of the dimension scores. Each of the 88 items is rated by a trained evaluator 
on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The 
GMFM-88 was originally developed to assess gross motor function in patients with cerebral 
palsy (from 5 months through 16 years old) by evaluation of a broad range of tasks that could be 
accomplished independently by a child of 5 years of age without any motor disability
(Russell et al. 2013). GMFM-88 total scores range from 0% (no mobility) to a score of 100%, 
which can be obtained by an average child, 5 years of age or older with unimpaired motor 
abilities. Although the GMFM-88 is widely used for patients with cerebral palsy, the assessment 
has also been used across numerous other populations, including patients with traumatic brain 
injury (Linder-Lucht et al. 2007), Down syndrome (Russell et al. 1998), and spinal muscular 
atrophy (Iannaccone and Hynan 2003), among others (Russell et al. 2013).
Assessments of gross motor function using the GMFM-88 will be video-recorded.
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8.2.2.3
Global Impression of Motor Function Change and Severity
The GIMF-C and GIMF-S will be used to evaluate the minimal clinically important change in 
GMFM-88 response to IT administration of SHP611. Each questionnaire contains 6 items 
addressing the clinician’s global impression of change or severity in the 5 GMFM-88 dimensions 
and overall. The GIMF-C assessment will be compared to baseline. 
8.2.2.4
Alberta Infant Motor Scale (Group D only)
The AIMS will be used to assess motor function in subjects <18 months of age. This 
observational assessment scale was constructed to measure gross motor maturation in infants 
from birth through independent walking. Fifty-eight items are generated and organized into 
4 positions: prone (21 items), supine (9 items), sitting (12 items), and standing (16 items). Each 
item is scored as ‘observed’ or ‘not observed’ and all items combined describe 3 aspects of 
motor performance: weight-bearing, posture, and antigravity movements (Piper et al. 1992).
8.2.2.5
Note Documenting Current Motor Function
At baseline and each main site visit, the investigator or sub-investigator will document the 
subject’s current motor function, including a description of observations that support the 
GMFC-MLD category assigned at that visit, in a text note entered into the source documents.
8.2.2.6
Expressive Language Function Classification in MLD (ELFC-MLD)
The ELFC-MLD (Table 6) is a 5-category rating system that was developed by researchers to 
describe the regression of language abilities of patients with late infantile and juvenile MLD 
(Kehrer et al. 2014).
Table 6
Expressive Language Function Classification-MLD
Category
Description
E0
Communicates in complete sentences at a quality and performance normal for age 
E1
Communicates in complete sentences at a reduced quality of performance for age
E2
Cannot communicate in complete sentences, but able to use 2-word phrases 
E3
Cannot communicate 2-word phrases, but able to use single, meaningful 
words/ideas 
E4
Complete loss of expressive language 
Source: (Kehrer et al. 2014)
8.2.2.7
The Eating and Drinking Ability Classification System (EDACS)
The EDACS (Table 7) is a 5-category rating system that was developed by researchers to 
describe feeding and swallowing abilities in patients with cerebral palsy. It has been shown to be 
valid and highly reliable (Benfer et al. 2017; Goh et al. 2018; Sellers et al. 2014; 
Tschirren et al. 2018).
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Table 7
The Eating and Drinking Ability Classification System
Level
Description
Level of Assistance
I
Eats and drinks safely and efficiently
Independent
II
Eats and drinks safely but with some limitations to 
efficiency
Requires assistance
III
Eats and drinks with some limitations to safety; there 
may be limitations to efficiency
Totally dependent
IV
Eats and drinks with significant limitations to safety
Totally dependent
V
Unable to eat and drink safely – tube feeding may be 
considered to provide nutrition
Totally dependent
Source: (Sellers et al. 2014)
8.2.2.8
Anesthesia
Anesthesia may be required for certain procedures (at the discretion of the investigator). Any
anesthesia used will be recorded as Concomitant Medications (see Section 6.6).
Administration of anesthesia may be given prior to obtaining CSF by lumbar puncture, if the use 
of the IDDD is precluded.
Anesthesia may also be administered prior to performing the following:

Brain MRI and MRS

Lumbar puncture

Implantation of the IDDD

Injection of SHP611
The physical examination, GMFC-MLD, GMFM-88, AIMS, ELFC-MLD, auditory, and visual 
assessments must be performed prior to the administration of anesthesia, or after the patient has 
fully recovered from anesthesia.
8.2.2.9
Magnetic Resonance Imaging and Brain Magnetic Resonance 
Spectroscopy
Each subject will have an MRI and MRS of the brain (may be performed under anesthesia), 
using methods specified in the Imaging Protocol contained in the Imaging Manual. Review of 
the images will focus on MLD-related abnormalities with measurement of metabolite levels 
(N-acetylaspartate, choline, and creatine) in regions of interest, eg, the frontal and 
parieto-occipital white matter, corpus callosum, centrum semiovale, and occipital cortex. Other 
metabolites and regions of interest may be explored.
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8.2.3
Safety
8.2.3.1
Physical Examination
A physical examination will be performed by the investigator. A complete physical examination 
will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, 
neurological systems, and an evaluation of the port and catheter track. A symptom-directed 
physical examination will include at a minimum, neurological systems and other assessments at 
the discretion of the investigator. An auditory and vision exam will also be conducted. 
Abnormalities will be recorded in the subject’s source documents. 
Height or length (cm) measured supine on a standard measuring board and weight (kg) will be 
recorded and used to calculate growth velocity. The clinical site staff will be instructed to use 
calibrated scales for weight measurement. It is recommended that the same scale be used at the 
clinical site for all subjects at each specified time point during the study. Body weight and height 
measurements will be used to calculate the body mass index (BMI). Head circumference will be 
measured in a uniform manner for all subjects.
If results of the physical examination show clinically significant worsening from the previous 
visit, the change will be documented as an AE/serious AE (SAE) in the eCRF and will be 
followed as an AE consistent with the procedure outlined in Appendix 3. Clinical significance is 
defined as any variation in physical findings that has medical relevance resulting in an alteration 
in medical care. The investigator will continue to monitor the subject until the parameter returns 
to baseline or until the investigator determines that follow-up is no longer medically necessary.
Abnormalities identified at the Screening Visit will be documented in the subject’s source 
documents and on the medical history eCRF. Changes after the Screening Visit will be captured 
as AEs on the AE eCRF page, as deemed appropriate by the investigator.
8.2.3.2
Adverse Events
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. Refer to Appendix 3.1
for AE definitions, assessment, collection time frame, and reporting procedures. Refer to 
Appendix 3.2 for Collection of Adverse Events.
8.2.3.3
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) will be obtained at 
each visit and recorded on the eCRF. Blood pressure should be determined by cuff. Note that 
height, weight, and head circumference will be recorded as part of vital signs, but will be done 
less frequently than vital signs per the Schedule of Activities (Table 1, Table 2, and Table 3). 
The investigator will assess whether a change from baseline in vital signs may be deemed 
clinically significant and whether the change should be considered and recorded as an AE.
Normal ranges for vital signs are presented in Appendix 7.
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8.2.3.4
Clinical Laboratory Tests
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. The 
investigator will assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.
Blood, urine, and CSF samples will be collected as described in the Laboratory Manual in the 
section for clinical laboratory testing. A complete list of the clinical laboratory tests to be 
performed is provided in Appendix 2.
8.2.3.5
Immunoassay for Anti-SHP611 Antibodies
Samples will be collected for the determination of anti-SHP611 antibodies in serum and CSF. 
Anti-SHP611 antibody testing will follow a tiered approach per regulatory guidance and industry 
best practices.
8.2.3.6
Electrocardiogram
The eligibility of the subject will be based on the assessment of the electrocardiogram (ECG) by 
the investigator. If abnormal results are observed, the investigator, in consultation with the 
appointed medical monitor, will reconfirm the subject’s eligibility to continue. Normal ranges for 
key ECG parameters are presented in Appendix 7.
8.2.4
Intrathecal Drug Delivery Device Considerations
8.2.4.1
Intrathecal Drug Delivery Device Implantation, Replacement, or Revision
The IDDD will be surgically implanted at the clinical site. Procedures for implantation are 
detailed in the device’s IFU Manual. Standard hospital procedures for surgery will be followed; 
the patient may be under general anesthesia for this procedure. It is planned that device 
explantation will occur at the main site unless urgent device removal is medically required to be 
performed locally or patient travel to the main site is medically inadvisable.
An additional medical device, the catheter passer, is necessary for the implantation procedure for 
patients receiving the SOPH-A-PORT Mini S. The catheter passer is a sterile, single-use device 
that will be used in the subcutaneous placement of the catheter. The Phoenix Neuro Disposable 
Catheter Passer, manufactured by Sophysa, is CE-marked in the European Union and cleared 
under K853370 in the United States (US) and may be provided; however, use of other catheter 
passers compatible with the SOPH-A-PORT Mini S is allowed.
At a minimum, the date of the implantation and spinal placement will be documented on the 
eCRF. If the device becomes nonfunctional at any time during the study, it will be removed and 
may be replaced or revised as appropriate.
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8.2.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement
A post-operative X-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. X-rays may be 
performed to check placement of the device, as needed, throughout the study. An X-ray will be 
performed at the end of the study (to verify that the IDDD is in the correct position).
At a minimum, the date of the X-ray verifying correct IDDD placement and the date that the 
X-ray is read will be documented on the eCRF. If the device requires revision or replacement 
during the study, additional X-rays will be taken to document proper positioning of the device.
Fluoroscopy should be used during device implantation procedures.
8.2.4.3
SOPH-A-PORT Mini S Assessments in CSF and Serum
As part of the assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the 
levels of leachables from the device into the CSF and blood. The subject’s parent(s) or legally 
authorized representative(s) has/have the option to allow testing of residual CSF and serum 
samples to determine the levels of leachable materials related to the IDDD.
8.2.4.4
Cerebrospinal Fluid Sampling Procedure
Cerebrospinal fluid will be obtained from patients via an IDDD in aliquots appropriate for the 
specified analyses prior to each IT injection. If on a scheduled day of dosing, the use of the 
IDDD is precluded, the CSF samples may be obtained by LP, under anesthesia (if deemed 
necessary by the investigator). Instructions for CSF withdrawal are included in the Manual of 
Operations. If it is not possible to withdraw CSF through the IDDD, study drug should not be 
administered through the IDDD. Assessment of the IDDD should occur as described in the 
IDDD manual.
CSF samples collected will be analyzed for cell count, protein, glucose, SHP611 levels, 
anti-SHP611 antibodies, and biomarkers (sulfatide, lysosulfatide, and exploratory biomarkers 
(eg, neurofilament light chain, glial fibrillary acidic protein, Tau and Ubiquitin C-terminal 
hydrolase L1) according to the Schedule of Activities (Table 1, Table 2, and Table 3).
Additional biomarker testing and additional testing related to the SOPH-A-PORT Mini S may be 
performed with any residual volume of sample, which will determine the CSF levels of other 
analytes.
8.2.4.5
Intrathecal Drug Delivery Device Removal
If at the time of a scheduled dosing, due to a device-related issue it is not possible to aspirate 
CSF prior to dose administration, administer a full medication dosage using the standard 
administration steps detailed in the device’s IFU, or flush the system following dose 
administration, the IDDD will be declared a device malfunction. If the device malfunction is 
irreversible and cannot be corrected without a partial or full device revision or removal, the 
IDDD will be declared a device failure, starting from the date of the initial malfunction. The 
IDDD will then be surgically removed or revised and a new device and/or device components 
will be re-implanted at the earliest possible opportunity, preferably at the same time. 
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A waiting period of 3 to 5 days after device re-implantation or revision must be observed before 
the administration of SHP611 may resume.
Details of the device removal will be recorded in the subject’s eCRF. Refer to the relevant IFU 
for further details.
Subjects are to have the IDDD removed when they discontinue from or complete the study, 
unless the subject is continuing to receive treatment through another mechanism (eg, commercial 
availability of the product) or the investigator determines that the IDDD should not be removed 
from the subject based upon a safety assessment and the IDDD (full or partial) should remain in 
the subject. 
If at any time during the study, administration of the study drug is discontinued for any reason 
and the investigator determines that the IDDD should not be removed from the subject, then the 
subject will have a safety follow-up visit via telephone upon completion of their last treatment 
period visit. When the IDDD is explanted, an incision check should occur within 2 weeks 
(±7 days) after surgery.
8.2.4.6
Pharmacokinetics
Blood and CSF samples for determination of SHP611 concentration will be collected at the 
following nominal times.
Blood samples for PK will be obtained per the Schedule of Activities (Table 1, Table 2, and 
Table 3). 
The concentration of SHP611 in CSF will be assessed as indicated in the Schedule of Activities 
(Table 1, Table 2, and Table 3). The CSF samples will be drawn prior to IT injection and post 
injection through the IDDD. Should the IDDD become clogged, undergo mechanical 
complications, or otherwise not be accessible, the CSF sample may also be obtained by LP. 
The effect of anti-SHP611 antibodies on SHP611 concentration-time profiles and PK parameters 
will be evaluated, if applicable.

At Weeks 0 and 106, serum samples will be drawn for PK assessments within 1 hour 
prior to IT administration and then drawn at 0.5, 1, 2, 4, 8, 12, 24, and 48 hours following 
completion of IT administration. At other visits, samples will be collected predose to 
assess attainment of steady state.

At Weeks 0 and 106, CSF samples will be collected within 1 hour prior to IT 
administration and then at 6 and 24 hours (+30 minutes) after administration; however, if 
the subject’s IDDD is not functioning or the subject is receiving doses via LP, the 6 and 
24 hour samples do not need to be collected. At other visits, samples will be collected 
predose.
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8.2.4.7
Sulfatide/Lysosulfatide Biomarker Assessments
Samples of blood, urine, and CSF will be collected from subjects according to the Schedule of 
Activities (Table 1, Table 2, and Table 3) and will be analyzed for determination of 
concentrations of sulfatides and lysosulfatide in CSF, and sulfatides in serum and urine.
8.2.4.8
Additional Biomarker Assessments
Additional biomarker analyses may be performed at the Takeda research laboratory or at 
Takeda-designated laboratories. A biomarker is defined as a characteristic that is objectively 
measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or 
pharmacologic responses to a therapeutic intervention.
Samples of blood, urine, and CSF will be collected from subjects participating in this trial 
according to the Schedule of Activities (Table 1, Table 2, and Table 3) and stored for biomarker 
studies that may elucidate the pathogenesis of MLD and help to better characterize the response 
to the experimental treatment.
Testing of residual blood, urine, and CSF samples for additional biomarker research is optional. 
The subject and/or subject’s parent(s) or legal representative(s) has the option to allow this 
testing for additional research assessments.
The identification of biomarkers that reflect the disease process and/or treatment response 
represent a potentially important exploratory aspect to this study that may contribute to subject 
and/or dose selection for future trials. Given our incomplete understanding of the pathogenesis of 
MLD, the range of biomarkers that might be informative is extensive. The CSF, serum, and urine 
samples will be examined for accumulation of sulfatides (and lysosulfatide in CSF), which are 
known to reflect the primary biochemical lesion in MLD.
Additional testing of residual sample volumes may include biomarkers that reflect the known 
pathological processes in MLD – demyelination, neuroaxonal degeneration, and 
neuroinflammation – as well as markers of lysosomal dysregulation (lysosomal proteins, 
enzymes, and their substrates).
Urine and serum will be examined in parallel with CSF samples to:

Assess CSF/blood quotients for biomarkers of interest to provide insight into their CNS 
versus peripheral provenance

Identify potential peripheral urinary and/or serum biomarkers that might reflect CNS 
disease and/or treatment response
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8.2.4.9
Genetics
All subjects in this study will undergo genotyping of the ASA gene.
In addition, Takeda intends to apply genomic research across the SHP611-201 development 
program. The intent of this exploratory research is to aid in biomarker development, design and 
interpretation of clinical studies, exploration of guided treatment strategies, and to increase 
disease understanding.
To support these aims, subjects will have the option to provide additional blood samples. 
Donation of samples is optional, has no impact on participation in the main study, and may 
require a separate informed consent. To ensure subject confidentiality, samples will be stored 
and analyzed in a de-identified format. Samples will be stored in biorepositories for up to 
15 years.
The scope of any present and/or future research will be restricted to candidate 
gene/proteins/markers related to the disease and/or responses to SHP611-201 and background 
products and concomitant medications.
The intent of this research is not to return results to subjects, unless required to do so by law. 
Subjects can request return of individual results, but it will not be possible to interpret these. No 
record of participation in any pharmacogenomic research, or any results derived from it should 
be recorded in a subject’s personal medical records.
Any results of this exploratory research will be reported separately from the main clinical study 
report. Results may be used internally to help support the design of additional clinical studies, 
form part of scientific publication, or be made known to the regulatory authorities as part of a 
new drug application. The sponsor has no obligation to perform this additional exploratory 
research.
For additional information and details, see Appendix 4.
8.2.4.10
Health-related Quality of Life (QoL) and Other Assessments
Further information concerning health-related QoL assessments included in the study is provided 
in Appendix 5.
Caregiver Impact Questionnaire (CIQ)
Caregiver burden will be assessed by the Caregiver Impact Questionnaire (CIQ). The CIQ 
includes 30 items in total and covers the key areas of impact for caregivers of patients with late
infantile and juvenile MLD, including: 1) impact on relationships, family, social life, and leisure 
activities; 2) impact on personal time and daily activities; 3) psychological impacts; 4) impact on 
physical health; and 5) impact on finances and productivity. This measure is still being 
developed and scoring has not been finalized; therefore, the data will be collected and 
summarized descriptively, with the results providing an opportunity to contribute to the 
recommended scoring for studies.
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Infant Toddler Quality of Life Questionnaire – 97 items (ITQOL-97)
Health Related Quality of Life (HRQOL) will be assessed using the Infant Toddler Quality of 
Life Questionnaire – 97 items (ITQOL-97). The ITQOL-97 was developed for use in infants and 
toddlers at least 2 months of age up to 5 years. It measures infant/toddler focused concepts and 
parent-focused concepts. Infant/toddler concepts include overall health (1 item), amount of 
limitation in physical activities (10 items), satisfaction with development (10 items), amount, 
frequency of bodily discomfort and the extent to which pain/discomfort interferes with normal 
activities (3 items), frequency of certain moods and temperaments (18 items), perceptions of 
current, past and future behavior (12 items), overall behavior (1 item) and frequency of behavior 
problems (15 items), perception of current, past and future health (11 items), perceptions of 
changes in health over the past year (1 item). Parent-focused concepts include amount of worry 
experienced by parent (7 items), amount of time limitations experienced by parent (7 items) and 
rating time of family’s ability to get along with one another (1 item). For each concept, item 
responses are scored, summed, and transformed to a scale from 0 (worst health) to 100 (best 
health).
Healthcare Utilization Questionnaire (HCUQ)
Measures of health-services utilization will include the number of hospitalizations, days in 
hospital, and reasons for admission as well as use of selected MLD-related procedures including 
use of a feeding tube, intubation, and type of respiratory support.
Utilization should be ascertained since the last study visit. Study visit is defined as that occurring 
at the main study site.
Work Productivity and Activity Impairment Questionnaire (WPAI) – Specific Health 
Problem V2.0
The Work Productivity and Activity Impairment (WPAI) Questionnaire is a well-validated 
instrument to measure impairments in work and activities. It measures absenteeism, reduced 
performance at work, and reduced duration of work. It has been validated to quantify work 
impairments for numerous diseases such as asthma, psoriasis, irritable bowel syndrome, 
ankylosing spondylitis, and Crohn’s disease. In addition, it has been used to compare work 
impairments between treatment groups in clinical trials or between subjects with different 
disease severity levels (Zhang et al. 2010).
Developmental and MLD Symptom Assessments
Developmental status and signs and symptoms of MLD will be assessed as indicated in the 
Schedule of Activities (Table 1, Table 2, and Table 3).
All assessments will be administered by qualified study personnel.
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Volume of Blood to Be Drawn from Each Subject 
It is expected that the cumulative maximum total volume of blood drawn per subject over the 
duration of this study will be approximately 162.5 mL. 
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the maximum total volume drawn over the course of the 
study per subject should not exceed approximately 162.5 mL. When more than 1 blood 
assessment is to be done at the time point/period, if they require the same type of tube, the 
assessments may be combined.
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9.
STATISTICAL CONSIDERATIONS
9.1
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include descriptions of sensitivity analyses for main efficacy outcomes, and a 
description of how missing, unused and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using Version 9.0 (or newer) SAS(SAS Institute, 
Cary, NC 27513) on a suitably qualified environment. 
9.2
Planned Analysis, Adaptive Design, and Data Monitoring Committee
The primary analysis will be performed after all subjects complete the primary treatment period
of the study; the database will be locked with the results presented in a clinical study report
(NB: the sponsor will remain blinded to postbaseline efficacy-related data until database 
lock). Following completion of the extension period, the database will be locked again and the 
results of the entire study (primary treatment and extension periods) will be described in the final 
clinical study report.
An external independent Data Monitoring Committee (DMC) will be involved in the conduct of 
this study. The purpose of the DMC is to review the data pertaining to safety, tolerability, and 
benefit/harm of the study therapy for the duration of the study. The DMC will oversee both 
administration of IT SHP611 and device safety. The DMC will be notified of IDDD failures and 
related complications on a periodic basis. Further details regarding the DMC can be found in the 
DMC Charter, which will be available prior to the administration of investigational product.
9.3
Sample Size and Power Considerations
Per original Protocol, sample size was calculated based on the response in Group A, (ie, the 
maintenance of gross motor function at Week 106, evaluated as no greater than 2 categories
decline from baseline in GMFC-MLD), and at least 12 paired completers is required to detect a 
treatment difference for a desired power of 90%, using McNemar’s test at a 2-sided significance 
level of 0.05, with the assumption that the response rates in Group A of current study and the 
matched external control group are 65% and 10% respectively. Furthermore, to adjust for 
potential unmatched and early discontinuation of subjects, a total of 16 subjects were originally 
planned to be enrolled (19 enrolled) into Group A of the current study. As the GLIA-MLD 
external control group for Group A cohort was expected to be large, efficient matching was 
plausible and incorporated in the assumptions.
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Type I error and power were assessed for the time to event primary endpoint for sample sizes 
similar to that planned in the original protocol, through simulations using an interval censoring 
approach. Comparable assumptions were made on the response rates for the time to event 
primary endpoint in simulations. The response rates (ie, proportion of subjects not reaching 
GMFC-MLD category 5 or higher, or death) at Week 106 for Group A in the current study and 
the matched external control group are 65% and 10%, respectively. The encounter structure from 
a subset of external control group for Group A subjects in the natural history study was 
considered. A simulated event time was randomly matched to a GLIA-MLD encounter schedule 
and was considered censored if it could not be observed within Week 106 under the matched 
schedule. The event time was assumed to follow a Weibull distribution, with a range of 
compatible shape parameters that allow approximation of the target response rates of 65% and 
10% in the two groups, and a 25% censoring proportion for the GLIA-MLD control group. The 
type I error was preserved well. The power is assessed to be approximately between 71% to 
82%. Matching efficiency is not assumed in the simulations.
9.4
Statistical Analysis Set(s)
Analysis Populations

The Screened Set will consist of all subjects who have signed informed consent

The Safety Analysis Set will consist of all subjects from Study SHP611-201 
(Groups A-F) who receive at least 1 dose of SHP611, or subjects who have undergone the 
IDDD implantation procedure

The Full Analysis Set (FAS) will consist of all subjects from the SHP611-201 Safety 
Analysis Set who receive at least 1 dose of SHP611 and have at least a screening
GMFC-MLD assessment

The modified Full Analysis Set (mFAS) will consist of all subjects from Group A in the 
FAS and the matched external control subjects for Group A from GLIA-MLD natural 
history study obtained after matching as described in the SAP

The Pharmacokinetic (PK) Analyses Set will consist of all subjects from the SHP611-201 
Safety Analysis Set who receive at least 1 dose of SHP611 and have at least 1 postdose 
measurable [ie, not below quantifiable limits (BQL)] concentration of SHP611 in serum 
or CSF

The Immunogenicity Analyses Set will consist of all subjects from the SHP611-201 
Safety Analysis Set who receive at least 1 dose of SHP611 and have at least 
1 anti-SHP611 antibody assessment with reportable result in serum or CSF
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Extension period
The same analysis populations, as in the primary treatment period, will be used for the extension 
period.
Device-related analyses will be conducted in the subset of subjects in the Safety Analysis Set 
who have the device implant procedure performed.
9.5
Efficacy Analyses
9.5.1
Matched External Control
The efficacy of SHP611 in SHP611-201 Group A will be compared to matched external control 
group data from untreated MLD subjects in the Global Leukodystrophy Initiative natural history 
study (GLIA-MLD). 
For Group A subjects in this study, the time to event (TTE) starting point is set at the Baseline
visit where patients receive the first dose of SHP611. The external control group for Group A
subjects will be selected from the GLIA-MLD database using appropriate filtering criteria. For 
each external control subject, a collection of “qualifying encounters” when the subject is in the 
appropriate age range for Group A and GMFC-MLD category of 1 or 2, will be identified and an 
appropriate TTE starting point will be defined. Details of this definition will be provided in the 
SAP.
For this matched external control study, an appropriate matching process will be applied to 
balance the baseline observed characteristics between the treatment and matched external control 
groups. Matching diagnostics will be conducted. Further details will be provided in the SAP.
An unblinded statistical group outside of the Sponsor’s SHP611-201 statistical analysis team will 
be formed to work on the available external control group data, in order to identify potential 
prognostic baseline variables and reduce potential matching biases, and the final matching 
variables recommended by this exercise will be specified in the SAP.
9.5.2
Multiplicity Adjustments
In order to protect the study-wide type I error at the 1-sided 0.025 level for testing the primary 
and secondary hypotheses, the Fixed-Sequence Test procedure will be applied. The hypotheses 
will be tested for the primary endpoint at the 1-sided 0.025 significance level first, and then all 
other efficacy endpoints will be tested in a prespecified order. A subsequent test for the 
secondary endpoints can only be reported as significant if all prior 1-sided tests are also found 
significant at the 0.025 level of significance. Details will be provided in the SAP.
9.5.3
Missing Data Imputations
For the primary and relevant secondary efficacy assessments, if a subject prematurely 
discontinues from the study, a “failure” response status will be assigned to the subject.
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9.5.4
Primary Efficacy Endpoint
9.5.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is time to loss of locomotion, measured by progression to 
GMFC-MLD category 5 or higher, or death, whichever occurs first, up to Week 106, evaluated 
on subjects in Group A, and analyzed using the mFAS.
For the analysis of the primary efficacy endpoint, the time to event data for Group A and 
matched external control group up to Week 106 will be compared using the stratified log-rank 
test, where the matching identification created from the matching process will be used as strata. 
Interval censoring methods will be used, with event assumed to have first happened between the 
last visit/encounter prior to the event observation, and the visit/encounter when the event is first 
observed. The null hypothesis of the stratified log-rank test will be evaluated at the 1-sided 
0.025 level of significance. Kaplan-Meier (KM) survival curves suitable for interval censoring 
data will be presented.
9.5.4.2
Sensitivity Analysis
As study drug dosing was affected by the COVID-19 pandemic, a sensitivity analysis will be 
conducted for Group A subjects who missed no more than two consecutive SHP611 doses due to 
COVID-19.
The details of the matching method and other sensitivity analyses will be specified in the SAP.
9.5.5
Analyses of Secondary and Exploratory Efficacy Endpoints
All inferential efficacy analyses will be based on the mFAS. All statistical tests will be 1-sided 
hypothesis tests performed at the 0.025 level of significance. All confidence intervals will be 
2-sided 95% confidence intervals, unless stated otherwise. Sensitivity analyses of the primary 
and secondary endpoints will also be based on the mFAS. 
Descriptive analysis of efficacy endpoints for all groups (A-F) will be conducted over the FAS. 
For categorical variables, descriptive statistics will include n, frequency, and 
proportions/percentages.
Only exploratory statistical and graphical evaluations involving Groups B, C, D, E, and F may be 
conducted. 
In general, Baseline for the treatment group is defined as the last assessment prior to the first 
administration of the investigational product, unless other clarification is made. For SHP611-201 
subjects, the GMFC-MLD assessment at the Screening visit will be treated as the last clinically 
valid assessment prior to the administration of the investigational product. However, the TTE 
starting point in Group A subjects of SHP611-201 is set at the Baseline visit where subjects 
receive the first dose of SHP611.
For continuous variables, descriptive statistics will include the number of subjects with 
nonmissing values, mean, median, standard deviation (SD), minimum, and maximum values, 
unless specified otherwise. These will be tabulated by subject group and overall. 
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Means and medians will be presented to 1 more decimal place than the recorded data. The SDs 
will be presented to 2 more decimal places than the recorded data.
Where applicable, analysis of covariance, utilizing the corresponding baseline levels as 
covariate, will be utilized to assess the treatment effect for the parametric endpoints. Two-sided 
95% Confidence Intervals will be constructed for the difference between the two comparator 
arms.
For the binary variables, descriptive statistics will include the counts and proportions of each 
value, including a missing category if applicable, unless specified otherwise. These will be 
tabulated by subject group and overall.
Where applicable, confidence intervals of two-sided 95% coverage will be constructed for the 
proportions for each comparator arm using the Clopper-Pearson method, and for the difference 
between the two comparator arms using the Wilson score method.
Categorical variables will be summarized in a contingency table by the number and percentage 
of subjects in each category, including a missing category if applicable. For categorical variables, 
descriptive statistics will include counts and proportions of each category, unless specified 
otherwise. These will be tabulated by subject group and overall.
All time-to-event variables will be presented with Kaplan-Meier survival curves, along with its 
95% confidence bands. Where applicable, interval or right censoring method will be used for the 
time to event variables (details specific to endpoints will be provided in the SAP).
A full description of analyses for the secondary and exploratory efficacy endpoints will be 
included in the SAP.
9.6
Safety Analyses
Safety analysis
Treatment-emergent adverse events (TEAEs) are defined as AEs that occurred at or after the first 
dose of investigational product or device implant surgery (whichever occurs first) and through 
the last follow-up date plus 14 days (inclusive). Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities. The number of events and percentage of TEAEs will be 
calculated overall, by system organ class (SOC), by preferred term, and by subject groups (A-F).
TEAEs will be further summarized by severity, relationship to investigational product, disease 
and outcomes, the IDDD, the IDDD surgical procedure, anesthesia, and IT administration 
process. Adverse events related to investigational product, AEs leading to withdrawal, serious 
adverse events (SAEs; all SAEs reported by the investigator, those SAEs considered as Related 
and those considered as Not Related by Takeda shall be collected), and deaths will be similarly 
summarized and listed.
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Clinical laboratory tests, vital signs, and ECG findings will be summarized by subject groups 
(A-F) and visit. Potentially clinically important findings will also be summarized and listed. 
Descriptive summaries will also be provided for 12-lead ECG, CSF laboratory parameters 
(chemistries, cell counts), anti-SHP611 antibodies in CSF and serum. An integrated analysis of 
PK and PD will be used to evaluate the impact of antibodies.
SOPH-A-PORT Mini S assessments
SOPH-A-PORT Mini S assessments will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. These 
data will be collected on the subject’s electronic case report form (eCRF) from the time of 
implantation and continue throughout the study as long as the SOPH-A-PORT Mini S remains 
implanted.
9.7
Other Analyses
9.7.1
Pharmacokinetic Analyses
Pharmacokinetic analyses
All PK analyses will be performed using the PK Analysis Set.
Blood and CSF samples will be collected for determination of SHP611 levels after IT 
administration. SHP611 concentrations in serum and CSF will be determined using the validated 
Enzyme-Linked Immunosorbent Assays (ELISA) method which was used for the previous 
SHP611 clinical studies (HGT-MLD-070/HGT-MLD-071). SHP611 activity in CSF and serum 
will also be determined by validated Activity assays. The SHP611 Activity results will be used 
as surrogate marker for anti-SHP611 neutralizing antibodies and its impact on PK profile.
CSF parameters:

Predose concentrations (Ctrough) of SHP611 at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106

Postdose concentrations of SHP611 at 6 and 24 hours (Weeks 0 and 106)
Serum parameters:

PK parameters after the first dose (Week 0) and after repeated doses (Week 106) of 
SHP611 determined by noncompartmental analysis will include but not limited to AUC, 
Cmax and CL/F

Predose concentrations (Ctrough) of SHP611 at Weeks 0, 13, 26, 40, 53, 79, and 106
Details of the PK analysis including handling of PK data, parameters estimated, and presentation 
of PK data will be provided in the Clinical Pharmacology Analysis Plan (CPAP).
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There will be no inferential statistical analysis of the PK data. Summary statistics (number of 
observations [N], mean, SD, coefficient of variation [CV%], median, maximum, minimum, 
geometric mean and geometric CV%) will be determined for all serum PK parameters and 
presented by bioanalytical method and visit for each group and for overall population. Serum and 
CSF concentrations at each nominal sampling time will also be summarized by bioanalytical 
method and visit for each group and for overall population using descriptive statistics. More 
details will be provided in the CPAP.
At the investigator’s discretion a blood sample for PK analysis may be collected at the time of 
occurrence of an SAE or AE of special interest.
The serum and CSF concentration data from this study may be pooled with the data from 
Studies HGT-MLD-070 and HGT-MLD-071 in a population PK analysis. A population PK/PD 
and exposure-response analyses may be conducted using data from this study and reported 
separately.
9.7.2
Extension Period
Summary statistics for continuous variables will include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
using the number and percentage of subjects in each category, including a missing category if 
applicable.
Statistical inferences for the primary and selected secondary endpoints may be performed during 
the extension period.
The safety analyses will be performed using all data through Week 106 and the extension period 
up to EOS. Baseline will be defined as the same as that for the study (this baseline is clinically 
relevant for assessing the long-term safety and efficacy outcomes of extended treatment with IT 
SHP611).
The same analysis populations, as in the primary treatment period, will be used for the extension 
period.
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10.
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
Appendix 1.1
Regulatory and Ethical Considerations
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements.
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki.
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
Appendix 1.2
Sponsor’s Responsibilities
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO\investigator as necessary.
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Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements.
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance.
The sponsor will provide the ECs with a copy of the same summary.
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
Appendix 1.3
Investigator’s Responsibilities
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
Protocol Adherence and Investigator Agreement
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
Documentation and Retention of Records
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
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Incorrect entries must be crossed with a single line as to not obscure the original entry. 
Corrections must be made adjacent to the item to be altered, initialed, and dated by an authorized 
investigator or designee as stated in the site delegation log. Overwriting of this information or 
use of liquid correcting fluid is not allowed.
The eCRFs should be approved by the investigator per study specifications and the sponsor’s 
data delivery requirements.
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s source documents.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. 
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The following information is collected: any significant payments from the sponsor or 
subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in investigational product; 
any significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
Compliance to all Local, State, and National Controlled-substance Biohazard and 
Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
Appendix 1.4
Data Management Considerations
Data Collection
Study SHP611-201 will be monitored according to GCP.
The investigators’ authorized site personnel must enter the information required by the study 
eCRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the eCRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the eCRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting.
A Monitoring Plan Addendum has been developed to provide guidance and study specific 
instructions to Project Management team and CRAs for the monitoring of the investigational 
sites in the study. This plan provides specific instructions in order to ensure oversight and 
consistency in study monitoring and site management activities in the context of unavoidable 
circumstances, such as the COVID-19 public health emergency.
Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan or 
similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
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Appendix 1.5
Ethical Considerations
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time. During the COVID-19 public health emergency, 
informed consent from a potential or current trial participant may be obtained via electronic 
informed consent (eIC) capabilities, or an electronic face-to-face consent interview when these 
individuals are unable to travel to the site.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form (and assent form 
where applicable) that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
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Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; or 
for multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures.
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the HIPAA of 1996. A site that is not a covered entity as defined by 
HIPAA must provide documentation of this fact to the CRO. 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP611; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. Subjects are assigned a unique 
identifying number; however, their initials and date of birth may also be collected, if permitted 
under local laws governing privacy.
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
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Study Results/Publication Policy
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multi-site study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions:
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review. Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s). All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study.
Takeda is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Takeda-supported research. Therefore, after 01 Jan 2018, Takeda
will require the submission of all Takeda-supported research manuscripts to journals that offer 
public availability via Open Access (including publisher platforms/repositories and 
self-archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications.
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Appendix 2
Clinical Laboratory Tests
The following clinical laboratory and biomarkers tests will be performed. All blood samples will 
be collected via venipuncture. Subjects will be in a seated or supine position during blood 
collection.
List of Clinical Laboratory and Biomarker Tests
Hematology
Hematocrit (Hct)
Hemoglobin (Hgb)
Platelet count
Red blood cell count 
White blood cell count with differential
Urinalysis
Bilirubin
Glucose
Ketones
Nitrite 
pH
Protein
Specific gravity
Cerebrospinal fluid
Routine analysis
Anti-SHP611 antibodies
SHP611 levels
Serum SHP611 level and anti-SHP611 antibodies
Serum chemistry
Albumin 
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Amylase
Blood urea nitrogen (BUN)
Calcium 
Creatinine
Creatine kinase
Gamma-glutamyl transferase (GGT)
Inorganic phosphate
Iron
Lactate dehydrogenase (LDH)
Magnesium
Potassium 
Sodium 
Total bilirubin (BILI)
Biomarkers (urine, serum, and CSF)
Sulfatides
Lysosulfatides (CSF only)
Other biomarkers (optional)
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Appendix 3
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Appendix 3.1
Adverse Event Definitions
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995).
Treatment-emergent Adverse Event
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product.
Serious Adverse Event
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not and at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of hospitalization. 
Note: Hospitalizations that are the result of elective or previously scheduled 
investigations procedures or surgery for pre-existing conditions and have not worsened 
after initiation of treatment should not be classified as SAEs. 

For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a hospitalization for an 
elective or previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s).

Results in persistent or significant disability/incapacity

Results in a congenital abnormality/birth defect
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
Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition. Examples of such medical events include:
o
Bronchospasm associated with anaphylaxis requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization; or the development of drug dependency or drug abuse.
o
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis 
E virus (HEV), or parvovirus B19 (B19V)
Unexpected Adverse Event
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB information as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the product, but are 
not specifically mentioned as occurring with the particular product under investigation. 
The expectedness of AEs will be determined by the sponsor using the IB information as the RSI. 
This determination will include considerations such as the number of AEs previously observed, 
but not on the basis of what might be anticipated form the pharmacological properties of a 
product.
Suspected Unexpected Serious Adverse Reaction 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active-comparators) that is both serious and 
unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
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Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
study protocol or product labeling; or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE.
Preexisting conditions prior to randomization or initiation of study medication are described in 
the medical history, and those that manifest with the same severity, frequency, or duration after 
drug exposure, are not be recorded as AEs. However, when there is an increase in the severity, 
duration or frequency of a preexisting condition, the event must be described on the AE eCRF.
Clinical Laboratory and Other Safety Assessment
A change in the value of a clinical laboratory parameter, vital sign measure, or ECG assessment 
can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values.
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
Collection of ECG parameters is suggested to be performed in triplicates and conducted by a 
central laboratory for all study subjects.
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Appendix 3.2
Collection of Adverse Events 
All AEs/SAEs are collected from the time the informed consent document is signed until the 
defined follow-up period stated in Section 8.1.6. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. 
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained.
Appendix 3.3
Assessment of Adverse Events
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of investigational 
product, must be recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, and the dyspepsia becomes severe and more frequent after first dose a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source.
The medical assessment of severity is determined by using the following definitions:

Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.

Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject.

Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. 
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Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting a 
possible cause-and-effect relationship between the investigational product and the occurrence of 
the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source.
Table A1
The following additional guidance may be helpful: Adverse Event 
Relationship Categorization
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling enough and/or follows a 
known or suspected response pattern to that product, and the event 
cannot be explained by the subject’s medical condition, other 
therapies, or accident.
Not related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
Outcome Categorization
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
If applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE eCRF.
Appendix 3.4
Safety Reporting
Reference Safety Information
The RSI for this study is the investigator’s brochure which the sponsor has provided under 
separate cover to all investigators.
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Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Takeda Global 
Drug Safety Department and the CRO/Takeda medical monitor immediately and within no more 
than 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see Appendix 
3.9) unless they result in an SAE.
The investigator must complete, sign, and date the Shire “Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol”, verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested), and fax or e-mail the form to the 
Takeda Global Drug Safety Department. A copy of the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any 
applicable follow-up reports) must also be sent to the CRO/Takeda medical monitor using the 
details specified in the emergency contact information section of the protocol.
Medical Device Safety Reporting
All serious injuries and UADEs must be reported to the sponsor as an SAE in the same process 
as described above. Serious injury (SI) is defined as:

Led to death

Led to a serious deterioration in health of a patient, user, or others that

Results in a life-threatening illness or injury

Results in a permanent impairment/ damage of a body function or body structure

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in medical or surgical intervention to prevent permanent impairment/damage to 
body function/ structure.

Led to fetal distress, fetal death or a congenital abnormality/birth defect
Appendix 3.5
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 8.1.6 and 
must be reported to the Takeda Global Drug Safety Department and the CRO/Takeda medical 
monitor immediately and within no more than 24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Takeda Global 
Drug Safety Department immediately and within no more than 24 hours of the first awareness of 
the event.
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Appendix 3.6
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms reported by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
Appendix 3.7
Fatal Outcome
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death.
Appendix 3.8
Pregnancy 
This study will not enroll subjects of child-bearing potential.
Appendix 3.9
Abuse, Misuse, Overdose and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Appendix 3.1. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category:

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol)
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
Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver.
Appendix 3.10
Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following:

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.
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Appendix 3.11
Device-associated Definitions
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: The device is removed (explanted) in its entirety, and a completely new 
device is implanted.
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
Device Adjustment
Surgery of the device which does not result in partial or complete device revision or removal (eg, 
surgical exploration only or placement of additional sutures, tissue glue, and/or fascial repair).
Appendix 3.12
Expected Adverse Device Effects
A list of the adverse effects expected with the SOPH-A-PORT Mini S is reproduced below from 
the device’s IFU.
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
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Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or 
subcutaneous CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, 
or hygroma, resulting in tissue damage or a loss of or change in therapy, or other 
potentially serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip
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Appendix 3.13
Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting
The sponsor and CRO are responsible for notifying the relevant regulatory authorities, central 
IRBs, and central ECs of related, unexpected SAEs.
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the SHP611-201 program.
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings that occur at his or her site as required by IRB/EC procedures (see Appendix 1.5).
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Appendix 4
Genetics 
All subjects will undergo genotyping of the ASA gene.
In addition, Takeda intends to apply genetic research across the SHP611-201 development 
program to explore how genomic variations may affect the clinical parameters associated with 
and response to SHP611-201 (and any background products, comparators, and concomitant 
medications), and potentially the basis of the indications under study in the protocol, in this case 
late infantile MLD. Collection of appropriate samples from populations with well described 
clinical characteristics may lead to improvements in the design and interpretation of clinical 
studies, genetically guided treatment strategies, and a better understanding of disease etiology, 
which may lead to new therapeutic approaches.
Candidate genes which may be studied include those potentially related to the mechanism of 
action of SHP611-201 as well as those potentially responsible for absorption, disposition, 
metabolism, and excretion of SHP611-201. Future research may suggest other genes, gene 
categories, proteins, etc., as candidates for influencing not only response to SHP611-201, but 
also susceptibility to disease for which SHP611-201 may be evaluated. Thus, this additional 
genomic research may involve the future study of additional unnamed genes or gene categories, 
but only as they relate to disease susceptibility and drug action. Samples may only be collected 
from subjects who provide separate informed consent, as detailed in the laboratory manual.
Samples will be labeled with the study protocol number, the subject’s study identification 
number, and information related to the sample. No personal identifiers will be recorded on the 
sample labels.
Subjects terminating early from the study due to AE, tolerability, or drug-related issues should, 
where possible, be approached for their remaining protocol-defined samples at the earliest 
possible time. Unscheduled samples should be labeled with free text capturing study protocol 
number, subject’s study identification number, and information related to the sample (RNA or 
protein, sampling date, and time). Samples will be shipped to and stored at biorepositories as 
detailed in the laboratory manual. DNA, RNA, and protein will be extracted from the samples 
only when, and if, any separate exploratory research will be undertaken.
As an added level of security, the sample will be recoded with a new, unique number at the 
biorepository laboratory. This unique number is the only code used in any subsequent analysis 
and will be used to link a sample to a subject and to ensure that the subject’s identity remains 
confidential.
A link file linking the first and second codes will be kept in a secure place at the sponsor, with 
restricted access. This will be in a secure environment outside of the clinical study database and 
separate to any analysis results. This file will be used to identify the relevant samples for 
analysis, facilitate correlation of any results with clinical data, allow regulatory audit, and trace 
samples for destruction in the case of withdrawal of consent. No record of participation in this 
pharmacogenomics portion of the protocol, or any results derived from it, should be recorded in 
the subjects’ personal medical records. 
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A record of participation in the pharmacogenomics portion of the protocol will, however, be 
captured in the study-specific source documentation records or eCRF.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. The link will also be destroyed at the same time as 
any remaining sample(s) are destroyed. Any results already generated from the samples will not 
be removed from any analyses that have already been performed.
Participation in this portion of the study is optional and does not impact the subject’s eligibility 
for participation in the main clinical study. Subjects may continue to participate in the primary 
study if they refuse to provide a blood sample or if they withdraw their samples.
Results of the genetic analyses may contribute to the global understanding of late infantile MLD 
and its treatment and may be used internally to help support the design of additional clinical 
studies, form part of scientific publication, or be made known to the regulatory authorities as part 
of a new drug application. Any results generated will be for exploratory research purposes only 
and will not be made available unless required by law (ie, to regulatory authorities). 
Additionally, as any potential analysis does not form part of predefined analysis within the 
clinical study protocol, any results will be reported separately from the main clinical study 
report. Subjects may request the results of any analysis on their samples, although the 
significance of genetic variation in individuals is often not known. Genetic counseling will be 
made available to subjects when the results of genetic analyses performed in this study are 
shared with them.
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Appendix 5
Scales and Assessments
The following scales/assessments will be utilized in this study. Refer to the current version of the 
relevant user manual for detailed instructions.
Full Title of Scale/Assessment
Gross Motor Function Classification in MLD (GMFC-MLD)
Gross Motor Function Measure 88 (GMFM-88)
Global impression of motor function-change (GIMF-C)
Global impression of motor function-severity (GIMF-S)
Alberta Infant Motor Scale (AIMS)
Elective Language Function Classification in MLD (ELFC-MLD)
Caregiver Impact Questionnaire (CIQ)
Infant Toddler Quality of Life Questionnaire (ITQOL) (HRQOL)
Healthcare Utilization Questionnaire (HCUQ)
Work Productivity and Activity Impairment (WPAI) Questionnaire – Specific Health 
Problem, V2.0
Eating and Drinking Ability Classification System (EDACS)
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Appendix 6
Bioanalysis
All assessments referenced in the protocol, including sample collection instructions for the 
investigator, are in the study operations manual and the laboratory manual.
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Appendix 8
Premature Closure of the Study
If the sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the sponsor and the 
investigator(s). In addition, a decision on the part of the sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled 
in the study

Failure of the investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the investigator to protocol requirements
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Appendix 9
Abbreviations
Abbreviation
Definition
Ab
antibody
AE 
adverse event
AIMS
Alberta Infant Motor Scale
ALP
alkaline phosphatase
ALT
alanine aminotransferase (synonymous with SGPT)
AST
aspartate aminotransferase (synonymous with SGOT)
AUC
area under the curve
AUC0-
area under the curve from time 0 to infinity
AUC0-t
area under the curve from time 0 to the time of last concentration measured
BBB
blood brain barrier
-hCG
beta-human chorionic gonadotropin
BILI
total bilirubin
BMI
body mass index
BMT
bone marrow transplantation
CAS
completer analysis set
CFR
Code of Federal Regulations
CI
confidence interval
CL
Clearance
CL/F
clearance after IT administration
Cmax
maximum concentration
CNS
central nervous system 
COVID-19
Coronavirus Disease 2019
CPAP
Clinical Pharmacology Analysis Plan
CRA
clinical research associate
CRIM
cross-reacting immunologic material
CRO
contract research organization
CSF
cerebrospinal fluid
CV
coefficient of variation
DMC
data monitoring committee
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Abbreviation
Definition
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form 
eIC
electronic informed consent
ELISA
Enzyme-linked Immunosorbent Assay
EOT
end of treatment
EOS
end of study 
EU
European Union
EUDRA
European Union Drug Regulatory Authorities
EUDRACT
European Union clinical trials database
FDA
Food and Drug Administration
EDACS
Eating and Drinking Ability Classification System
GCP
Good Clinical Practice
GGT
gamma-glutamyl-transpeptidase
GIMF-C
Global impression of motor function-change
GIMF-S
Global impression of motor function-severity
GMFC-MLD
Gross Motor Function Classification in Metachromatic Leukodystrophy
GMFM-88
Gross Motor Function Measure-88
GMP
Good Manufacturing Practice
Hct
Hematocrit
HCUQ
Healthcare Utilization Questionnaire
Hgb
Hemoglobin
HSCT
hematopoietic stem cell transplantation
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IDDD
intrathecal drug delivery device
IFU
Instructions for Use
INN/USAN
International Nonproprietary Name/United States adopted name
IRB
institutional review board
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Abbreviation
Definition
IT
intrathecal(ly)
ITQOL-97
Infant Toddler Quality of Life Questionnaire – 97 items
Local Site
approved investigational site at which a subject may complete study 
procedures for dosing visits
LP
lumbar puncture
Main Site
approved investigational site at which a subject is enrolled into the study 
and must complete certain study procedures for dosing visits
MedDRA
Medical Dictionary for Regulatory Activities
MLD
metachromatic leukodystrophy
MNC
mononuclear leukocytes
MPS I
mucopolysaccharidosis I
MRI
magnetic resonance imaging
MRS
magnetic resonance spectroscopy
NAA/Cr
N-acetylaspartate/creatine
PBMC
peripheral blood mononuclear cells
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PNS
peripheral nervous system
QoL
quality of life
rhASA
recombinant human arylsulfatase A
RSI
reference safety information
SAE
serious adverse event 
SAP
statistical analysis plan
SAS
statistical analysis system
SD
standard deviation
Shire
Shire Human Genetic Therapies, Inc.
SI
serious injury
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
t1/2
Half-life
TBD
to be determined
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Abbreviation
Definition
TEAE
treatment-emergent adverse event
Tmax
time to maximum concentration
TTE
time to event
UADE
unanticipated adverse device effect
UK
United Kingdom
US
United States
WPAI
Work Productivity and Activity Impairment Questionnaire
For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

For non-commercial use only

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11.
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