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

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ClinicalTrials.gov Identifier: NCT03771898
Recruitment Status : Not yet recruiting
First Posted : December 11, 2018
Last Update Posted : December 11, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:
The primary purpose of this study is to evaluate the effects of intrathecal (IT) administration of SHP611 on gross motor function, using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) compared with matched historical control data in children with metachromatic leukodystrophy (MLD).

Condition or disease Intervention/treatment Phase
Metachromatic Leukodystrophy (MLD) Drug: SHP611 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Global, Multicenter, Open-label, Matched Historical Control Study of Intrathecal SHP611 in Subjects With Late Infantile Metachromatic Leukodystrophy
Estimated Study Start Date : April 30, 2019
Estimated Primary Completion Date : August 15, 2022
Estimated Study Completion Date : August 15, 2022


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 105 weeks.
Drug: SHP611
Participants will receive 150 mg of SHP611 IT via IDDD or LP once weekly for 105 weeks.




Primary Outcome Measures :
  1. Response in Group A Evaluated Using Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 [ Time Frame: Week 106 ]
    The response in Group A is defined as maintenance of gross motor function at 2 years (Week 106), evaluated as no greater than 2 levels decline from baseline in GMFC-MLD. 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. The GMFC-MLD covers clinically relevant gross motor stages occurring in participants with metachromatic leukodystrophy (MLD) and consists of 7 levels 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 :
  1. Response in Group A Evaluated Using Gross Motor Function Measure (GMFM)-88 at Week 106 [ Time Frame: Week 106 ]
    The response in Group A gross motor function is defined as maintenance of gross motor function at 2 years (Week 106), defined as a GMFM-88 total score greater than (>) 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.

  2. Change From Baseline in Gross Motor Function evaluated by Using the Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) at Week 106 [ Time Frame: Baseline, Week 106 ]
    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.

  3. Change From Baseline in Gross Motor Function Evaluated by Using Gross Motor Function Measure (GMFM)-88 Total Score at Week 106 [ Time Frame: Baseline, Week 106 ]
    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.

  4. Number of Participants With Gross Motor Function Measure (GMFM)-88 Total Score Decline of no More Than 20 Points From Baseline and a Total Score That is Greater Than or Equal to (>=) 40 at Week 106 [ Time Frame: Week 106 ]
    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 decline of no more than 20 points from baseline and a total score that is >= 40 at week 106 will be reported.

  5. Time to Unreversed Decline From Baseline in Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) of More Than 2 Categories [ Time Frame: Baseline through 106 weeks ]
    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.

  6. Time to Unreversed Decline From Baseline in Gross Motor Function Measure (GMFM)-88 Total Score of More Than (>) 20 Points or Unreversed Decline to Less Than (<) 40 Points Whichever Occurs First [ Time Frame: Baseline through 106 weeks ]
    The GMFM-88 is a clinician-evaluated assessment of motor function as described in above outcome measure. Time to unreversed decline from baseline in GMFM-88 total score of >20 points or unreversed decline to < 40 points whichever occurs first will be reported.

  7. 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 ]
    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.

  8. Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatides Levels at Week 106 [ Time Frame: Baseline, Week 106 ]
    Change from baseline in CSF sulfatides levels will be assessed.

  9. Change From Baseline in Proton Magnetic Resonance Spectroscopy (MRS) Metabolite Level of N-acetylaspartate/Creatine at Week 106 [ Time Frame: Baseline, Week 106 ]
    Change from baseline in N-acetylaspartate/creatine (NAA/Cr) will be assessed.

  10. 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 ]
    The Cmax of SHP611 in serum will be assessed.

  11. Time of Maximum Observed Concentration (tmax) of SHP611 in Serum [ Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post dose ]
    The tmax of SHP611 in serum will be assessed.

  12. 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 ]
    The AUC0-inf of SHP611 in serum will be assessed.

  13. 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 ]
    The AUC0-t of SHP611 in serum will be assessed.

  14. Terminal Half-life (t1/2) of SHP611 in Serum [ Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post dose ]
    The t1/2 of SHP611 in serum will be assessed.

  15. 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 ]
    The CL/F of SHP611 in serum will be assessed.

  16. Terminal Phase Rate Distribution Constant (Lambda) of SHP611 in Serum [ Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post dose ]
    The Lambda of SHP611 in serum will be assessed.

  17. Volume of Distribution Associated With the Terminal Slope Following Extravascular Administration Divided by the Fraction of the Dose Absorbed (Vz/F) of SHP611 in Serum [ Time Frame: Pre dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post dose ]
    The Vz/F of SHP611 in serum will be assessed.

  18. Number of Participants With Treatment-emergent Adverse Event (TEAEs) [ Time Frame: From start of study drug administration up to 108 weeks ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Months to 72 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The participant must have a documented diagnosis of metachromatic leukodystrophy (MLD) (Groups A-D): a. low arylsulfatase A (ASA) activity in leukocytes; b. elevated sulfatides in urine.
  • The participant must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by a pediatric neurologist or medical geneticist by 30 months of age (Groups A-C) or presymptomatic (Group D).
  • 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: less than (<) 18 months of age.
  • The participant's Gross Motor Function Classification in Metachromatic Leukodystrophy (GMFC-MLD) level at screening must be: Group A: GMFC-MLD level of 1 or 2; Group B: GMFC-MLD level of 3; Group C: GMFC-MLD level of 4; Group D: presymptomatic, are younger siblings of enrolled participants, and have the same ASA allelic constitution.
  • 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.

Inclusion criteria for matched historical controls:

  • The participant must have a documented diagnosis of MLD: a. low ASA activity in leukocytes; b. elevated sulfatides in urine.
  • Participant must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented at baseline.
  • Participant must have at least 2 motor assessments by GMFC-MLD with the second assessment occurring at approximately 106 (+/-6) weeks after the first assessment or else a second assessment measured before week 100 with a GMFC-MLD level 5 or 6. Participant with GMFC-MLD data (pro or retrospectively determined) must have the earliest observation of level 1 or 2 (walking with support) in the data source-verified medical record.
  • Participant must be 18 to 48 months of age at the earliest assessment.

Exclusion Criteria:

  • Multiple sulfatase disorder as determined by abnormal activity of another lysosomal sulfatase (based upon the reference laboratory's normal range).
  • History of hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study.
  • Initial presentation of behavioral or cognitive symptoms of MLD (per investigator's clinical judgment).
  • 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.
  • The participant is enrolled in another clinical study that involves use of any investigational product (drug or device) within 30 days prior to study enrollment or at any time during the study.
  • The participant has a condition that is contraindicated as described in the SOPH-A-PORT Mini S intrathecal drug delivery device (IDDD) Instructions for Use (IFU).

Exclusion criteria for matched historical controls:

  • History of hematopoietic stem cell transplantation (HSCT) or gene therapy or undergoes HSCT or gene therapy at any point during the study.
  • Initial presentation of behavioral or cognitive symptoms of MLD (per investigator's clinical judgment).
  • The participant is enrolled in another clinical study that involves use of any investigational product (drug or device).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03771898


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

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Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03771898     History of Changes
Other Study ID Numbers: SHP611-201
2018-003291-12 ( EudraCT Number )
First Posted: December 11, 2018    Key Record Dates
Last Update Posted: December 11, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. 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.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Leukodystrophy, Metachromatic
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Leukoencephalopathies
Demyelinating Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders