A Single-arm Study of Intrathecal SHP611 in Subjects with Metachromatic Leukodystrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Shire Human Genetic Therapies Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

9 Sep 2019 → 9 May 2026

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2024-514402-31-00

EudraCT number

2018-003291-12

ClinicalTrials.gov

NCT03771898

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Safety, Efficacy

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 external control group data in children with late infantile MLD.

Secondary objectives 4

1. 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
2. To evaluate the effects of IT administration of SHP611 on the decline in gross motor function, as measured by an unreversed decline in GMFCMLD 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
3. To evaluate the effects of IT administration of SHP611 on cerebrospinal fluid (CSF) sulfatides (pharmacodynamic [PD] biomarker)
4. 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

Conditions and MedDRA coding

Late Metachromatic Leukodystrophy (MLD)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration, Pharmaceuticals And Medical Devices Agency, Federal Institute For Drugs And Medical Devices

Plan to share 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.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 01. 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. 02. 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. 03. 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. 04. 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: early symptomatic, ≥12 to <18 months of age with a GMFCMLD 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
5. 05. The subject and his/her parent/representative(s) must have the ability to comply with the clinical protocol.
6. 06. 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 10

1. 01. 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. 02. 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. 03. 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. 04. 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. 05. Any other medical condition or serious comorbid illness that in the opinion of the investigator would preclude participation in the study
6. 06. 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. 07. The subject is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days or 5 halflives (whichever is longer) prior to study enrollment or at any time during the study
8. 08. The subject has had prior exposure to SHP611
9. 09. The subject must weight > 11lbs (5kg)
10. 10. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use a. The subject has had, or may have, an allergic reaction to the materials of construction b. The subject has shown an intolerance to an implanted device c. The subject's body size is too small to support the size of the SOPH-APORT Mini S Access Port d. The subject's drug therapy requires substances known to be incompatible with the materials of construction e. The subject has a known or suspected local or general infection f. The subject is at risk of abnormal bleeding due to a medical condition or therapy g. The subject has one or more spinal abnormalities that could complicate safe implantation or fixation h. The subject has a functioning CSF shunt device

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 01. 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 endpoints 8

1. 01. 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
2. 02. Decline in gross motor function using GMFC MLD: - Change from baseline at Week 106 and EOS in gross motor function, using the 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
3. 02. 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
4. 03. Change from baseline at Week 106 and EOS in CSF sulfatides levels
5. 04. Response in Group A, defined as maintenance of gross motor function at Week 106, defined as a GMFM 88 total score ≥40
6. 05. 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
7. 05. 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 - 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
8. 06. Change from baseline at Week 106 and EOS in expressive language using the ELFC-MLD

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Shire Human Genetic Therapies Inc.

Sponsor organisation

Shire Human Genetic Therapies Inc.

Address

300 Shire Way

City

Lexington

Postcode

02421-2101

Country

United States

Scientific contact point

Organisation

Shire Human Genetic Therapies Inc.

Contact name

CJ Malanga

Public contact point

Organisation

Shire Human Genetic Therapies Inc.

Contact name

Takeda

Third parties 12

Locations

6 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 34 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications