A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy (EMBOLDEN)

A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in Subjects With Late Infantile Metachromatic Leukodystrophy

The main aim of the study is to determine if SHP611 given by injection into the spinal fluid that surrounds the brain and spinal cord (intrathecal; IT) prolongs the time for children with Metachromatic Leukodystrophy (MLD) to retain the ability to move from place to place. Other aims of the study are to determine the effects of intrathecal administration of SHP611 on movement and speech functions and to learn how well SHP611 injected in the spinal fluid that surrounds the brain and spinal cord is tolerated.

Study participants will receive SHP611 for about 2 years with the possibility of an extended treatment period.

Study Overview

• Status: Active, not recruiting
• Conditions: Metachromatic Leukodystrophy (MLD)
• Intervention / Treatment: Drug: SHP611

Detailed Description

A Study of Intrathecal SHP611 in Participants With Late Infantile Metachromatic Leukodystrophy

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Ciudad Autónoma Buenos Aires, Buenos Aires, Argentina, B1629AHJ
      • Hospital Universitario Austral - PIN
• Belgium
  • Edegem, Belgium, 2650
    • UZ Antwerpen
• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Hospital De Clinicas De Porto Alegre
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R7
      • Stollery Children's Hospital University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital
• France
  • Le Kremlin-Bicêtre, France, 94275
    • Hôpital Bicêtre - Paris Sud
  • Nice, France, 06200
    • CHU Lenval
• Germany
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg Eppendorf
  • Tübingen, Germany, 72076
    • Universitätsklinikum Tübingen
• Greece
  • Attica
    • Chaïdári, Attica, Greece, 124 62
      • Attikon University General Hospital
• Israel
  • Tel Aviv, Israel, 64239
    • Tel Aviv Sourasky Medical Center
• Italy
  • Roma, Italy, 165
    • IRCCS Ospedale Pediatrico Bambino Gesu - INCIPIT - PIN
• Japan
  • Kanazawa, Japan, 920-8641
    • Kanazawa University Hospital
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU Medisch Centrum
• Spain
  • Barcelona, Spain, 8035
    • Hospital Vall d'Hebron
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital Universitario Cruces
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital NHS Foundation Trust
• United States
  • California
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute at Harbor-UCLA
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Childrens Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Rare Disease Research, LLC
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Stead Family Children's Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - PPDS
  • New York
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• The participant must have a documented diagnosis of MLD (Groups A-F):

  1. Low ASA activity in leukocytes (compared to laboratory normal range).
  2. Elevated sulfatides in urine.
• The participant 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 greater than or equal to (> =) 6 to less than (<) 18 months of age (Group D) or be early symptomatic and > =12 to < 18 months of age (Group E). Participants in Group E must have neurological symptoms either documented by either a primary care physician or a specialist physician.
• The participant'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.
• The participant'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 arylsulfatase (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 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.
• The participant and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
• Participant'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 participant.

Exclusion Criteria:

• 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.
• 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.
• Primary presentation of MLD was behavioral or cognitive symptoms (per investigator's clinical judgment); behavioral symptoms that are secondary to motor deficits (example [eg], tantrums in response to loss of motor skills) are not exclusionary.
• The participant has any known or suspected hypersensitivity to agents used for anesthesia or has history of difficult airway or potential for airway compromise.
• Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study.
• Participants 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.
• The participant 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.
• The participant has had prior exposure to SHP611.
• The participants must weigh > 11 pound (lbs) (5 kilograms [kg]).

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

  1. The participant has had, or may have, an allergic reaction to the materials of construction.
  2. The participant has shown an intolerance to an implanted device.
  3. The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port.
  4. The participant's drug therapy requires substances known to be incompatible with the materials of construction.
  5. The participant has a known or suspected local or general infection.
  6. The participant is at risk of abnormal bleeding due to a medical condition or therapy.
  7. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation.
  8. The participant has a functioning Cerebro spinal fluid(CSF) shunt device .

Matched External Control Participants for Group A from Global Leukodystrophy Initiative of Metachromatic Leukodystrophy (GLIA-MLD) The matched external control group must have data for at least baseline gross motor function evaluation. Selection of the external control participants from GLIA-MLD will follow a set of criteria as similar as possible to the inclusion criteria for Group A in the SHP611-201 study protocol.

A filtering process will be applied to select the external control participants from the GLIA-MLD database, by meeting all of the following 3 filtering criteria:

1. Filtering criterion 1: requiring documented diagnosis of MLD, based on

   • low arylsulfatase A (ASA) activity in leukocytes AND elevated sulfatides in urine. OR
   • biallelic variants in arylsulfatase A gene (ARSA) AND (either low ASA activity in leukocytes OR elevated sulfatides in urine).
2. Filtering criterion 2: requiring documented gait disorder. Participants will be considered qualifying if they present with a gait disorder before 2.5 years (30 months) of age and have a medical record reporting a gait abnormality including, but not limited to, the following terms: ataxia, spasticity, and hyper/hypotonia.
3. Filtering criterion 3: participants will be considered qualifying if they have at least 1 clinical encounter occurring between the age of 18 to 48 months with a GMFC-MLD category either 1 or 2.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SHP611; Participants will receive 150 milligrams (mg) of SHP611 intrathecally (IT) via intrathecal drug delivery device (IDDD) or lumbar puncture (LP) once weekly for 106 weeks in six groups (Group A, B, C, D, E, and F) based on participant's age and motor dysfunction.	Drug: SHP611; Participants will receive 150 mg of SHP611 IT via IDDD or LP once weekly for 106 weeks.; Other Names: recombinant human arylsulfatase A [rhASA]; HGT-1110, TAK-611

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Probability of Free of Loss of Locomotion in the Last Time Interval Up to 2 Years (Week 106) Based on GMFC-MLD for SHP611 Group A and GLIA-MLD Matched External Control	Loss of locomotion was estimated using interval censoring survival analysis. Survival probability free of loss of locomotion based on GMFC-MLD was estimated up to Week 106 (or two years), with associated 2-sided 95 percent (%) confidence interval (CI). GMFC-MLD scale consists of 7 categories, scores ranging from 0 (walking without support with quality of performance normal for age) to 6 (loss of any locomotion as well as loss of any head and trunk control). Higher scores mean a worse outcome. The data was reported in terms of Mean as survival function was quantified using a weighted average of percentage of participants not reaching the event of interest, with weights derived from the relative size of treated and control units in the strata used for the stratified log-rank test in the primary analysis.	Baseline up to Week 106

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Group A: Number of Participants Who Maintained Their Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106 Compared With Matched External Control Group Data	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Change From Baseline in Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Group A: Number of Participants With Decline From Baseline in GMFC-LMD of More Than 2 Categories	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Group A: Time to Decline From Baseline in GMFC-MLD of More Than 2 Categories	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Percent Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Group A: Number of Participants With Maintenance of Gross Motor Function at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Time to Unreversed Decline From Baseline in GMFM-88 Total Score of Greater Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Change From Baseline in GMFM-88 Total Score at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Group A: Number of Participants With GMFM-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score >=40 Points at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Number of Participants With Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) Scale Categories at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline, Week 106
Number of Participants With Treatment-emergent Adverse Event (TEAEs)	Data collection is ongoing and detailed reporting will be available after the study completion date.	From start of study drug administration up to Week 106
Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Clinically Significant Change From Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Anti-Drug Antibody (ADA) Response to SHP611	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With IDDD Implantations	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With Any IDDD Related Malfunctions	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
IDDD Longevity as Assessed by Time to IDDD Failure	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106
Number of Participants With TEAE Related to IDDD and Surgical Procedure	Data collection is ongoing and detailed reporting will be available after the study completion date.	Baseline up to Week 106

Collaborators and Investigators

• Sponsor: Shire
• Collaborators: Takeda Development Center Americas, Inc.
• Investigators: Study Director: Study Director, Shire

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2019
• Primary Completion (Actual): March 8, 2023
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: December 10, 2018
• First Submitted That Met QC Criteria: December 10, 2018
• First Posted (Actual): December 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Demyelinating Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Sulfatidosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Leukodystrophy, Metachromatic
• Other Study ID Numbers: SHP611-201; 2018-003291-12 (EudraCT Number); jRCT2041200086 (Registry Identifier: jRCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No