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
• 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.

Outcome(s)

Primary Outcome

1. 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
Time Frame: 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

1. Response in Group A: Maintenance of Gross Motor Function at Week 106 in Participants who do not Experience any Event within Week 106
Time Frame: 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.

2. Change From Baseline in Gross Motor Function Evaluated by Using the GMFC-MLD at Week 106 and End of Study (EOS)
Time Frame: Baseline, Week 106 and EOS (Week 211)
Change from baseline in gross motor function evaluated by using the GMFC-MLD will be reported.

3. Number of Participants With Unreversed Decline From Baseline in Metachromatic Leukodystrophy (GMFC-MLD) of More than 2 Categories
Time Frame: Baseline, Week 106 and EOS (Week 211)
Number of participants with unreversed Decline from baseline in metachromatic leukodystrophy (GMFC-MLD) of more than 2 categories evaluated on participants in Group A will be reported.

4. Time to Unreversed Decline From Baseline in Gross Motor Function Classification in GMFC-MLD of More Than 2 Categories
Time Frame: Baseline up to EOS (Week 211)
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.

5. Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
Change from baseline in CSF sulfatides levels will be assessed.

6. Response in Group A: Maintenance of Gross Motor function in Participants at Week 106 Using Gross Motor Function Measure 88 (GMFM-88) Total Score >= 40
Time Frame: Week 106
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.

7. 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 up to EOS (Week 211)
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.

8. Change From Baseline in Gross Motor Function Evaluated by Using GMFM-88 Total Score at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
Change from baseline in gross motor function evaluated by using the GMFM-88 total score will be reported.

9. Number of Participants With GMFM-88 Total Score Decrease of <= 20 Points From Baseline and a Total Score > 40 at Week 106 and EOS
Time Frame: Week 106, EOS (Week 211)
Number of participants with GMFM-88 total score decrease of <= 20 points from baseline and a total score that is >= 40 will be reported.

10. Change From Baseline in Expressive Language Evaluated by Using the Expressive Language Function Classification in Metachromatic Leukodystrophy (ELFC-MLD) at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
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.

11. Ctrough of SHP611 in CSF
Time Frame: Predose at Weeks 0, 5, 9, 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 CSF parameters at Weeks 0, 5, 9, 13, 26, 40, 53, 79, and 106 will be reported.

12. Concentrations of SHP611 in CSF Following Single and Repeat IT Dosing of SHP611
Time Frame: Post dose at Week 0 and 106
The concentrations of SHP611 in CSF following single and repeat IT dosing of SHP611 will be evaluated.

13. Maximum Observed Plasma Concentration (Cmax) of SHP611 in Serum
Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
The Cmax of SHP611 in serum will be assessed.

14. Area Under the Plasma Concentration Versus Time Curve Extrapolated to Infinity (AUC0-inf) of SHP611 in Serum
Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
The AUC0-inf of SHP611 in serum will be assessed.

15. Area Under the Curve From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of SHP611 in Serum
Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
The AUC0-t of SHP611 in serum will be assessed.

16. Total Body Clearance (CL/F) of SHP611 in Serum
Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24 and 48 hours post dose on Week 0 and Week 106
The CL/F of SHP611 in serum will be assessed.

17. Ctrough of SHP611 in Serum at Weeks 0, 13, 26, 40, 53, 79, and 106
Time Frame: Predose 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.

18. Number of Participants With Treatment-emergent Adverse Event (TEAEs)
Time Frame: From start of study drug administration up to follow-up (Week 213)
A 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.

19. Change from Baseline in Clinical Laboratory Result at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
Clinical laboratory analysis includes serum chemistry, hematology, and urinalysis.

20. Change from Baseline in Physical Examination at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
Physical examination includes documentation of signs and symptoms of MLD (tone, reflexes, and vision).

21. Change from Baseline in Electrocardiogram (ECG) at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
12-lead ECG will be recorded and measured.

22. CSF Laboratory Parameters at Week 106 and EOS
Time Frame: Baseline, Week 106 and EOS (Week 211)
CSF laboratory parameters includes chemistries and cell counts.

23. Number of Participants With Anti-SHP611 Antibodies
Time Frame: Baseline, Week 106 and EOS (Week 211)
Number of participants with presence of Anti-SHP611 antibodies in CSF and serum will be reported.

24. Number of Participants With Adverse Events Related to SOPH-A-PORT Mini S Device
Time Frame: Up to EOS (Week 211)
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.

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.
Filtering criteria for the selection of the matched external control group will be provided in the Statistical Analysis Plan (SAP).

Related Information

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