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

JRCT ID: jRCT2041200086

Registered date:25/12/2020

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Metachromatic Leukodystrophy
• Date of first enrollment: 30/04/2019
• Target sample size: 36
• Countries of recruitment: United States,Japan,Belgium,Japan,Brazil,Japan,Canada,Japan,France,Japan,Germany,Japan,Israel,Japan,Netherlands,Japan,Spain,Japan,United Kingdom,Japan,Argentina,Japan,Greece,Japan,Italy,Japan
• Study type: Interventional
• Intervention(s): 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.

Outcome(s)

Primary Outcome

1.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
Time Frame: Baseline up to Week 106
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.

Secondary Outcome

1.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
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

2.Number of Participants With Change From Baseline in Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

3.Group A: Number of Participants With Decline From Baseline in GMFC-MLD of More than 2 Categories
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

4.Group A: Time to Decline From Baseline in GMFC-MLD of More Than 2 Categories
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

5.Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

6.Percent Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

7.Group A: Number of Participants With Maintenance of Gross Motor function at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

8.Time to Unreversed Decline From Baseline in GMFM-88 Total Score of > 20 Points or Unreversed Decline to < 40 Points Whichever Occurs First
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

9.Change From Baseline in GMFM-88 Total Score at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

10.Group A: Number of Participants With GMFM-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score >= 40 at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

11.Number of Participants With Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) at Week 106
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

12.Number of Participants With Treatment-emergent Adverse Event (TEAEs)
Time Frame: From start of study drug administration up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

13.Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values at Week 106
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

14.Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings at Week 106
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

15.Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values at Week 106
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

16.Number of Participants With Clinically Significant Change From Baseline in Cerebrospinal Fluid (CSF) Laboratory Parameters at Week 106
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

17.Number of Participants With Anti-Drug Antibody (ADA) Response to SHP611
Time Frame: Baseline, Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

18.Number of Participants With IDDD Implantations
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

19.Number of Participants With Any IDDD Related Malfunctions
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

20.IDDD Longevity as Assessed by Time to IDDD Failure
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

21.Number of Participants With TEAE Related to IDDD and Surgical Procedure
Time Frame: Baseline up to Week 106
Data collection is ongoing and detailed reporting will be available after the study completion date.

Key inclusion & exclusion criteria

• Age minimum: >= 6month old
• Age maximum: < 72month old
• Gender: Both

Include criteria

1. The participant must have a documented diagnosis of Metachromatic Leukodystrophy (MLD) (Groups A-F):
1) Low arylsulfatase A (ASA) activity in leukocytes (compared to laboratory normal range).
2) Elevated sulfatides in urine.
2. 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.
3. 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.
4. 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.
5. The participant and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
6. 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.

Exclude 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 (e.g., tantrums in response to loss of motor skills) are not exclusionary.
4. The participant 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. 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.
7. 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.
8. The participant has had prior exposure to SHP611.
9. The participants must weigh > 11 pound (lbs) (5 kilograms [kg]).
10. 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 Cerebrospinal 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.

Related Information

• Primary Sponsor: Enya Kazuaki
• Secondary ID(s): NCT03771898,2018-003291-12