Back to resultsA Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy (EMBOLDEN)
Primary Purpose
Metachromatic Leukodystrophy (MLD)
Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
SHP611
Sponsored by
About this trial
This is an interventional treatment trial for Metachromatic Leukodystrophy (MLD)
Eligibility Criteria
Inclusion Criteria:
The participant must have a documented diagnosis of MLD (Groups A-F):
- Low ASA activity in leukocytes (compared to laboratory normal range).
- 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)
- The participant has had, or may have, an allergic reaction to the materials of construction.
- The participant has shown an intolerance to an implanted device.
- The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port.
- The participant's drug therapy requires substances known to be incompatible with the materials of construction.
- The participant has a known or suspected local or general infection.
- The participant is at risk of abnormal bleeding due to a medical condition or therapy.
- The participant has one or more spinal abnormalities that could complicate safe implantation or fixation.
- The participant has a functioning Cerebro spinal fluid(CSF) shunt device.
Filtering criteria for the selection of the matched external control group will be provided in the Statistical Analysis Plan (SAP)
Sites / Locations
- Los Angeles Biomedical Research Institute at Harbor-UCLA
- Childrens Hospital Colorado
- Rare Disease Research, LLC
- Ann & Robert H. Lurie Children's Hospital of Chicago
- University of Iowa Stead Family Children's Hospital
- Mayo Clinic - PPDS
- New York University Langone Medical Center
- Cincinnati Children's Hospital Medical Center
- Children's Hospital of Philadelphia
- Children's Hospital of Pittsburgh
- University of Utah
- Hospital Universitario Austral - PIN
- UZ Antwerpen
- Hospital de Clínicas de Porto Alegre
- Stollery Children's Hospital University of Alberta
- British Columbia Children's Hospital
- Hospital for Sick Children
- Montreal Children's Hospital
- Hôpital Bicêtre - Paris Sud
- CHU Lenval
- Universitätsklinikum Hamburg Eppendorf
- Universitätsklinikum Tübingen
- Attikon University General Hospital
- Tel Aviv Sourasky Medical Center
- IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
- Kanazawa University Hospital
- VU Medisch Centrum
- Hospital Universitario Cruces
- Hospital Vall d'Hebrón
- Birmingham Children's Hospital NHS Foundation Trust
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
SHP611
Arm Description
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.
Outcomes
Primary Outcome Measures
Response in Group A: Time to Loss of Locomotion Measured by Progression to Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106
The 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 participants in Group A. The GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is 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).
Secondary Outcome Measures
Response in Group A: Maintenance of Gross Motor Function at Week 106 in Participants who do not Experience any Event within Week 106
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, evaluated as participants 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 GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is 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).
Change From Baseline in Gross Motor Function Evaluated by Using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 and End of Study (EOS)
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFC-MLD will be reported.
Number of Participants With Unreversed Decline From Baseline in Metachromatic Leukodystrophy (GMFC-LMD) of More than 2 Categories
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Number of participants with unreversed Decline from baseline in metachromatic leukodystrophy (GMFC-LMD) of more than 2 categories evaluated on participants in Group A will be reported.
Time to Unreversed Decline From Baseline in Gross Motor Function Classification in GMFC-MLD of More Than 2 Categories
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories is 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 in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106 and End of Study (EOS)
Change from baseline in CSF sulfatides levels will be assessed.
Response in Group A: Maintenance of Gross Motor function in Participants at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score Greater than or Equal to (>=) 40
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, defined as a GMFM-88 total score >= 40. The GMFM-88 is a clinician-evaluated assessment of motor function across 5 dimensions: 1) lying and rolling 2) sitting 3) kneeling and crawling 4) standing and 5) walking, running, and jumping. 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 on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. GMFM-88 total score range is between 100 percent and 0 percent, with 0 percent corresponding to no mobility.
Time to Unreversed Decline From Baseline in Gross Motor Function Measure (GMFM)-88 Total Score of Greater Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score of decrease of >20 points or unreversed decline to a score <40 points, whichever occurs first will be reported.
Change From Baseline in Gross Motor Function Evaluated by Using Gross Motor Function Measure (GMFM)-88 Total Score at Week 106 and End of Study (EOS)
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFM-88 total score will be reported.
Number of Participants With Gross Motor Function Measure (GMFM)-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score > 40 at Week 106 and End of Study (EOS)
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Number of participants with GMFM-88 total score decrease of <= 20 points from baseline and a total score that is >= 40 will be reported.
Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) at Week 106 and End of Study (EOS)
The ELFC-MLD is a 5-category rating system to describe the regression of language abilities of participant with late infantile and juvenile MLD. The scoring range is from E0 (Communicates in complete sentences at a quality and performance normal for age) to E4 (Complete loss of expressive language). Change from baseline in expressive language evaluated by using the ELFC-MLD will be reported.
Ctrough of SHP611 in CSF
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 CSF parameters at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106 will be reported.
Concentrations of SHP611 in CSF Following Single and Repeat IT Dosing of SHP611
The concentrations of SHP611 in CSF following single and repeat IT dosing of SHP611 will be evaluated.
Maximum Observed Plasma Concentration (Cmax) of SHP611 in Serum
The Cmax of SHP611 in serum will be assessed.
Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of SHP611 in Serum
The AUC0-inf of SHP611 in serum will be assessed.
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of SHP611 in Serum
The AUC0-t of SHP611 in serum will be assessed.
Total Body Clearance (CL/F) of SHP611 in Serum
The CL/F of SHP611 in serum will be assessed.
Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106 will be reported.
Number of Participants With Treatment-emergent Adverse Event (TEAEs)
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. Number of participants with TEAEs will be reported.
Change from Baseline in Clinical Laboratory Result at Week 106 and End of Study (EOS)
Clinical laboratory analysis includes serum chemistry, hematology, and urinalysis.
Change from Baseline in Physical Examination at Week 106 and End of Study (EOS)
Physical examination includes documentation of signs and symptoms of Metachromatic Leukodystrophy (MLD) (tone, reflexes, and vision).
Change from Baseline in Electrocardiogram (ECG) at Week 106 and End of Study (EOS)
2-lead ECG will be recorded and measured.
Change from Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106 and End of Study (EOS)
CSF laboratory parameters includes chemistries and cell counts.
Number of Participants With Anti-SHP611 Antibodies
Number of participants with presence of Anti-SHP611 antibodies in CSF and serum will be reported.
Number of Participants With Adverse Events Related to SOPH-A-PORT Mini S Device
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.
Full Information
NCT ID
NCT03771898
First Posted
December 10, 2018
Last Updated
June 6, 2023
Sponsor
Shire
Collaborators
Takeda Development Center Americas, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT03771898
Brief Title
A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
Acronym
EMBOLDEN
Official Title
A Global, Multicenter, Single-arm, Matched External Control Study of Intrathecal SHP611 in Subjects With Late Infantile Metachromatic Leukodystrophy
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 30, 2019 (Actual)
Primary Completion Date
March 8, 2023 (Actual)
Study Completion Date
March 6, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shire
Collaborators
Takeda Development Center Americas, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metachromatic Leukodystrophy (MLD)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SHP611
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SHP611
Other Intervention Name(s)
HGT-1110, TAK-611, recombinant human arylsulfatase A [rhASA]
Intervention Description
Participants will receive 150 mg of SHP611 IT via IDDD or LP once weekly for 106 weeks.
Primary Outcome Measure Information:
Title
Response in Group A: Time to Loss of Locomotion Measured by Progression to Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106
Description
The 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 participants in Group A. The GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is 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).
Time Frame
Week 106
Secondary Outcome Measure Information:
Title
Response in Group A: Maintenance of Gross Motor Function at Week 106 in Participants who do not Experience any Event within Week 106
Description
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, evaluated as participants 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 GMFC-MLD is an instrument developed specifically for MLD participants. It is applicable from the age of 18 months onward and can be assessed retrospectively based on medical records as well as prospectively with directed examinations. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 categories of walking, sitting, locomotion, trunk and head control. The scoring range is 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).
Time Frame
Week 106
Title
Change From Baseline in Gross Motor Function Evaluated by Using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 and End of Study (EOS)
Description
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFC-MLD will be reported.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Number of Participants With Unreversed Decline From Baseline in Metachromatic Leukodystrophy (GMFC-LMD) of More than 2 Categories
Description
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Number of participants with unreversed Decline from baseline in metachromatic leukodystrophy (GMFC-LMD) of more than 2 categories evaluated on participants in Group A will be reported.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Time to Unreversed Decline From Baseline in Gross Motor Function Classification in GMFC-MLD of More Than 2 Categories
Description
The GMFC-MLD is an instrument developed specifically for MLD participants as described in above outcome measure. Time to unreversed decline from baseline in GMFC-MLD of more than 2 categories is 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.
Time Frame
Baseline up to EOS (Week 211)
Title
Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106 and End of Study (EOS)
Description
Change from baseline in CSF sulfatides levels will be assessed.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Response in Group A: Maintenance of Gross Motor function in Participants at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score Greater than or Equal to (>=) 40
Description
The response in Group A gross motor function is defined as maintenance of gross motor function at Week 106, defined as a GMFM-88 total score >= 40. The GMFM-88 is a clinician-evaluated assessment of motor function across 5 dimensions: 1) lying and rolling 2) sitting 3) kneeling and crawling 4) standing and 5) walking, running, and jumping. 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 on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. GMFM-88 total score range is between 100 percent and 0 percent, with 0 percent corresponding to no mobility.
Time Frame
Week 106
Title
Time to Unreversed Decline From Baseline in Gross Motor Function Measure (GMFM)-88 Total Score of Greater Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First
Description
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Time to unreversed decline from baseline at Week 106 and EOS in GMFM-88 total score of decrease of >20 points or unreversed decline to a score <40 points, whichever occurs first will be reported.
Time Frame
Baseline up to EOS (Week 211)
Title
Change From Baseline in Gross Motor Function Evaluated by Using Gross Motor Function Measure (GMFM)-88 Total Score at Week 106 and End of Study (EOS)
Description
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Change from baseline in gross motor function evaluated by using the GMFM-88 total score will be reported.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Number of Participants With Gross Motor Function Measure (GMFM)-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score > 40 at Week 106 and End of Study (EOS)
Description
The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Number of participants with GMFM-88 total score decrease of <= 20 points from baseline and a total score that is >= 40 will be reported.
Time Frame
Week 106, EOS (Week 211)
Title
Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) at Week 106 and End of Study (EOS)
Description
The ELFC-MLD is a 5-category rating system to describe the regression of language abilities of participant with late infantile and juvenile MLD. The scoring range is from E0 (Communicates in complete sentences at a quality and performance normal for age) to E4 (Complete loss of expressive language). Change from baseline in expressive language evaluated by using the ELFC-MLD will be reported.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Ctrough of SHP611 in CSF
Description
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 CSF parameters at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106 will be reported.
Time Frame
Predose at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106
Title
Concentrations of SHP611 in CSF Following Single and Repeat IT Dosing of SHP611
Description
The concentrations of SHP611 in CSF following single and repeat IT dosing of SHP611 will be evaluated.
Time Frame
Post dose at Week 0 and 106
Title
Maximum Observed Plasma Concentration (Cmax) of SHP611 in Serum
Description
The Cmax of SHP611 in serum will be assessed.
Time Frame
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
Title
Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of SHP611 in Serum
Description
The AUC0-inf of SHP611 in serum will be assessed.
Time Frame
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
Title
Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of SHP611 in Serum
Description
The AUC0-t of SHP611 in serum will be assessed.
Time Frame
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
Title
Total Body Clearance (CL/F) of SHP611 in Serum
Description
The CL/F of SHP611 in serum will be assessed.
Time Frame
Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
Title
Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106
Description
Ctrough is pre-dose trough concentration, defined as the drug concentration observed at the last planned timepoint prior to dosing, Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106 will be reported.
Time Frame
Predose at Weeks 0, 13, 26, 40, 53, 79, and 106
Title
Number of Participants With Treatment-emergent Adverse Event (TEAEs)
Description
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. Number of participants with TEAEs will be reported.
Time Frame
From start of study drug administration up to follow-up (Week 213)
Title
Change from Baseline in Clinical Laboratory Result at Week 106 and End of Study (EOS)
Description
Clinical laboratory analysis includes serum chemistry, hematology, and urinalysis.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Change from Baseline in Physical Examination at Week 106 and End of Study (EOS)
Description
Physical examination includes documentation of signs and symptoms of Metachromatic Leukodystrophy (MLD) (tone, reflexes, and vision).
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Change from Baseline in Electrocardiogram (ECG) at Week 106 and End of Study (EOS)
Description
2-lead ECG will be recorded and measured.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Change from Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106 and End of Study (EOS)
Description
CSF laboratory parameters includes chemistries and cell counts.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Number of Participants With Anti-SHP611 Antibodies
Description
Number of participants with presence of Anti-SHP611 antibodies in CSF and serum will be reported.
Time Frame
Baseline, Week 106 and EOS (Week 211)
Title
Number of Participants With Adverse Events Related to SOPH-A-PORT Mini S Device
Description
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.
Time Frame
Up to EOS (Week 211)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
72 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
The participant must have a documented diagnosis of MLD (Groups A-F):
Low ASA activity in leukocytes (compared to laboratory normal range).
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)
The participant has had, or may have, an allergic reaction to the materials of construction.
The participant has shown an intolerance to an implanted device.
The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port.
The participant's drug therapy requires substances known to be incompatible with the materials of construction.
The participant has a known or suspected local or general infection.
The participant is at risk of abnormal bleeding due to a medical condition or therapy.
The participant has one or more spinal abnormalities that could complicate safe implantation or fixation.
The participant has a functioning Cerebro spinal fluid(CSF) shunt device.
Filtering criteria for the selection of the matched external control group will be provided in the Statistical Analysis Plan (SAP)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Shire
Official's Role
Study Director
Facility Information:
Facility Name
Los Angeles Biomedical Research Institute at Harbor-UCLA
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
Childrens Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Rare Disease Research, LLC
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30303
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Iowa Stead Family Children's Hospital
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Mayo Clinic - PPDS
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
New York University Langone Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84108
Country
United States
Facility Name
Hospital Universitario Austral - PIN
City
Ciudad Autónoma Buenos Aires
State/Province
Buenos Aires
ZIP/Postal Code
B1629AHJ
Country
Argentina
Facility Name
UZ Antwerpen
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Hospital de Clínicas de Porto Alegre
City
Porto Alegre
ZIP/Postal Code
90035-903
Country
Brazil
Facility Name
Stollery Children's Hospital University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2R7
Country
Canada
Facility Name
British Columbia Children's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3V4
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Montreal Children's Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3H 1P3
Country
Canada
Facility Name
Hôpital Bicêtre - Paris Sud
City
Le Kremlin-bicetre
ZIP/Postal Code
94275
Country
France
Facility Name
CHU Lenval
City
Nice
ZIP/Postal Code
06200
Country
France
Facility Name
Universitätsklinikum Hamburg Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Universitätsklinikum Tübingen
City
Tubingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Attikon University General Hospital
City
Chaidari
State/Province
Attiki
ZIP/Postal Code
124 62
Country
Greece
Facility Name
Tel Aviv Sourasky Medical Center
City
Tel Aviv
ZIP/Postal Code
64239
Country
Israel
Facility Name
IRCCS Ospedale Pediatrico Bambino Gesù - INCIPIT - PIN
City
Roma
ZIP/Postal Code
165
Country
Italy
Facility Name
Kanazawa University Hospital
City
Kanazawa
ZIP/Postal Code
920-8641
Country
Japan
Facility Name
VU Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands
Facility Name
Hospital Universitario Cruces
City
Barakaldo
State/Province
Vizcaya
ZIP/Postal Code
48903
Country
Spain
Facility Name
Hospital Vall d'Hebrón
City
Barcelona
ZIP/Postal Code
8035
Country
Spain
Facility Name
Birmingham Children's Hospital NHS Foundation Trust
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
De-identified individual participant data from this particular study will not be shared as there is a reasonable likelihood that individual patients could be re-identified (due to the limited number of study participants).
Links:
URL
https://clinicaltrials.takeda.com/study-detail/5f6b5fd64db2bf003ab46e0b
Description
To obtain more information on the study, click here/on this link
Learn more about this trial
A Study of Intrathecal SHP611 in Children With Metachromatic Leukodystrophy
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