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An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy

Primary Purpose

Metachromatic Leukodystrophy (MLD)

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
HGT-1110
Sponsored by
Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metachromatic Leukodystrophy (MLD)

Eligibility Criteria

0 Years - 13 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Participant has participated in Study HGT-MLD-070 (NCT01510028) through Week 40.
  2. Participant must have no safety or medical issues that contraindicate participation.
  3. The participant, participant's parent(s), or legally authorized representative(s) must provide written informed consent and/or assent (if applicable) prior to performing any study-related activities.

Exclusion Criteria:

  1. The participant is unable to comply with the protocol (example, is unable to return for safety evaluations, or is otherwise unlikely to complete the study) as determined by the investigator.
  2. Undergoes bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), or gene therapy at any point during the study.
  3. The participant has any known or suspected hypersensitivity to agents used for anesthesia or is thought to be at an unacceptably high risk for associated potential complications of airway compromise or other conditions.
  4. The participant is pregnant or breastfeeding.
  5. The participant is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or drug delivery device) other than those used in HGT-MLD-070 (NCT01510028) within 6 months prior to study enrollment or at any time during the study.

  6. The participant has a condition that is contraindicated as described in the SOPH-A-PORT Mini SIDDD Instructions for Use (IFU), including:

    1. The participant has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
    2. The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the investigator.
    3. The participant has a known or suspected local or general infection.
    4. The participant is at risk of abnormal bleeding due to a medical condition or therapy.
    5. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation.
    6. The participant has a functioning CSF shunt device.
    7. The participant has shown an intolerance to an implanted device.

Sites / Locations

  • The Children's Hospital at Westmead
  • Hospital de Clinicas de Porto Alegre
  • Detska Interni Klinika, Lf Mu A Fn Brno
  • Rigshospitalet
  • Hôpital de Bicêtre
  • Hopital Femme Mere Enfant
  • Hopital Gui de Chauliac - CHRU de Montpellier
  • CHU de Nantes
  • CHR Orleans - Hopital La Source
  • Center for Pediatric Clinical Studies (CPCS)
  • Klinikum Oldenburg
  • Marien-Hospital Wesel gGmbh
  • Kitakyushu Municipal Yahata Hospital
  • Kurashiki Central Hospital
  • Osaka University Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Arm Description

Participants will receive 10 milligram (mg) of HGT-1110 (Recombinant human arylsulfatase A) intrathecal (IT) injection every-other-week (EOW).

Participants will receive 30 mg of HGT-1110 IT injection EOW.

Participants will receive 100 mg of HGT-1110 IT injection EOW.

Participants will receive 100 mg of HGT-1110 IT injection once weekly for 12 weeks followed by 150 mg EOW.

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational drug product-related. TEAEs are defined as all AEs occurring or worsening at or after the first dose of investigational drug product in HGT-MLD-071 or ongoing from HGT-MLD-070 at the time of enrollment into HGT-MLD-071.
Presence of Anti-HGT-1110 Antibodies in Cerebrospinal Fluid (CSF) and Serum
The presence of anti-HGT-1110 antibodies in CSF and serum will be assessed.

Secondary Outcome Measures

Change From Baseline in Motor Function as Assessed by Gross Motor Function Measure (GMFM-88) Total Score at Week 624
The GMFM-88 item scores can be used to calculate a domain-specific percent score for each of the 5 GMFM-88 dimensions, which are the following: Lying and rolling; Sitting; Crawling and kneeling; Standing; Walking, running, and jumping. Each of the 88 items is rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores range from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities. The domain-specific percent scores are averaged to obtain the total score (percent).
Change From Baseline in the Adaptive Behavior Composite Standard Score Measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The ABC score ranges from 20 to 160 on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning.
Change From Baseline in the Domain-Specific Caregiver Observed Metachromatic Leukodystrophy Functioning and Outcomes Reporting Tool (COMFORT) Scores
The COMFORT is a questionnaire that will be used to assess health status and the impact of disease on the ability of participants with MLD to carry out activities of daily life. The questionnaire is organized by 8 domains (that is, Personal Care, Positioning, Transfer or Mobility, Eating, Pain and Discomfort During the Day, Sleep, Emotions, Communication, Play and Leisure Activities) and will be completed by the participant's parent(s) or legal representative(s). It will be conducted in available validated languages. The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning.
Maximum Observed Serum Concentration (Cmax) of HGT-1110
The Cmax of HGT-1110 will be assessed.
Time of Maximum Observed Serum Concentration (Tmax) of HGT-1110
The Tmax of HGT-1110 will be assessed.
Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time at Which Serum Concentrations Were Measurable (AUC0-last) of HGT-1110
The AUC0-last of HGT-1110 will be assessed.
Area Under the Serum Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of HGT-1110
The AUC0-inf of HGT-1110 will be assessed.
Apparent Terminal Rate Constant (lambda z) of HGT-1110
The lambda z of HGT-1110 will be assessed.
Terminal Half-Life (t1/2) of HGT-1110
The t1/2 of HGT-1110 will be assessed.
Clearance (CL/F) of HGT-1110
The CL/F of HGT-1110 will be assessed.
Volume of Distribution (Vz/F) of HGT-1110
The Vz/F of HGT-1110 will be assessed.
Concentrations of HGT-1110 in Cerebrospinal Fluid (CSF)
Concentrations of HGT-1110 in CSF will be assessed.

Full Information

First Posted
June 20, 2013
Last Updated
July 19, 2023
Sponsor
Shire
Collaborators
Takeda Development Center Americas, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01887938
Brief Title
An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy
Official Title
An Open-Label Extension of Study HGT-MLD-070 Evaluating Long Term Safety and Efficacy of Intrathecal Administration of HGT-1110 in Patients With Metachromatic Leukodystrophy
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 23, 2013 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shire
Collaborators
Takeda Development Center Americas, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to collect long-term safety data in participants with metachromatic leukodystrophy (MLD) who are receiving HGT-1110 and have participated in Study HGT-MLD-070 (NCT01510028) through Week 40.
Detailed Description
MLD is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare orphan disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD. This study is a multicenter open-label study designed to evaluate safety and efficacy outcomes of HGT-1110 administered intrathecally in children with MLD who have participated in the dose escalation study, HGT-MLD-070 (NCT01510028), through Week 40 and are receiving study drug every other week (EOW). Treatment groups will be identical to those in HGT-MLD-070 (NCT01510028), ie, participants assigned to Cohort 1 in Study HGT-MLD-070 (NCT01510028) will continue to receive a dose of 10 milligrams (mg), participants assigned to Cohort 2 in Study HGT-MLD-070 (NCT01510028) will continue to receive a dose of 30 mg, and participants assigned to Cohorts 3 and 4 in Study HGT-MLD-070 (NCT01510028) will continue to receive a dose of 100 mg. Participants in Cohort 4 are to exclusively receive drug product produced with Process B in Study HGT-MLD-070 (NCT01510028) and will continue receiving this drug product in this study. Participants enrolled in this study from Cohorts 1 to 3 in Study HGT-MLD-070 (NCT01510028) were transitioned to Process B after all necessary approvals were obtained. In HGT-MLD-071, all participants in the 10 mg dose cohort who experienced disease progression, as determined by the Investigator, increased to the 30 mg dose after agreement by the Medical Monitor. Based on the interim analysis results from HGT-MLD-070 (NCT01510028 [Cohorts 1-3]), the dose of HGT-1110 will be increased to 100 mg for all participants in HGT-MLD-071 after all necessary approvals were obtained.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metachromatic Leukodystrophy (MLD)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Participants will receive 10 milligram (mg) of HGT-1110 (Recombinant human arylsulfatase A) intrathecal (IT) injection every-other-week (EOW).
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Participants will receive 30 mg of HGT-1110 IT injection EOW.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
Participants will receive 100 mg of HGT-1110 IT injection EOW.
Arm Title
Cohort 4
Arm Type
Experimental
Arm Description
Participants will receive 100 mg of HGT-1110 IT injection once weekly for 12 weeks followed by 150 mg EOW.
Intervention Type
Biological
Intervention Name(s)
HGT-1110
Other Intervention Name(s)
Recombinant human arylsulfatase A
Intervention Description
Participants will receive IT injection of HGT-1110.
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational drug product-related. TEAEs are defined as all AEs occurring or worsening at or after the first dose of investigational drug product in HGT-MLD-071 or ongoing from HGT-MLD-070 at the time of enrollment into HGT-MLD-071.
Time Frame
Baseline to Follow-up (Week 628)
Title
Presence of Anti-HGT-1110 Antibodies in Cerebrospinal Fluid (CSF) and Serum
Description
The presence of anti-HGT-1110 antibodies in CSF and serum will be assessed.
Time Frame
Baseline until end of the study (Week 624)
Secondary Outcome Measure Information:
Title
Change From Baseline in Motor Function as Assessed by Gross Motor Function Measure (GMFM-88) Total Score at Week 624
Description
The GMFM-88 item scores can be used to calculate a domain-specific percent score for each of the 5 GMFM-88 dimensions, which are the following: Lying and rolling; Sitting; Crawling and kneeling; Standing; Walking, running, and jumping. Each of the 88 items is rated on a 4-point scale: 0=does not initiate; 1=initiates; 2=partially completes; and 3=completes. The GMFM-88 total scores range from 0% (no mobility) to a score of 100%, that is (i.e,) the score that can be obtained by an average 5-year-old or older child with normal motor abilities. The domain-specific percent scores are averaged to obtain the total score (percent).
Time Frame
Baseline, Week 624
Title
Change From Baseline in the Adaptive Behavior Composite Standard Score Measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
Description
The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 4 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The ABC score ranges from 20 to 160 on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning.
Time Frame
Baseline, Week 624
Title
Change From Baseline in the Domain-Specific Caregiver Observed Metachromatic Leukodystrophy Functioning and Outcomes Reporting Tool (COMFORT) Scores
Description
The COMFORT is a questionnaire that will be used to assess health status and the impact of disease on the ability of participants with MLD to carry out activities of daily life. The questionnaire is organized by 8 domains (that is, Personal Care, Positioning, Transfer or Mobility, Eating, Pain and Discomfort During the Day, Sleep, Emotions, Communication, Play and Leisure Activities) and will be completed by the participant's parent(s) or legal representative(s). It will be conducted in available validated languages. The COMFORT scores range from 0 to 100, with higher scores indicating a decline in the functioning.
Time Frame
Baseline, Week 624
Title
Maximum Observed Serum Concentration (Cmax) of HGT-1110
Description
The Cmax of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Time of Maximum Observed Serum Concentration (Tmax) of HGT-1110
Description
The Tmax of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Area Under the Serum Concentration-Time Curve From Time Zero to the Last Sampling Time at Which Serum Concentrations Were Measurable (AUC0-last) of HGT-1110
Description
The AUC0-last of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Area Under the Serum Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of HGT-1110
Description
The AUC0-inf of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Apparent Terminal Rate Constant (lambda z) of HGT-1110
Description
The lambda z of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Terminal Half-Life (t1/2) of HGT-1110
Description
The t1/2 of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Clearance (CL/F) of HGT-1110
Description
The CL/F of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Volume of Distribution (Vz/F) of HGT-1110
Description
The Vz/F of HGT-1110 will be assessed.
Time Frame
Pre-dose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours post-dose on Weeks 104, 258, 364 and 622 in Cohort 4 and Week 8 in Cohorts 1-3
Title
Concentrations of HGT-1110 in Cerebrospinal Fluid (CSF)
Description
Concentrations of HGT-1110 in CSF will be assessed.
Time Frame
Baseline to End of the study (Week 624)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Years
Maximum Age & Unit of Time
13 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participant has participated in Study HGT-MLD-070 (NCT01510028) through Week 40. Participant must have no safety or medical issues that contraindicate participation. The participant, participant's parent(s), or legally authorized representative(s) must provide written informed consent and/or assent (if applicable) prior to performing any study-related activities. Exclusion Criteria: The participant is unable to comply with the protocol (example, is unable to return for safety evaluations, or is otherwise unlikely to complete the study) as determined by the investigator. Undergoes bone marrow transplant (BMT), hematopoietic stem cell transplantation (HSCT), or gene therapy at any point during the study. The participant has any known or suspected hypersensitivity to agents used for anesthesia or is thought to be at an unacceptably high risk for associated potential complications of airway compromise or other conditions. The participant is pregnant or breastfeeding. The participant is enrolled in another clinical study that involves clinical investigations or use of any investigational product (drug or drug delivery device) other than those used in HGT-MLD-070 (NCT01510028) within 6 months 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 SIDDD Instructions for Use (IFU), including: The participant has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device. The participant's body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the investigator. The participant has a known or suspected local or general infection. The participant is at risk of abnormal bleeding due to a medical condition or therapy. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation. The participant has a functioning CSF shunt device. The participant has shown an intolerance to an implanted device.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Shire
Official's Role
Study Director
Facility Information:
Facility Name
The Children's Hospital at Westmead
City
Westmead
ZIP/Postal Code
2145
Country
Australia
Facility Name
Hospital de Clinicas de Porto Alegre
City
Porto Alegre
ZIP/Postal Code
90035-003
Country
Brazil
Facility Name
Detska Interni Klinika, Lf Mu A Fn Brno
City
Brno
ZIP/Postal Code
61300
Country
Czechia
Facility Name
Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Hôpital de Bicêtre
City
Le Kremlin Bicetre
State/Province
Ile-de-France
ZIP/Postal Code
94275
Country
France
Facility Name
Hopital Femme Mere Enfant
City
Bron Cedex
ZIP/Postal Code
69 677
Country
France
Facility Name
Hopital Gui de Chauliac - CHRU de Montpellier
City
Montpellier
ZIP/Postal Code
34000
Country
France
Facility Name
CHU de Nantes
City
Nantes Cedex 1
ZIP/Postal Code
44093
Country
France
Facility Name
CHR Orleans - Hopital La Source
City
Orleans
ZIP/Postal Code
45067
Country
France
Facility Name
Center for Pediatric Clinical Studies (CPCS)
City
Tubingen
State/Province
Baden-Wuerttemberg
ZIP/Postal Code
72076
Country
Germany
Facility Name
Klinikum Oldenburg
City
Oldenburg
ZIP/Postal Code
26133
Country
Germany
Facility Name
Marien-Hospital Wesel gGmbh
City
Wesel
ZIP/Postal Code
46483
Country
Germany
Facility Name
Kitakyushu Municipal Yahata Hospital
City
Fukuoka
ZIP/Postal Code
805-8534
Country
Japan
Facility Name
Kurashiki Central Hospital
City
Okayama Prefecture
ZIP/Postal Code
710-8602
Country
Japan
Facility Name
Osaka University Hospital
City
Osaka
ZIP/Postal Code
565-0871
Country
Japan

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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/study sites, …)
Links:
URL
https://clinicaltrials.takeda.com/study-detail/5f6b5fce4db2bf003ab467a0
Description
To obtain more information on the study, click here/on this link

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An Efficacy and Safety Study of HGT-1110 in Participants With Metachromatic Leukodystrophy

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