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

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ClinicalTrials.gov Identifier: NCT03771898
Recruitment Status : Recruiting
First Posted : December 11, 2018
Last Update Posted : October 3, 2019
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 : 42 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
Actual 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.
Other Names:
  • HGT-1110
  • recombinant human arylsulfatase A [rhASA]




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. Change From Baseline in Eichler Metachromatic Leukodystrophy (MLD) Magnetic Resonance Imgaing (MRI) Severity Score on Week 106 [ Time Frame: Baseline, Week 106 ]
    Change from baseline in Eichler MLD MRI severity score will be assessed.

  11. 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 105 / EOT ]
    The Cmax of SHP611 in serum will be assessed.

  12. 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 on week 0 and week 105 / EOT ]
    The tmax of SHP611 in serum will be assessed.

  13. 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 105 / EOT ]
    The AUC0-inf of SHP611 in serum will be assessed.

  14. 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 105 / EOT ]
    The AUC0-t of SHP611 in serum will be assessed.

  15. 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 on week 0 and week 105 / EOT ]
    The t1/2 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 105 / EOT ]
    The CL/F of SHP611 in serum will be assessed.

  17. 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 on week 0 and week 105 / EOT ]
    The Lambda of SHP611 in serum will be assessed.

  18. 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 on week 0 and week 105 / EOT ]
    The Vz/F of SHP611 in serum will be assessed.

  19. 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

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Ages Eligible for Study:   6 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 MLD (Groups A-F):

    1. Low ASA activity in leukocytes (compared to laboratory normal range).
    2. 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, 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 documented by a pediatric neurologist or medical geneticist.

  • 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 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: minimally symptomatic, > 6 to < 18 months of age, younger siblings of enrolled participants, and have the same arylsulfatase (ASA) allelic constitution; Group E: early symptomatic, > = 12 to < 18 months of age with a GMFC-MLD level 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 level 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.

Inclusion Criteria for Matched Historical Controls:

  • The participant must have a documented diagnosis of MLD

    1. Low ASA activity in leukocytes (compared to laboratory normal range).
    2. Elevated sulfatides in urine.
  • Participants must have a gait disorder due to spastic ataxia or weakness attributed to MLD by the investigator and documented by 30 months of age.
  • Participants must have at least 2 motor assessments by GMFC-MLD with the second assessment occurring at approximately 106 (+/-2) weeks after the first assessment or else a second assessment measured before Week 100 with a GMFC-MLD level 5 or 6.
  • Participants 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.
  • Participants 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) 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 Shire 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 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 Cerebro spinal fluid(CSF) shunt device.

Exclusion Criteria for Matched Historical Controls

  • 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 (eg, tantrums in response to loss of motor skills) are not exclusionary.
  • 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: October 3, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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).

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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