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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01887938
Recruitment Status : Active, not recruiting
First Posted : June 27, 2013
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Shire

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 through Week 40.

Condition or disease Intervention/treatment Phase
Metachromatic Leukodystrophy (MLD) Biological: HGT-1110 Phase 1 Phase 2

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, through Week 40 and are receiving study drug every other week (EOW).

Treatment groups will be identical to those in HGT-MLD-070, ie, participants assigned to Cohort 1 in Study HGT-MLD-070 will continue to receive a dose of 10 milligrams (mg), participants assigned to Cohort 2 in Study HGT-MLD-070 will continue to receive a dose of 30 mg, and participants assigned to Cohorts 3 and 4 in Study HGT-MLD-070 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 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 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 (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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 23, 2013
Estimated Primary Completion Date : April 27, 2023
Estimated Study Completion Date : April 27, 2023


Arm Intervention/treatment
Experimental: Cohort 1
Participants will receive 10 milligram (mg) of HGT-1110 (Recombinant human arylsulfatase A) intrathecal (IT) injection every-other-week (EOW).
Biological: HGT-1110
Participants will receive IT injection of HGT-1110.
Other Name: Recombinant human arylsulfatase A

Experimental: Cohort 2
Participants will receive 30 mg of HGT-1110 IT injection EOW.
Biological: HGT-1110
Participants will receive IT injection of HGT-1110.
Other Name: Recombinant human arylsulfatase A

Experimental: Cohort 3
Participants will receive 100 mg of HGT-1110 IT injection EOW.
Biological: HGT-1110
Participants will receive IT injection of HGT-1110.
Other Name: Recombinant human arylsulfatase A

Experimental: Cohort 4
Participants will receive 100 mg of HGT-1110 IT injection once weekly for 12 weeks followed by 150 mg EOW.
Biological: HGT-1110
Participants will receive IT injection of HGT-1110.
Other Name: Recombinant human arylsulfatase A




Primary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline to Follow-up (Week 628) ]
    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.

  2. Presence of Anti-HGT-1110 Antibodies in Cerebrospinal Fluid (CSF) and Serum [ Time Frame: Baseline until end of the study (Week 624) ]
    The presence of anti-HGT-1110 antibodies in CSF and serum will be assessed.


Secondary Outcome Measures :
  1. Change From Baseline in Motor Function as Assessed by Gross Motor Function Measure (GMFM-88) Total Score at Week 624 [ Time Frame: Baseline, 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).

  2. Percent Change From Baseline in N-Aacetylaspartate/Creatine (NAA/Cr) Ratio in Deep White Matter of the Brain as Measured by Proton Magnetic Resonance Spectroscopy (MRS) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Percent change from baseline in NAA/Cr ratio in deep white matter of the brain as measured by proton MRS will be reported.

  3. Percent Change From Baseline in Choline/Creatine Ratio in Deep White Matter of the Brain as Measured by Proton Magnetic Resonance Spectroscopy (MRS) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Percent change from baseline in choline/creatine ratio in deep white matter of the brain as measured by proton MRS will be reported.

  4. Percent Change From Baseline in Lactate/Creatine Ratio in Deep White Matter of the Brain as Measured by Proton Magnetic Resonance Spectroscopy (MRS) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Percent change from baseline in lactate/creatine ratio in deep white matter of the brain as measured by proton MRS will be reported.

  5. Change From Baseline in Nerve Conduction Velocity (NCV) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Change from baseline in NCV will be assessed.

  6. Change From Baseline in Amplitude (AMP) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Change from baseline in AMP will be assessed.

  7. Change From Baseline in Distal Latency (DL) at Week 624 [ Time Frame: Baseline, Week 624 ]
    Change from baseline in DL will be assessed.

  8. Change From Baseline in the Adaptive Behavior Composite Standard Score Measured by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) [ Time Frame: Baseline, Week 624 ]
    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.

  9. Change From Baseline in the Domain-Specific Caregiver Observed Metachromatic Leukodystrophy Functioning and Outcomes Reporting Tool (COMFORT) Scores [ Time Frame: Baseline, Week 624 ]
    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.

  10. Maximum Observed Serum Concentration (Cmax) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The Cmax of HGT-1110 will be assessed.

  11. Time of Maximum Observed Serum Concentration (Tmax) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The Tmax of HGT-1110 will be assessed.

  12. 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 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The AUC0-last of HGT-1110 will be assessed.

  13. Area Under the Serum Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The AUC0-inf of HGT-1110 will be assessed.

  14. Apparent Terminal Rate Constant (lambda z) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The lambda z of HGT-1110 will be assessed.

  15. Terminal Half-Life (t1/2) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The t1/2 of HGT-1110 will be assessed.

  16. Clearance (CL/F) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The CL/F of HGT-1110 will be assessed.

  17. Volume of Distribution (Vz/F) of HGT-1110 [ Time Frame: Predose, 0.5, 1, 2, 4, 8, 12, 24, and 48 hours postdose on Weeks 104 and 258 in Cohort 4 and Week 8 in Cohorts 1-3 ]
    The Vz/F of HGT-1110 will be assessed.

  18. Concentrations of HGT-1110 in Cerebrospinal Fluid (CSF) [ Time Frame: Baseline to End of the study (Week 624) ]
    Concentrations of HGT-1110 in CSF will be assessed.



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:   up to 13 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant has participated in Study HGT-MLD-070 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 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: a. The participant has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device; b. 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; c. The participant has a known or suspected local or general infection; d. The participant is at risk of abnormal bleeding due to a medical condition or therapy; e. The participant has one or more spinal abnormalities that could complicate safe implantation or fixation; f. The participant has a functioning CSF shunt device; g. The participant has shown an intolerance to an implanted 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): NCT01887938


Locations
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Australia
The Children's Hospital at Westmead
Westmead, Australia, 2145
Brazil
Hospital de Clinicas de Porto Alegre
Porto Alegre, Brazil, 90035-003
Czechia
Detska Interni Klinika, Lf Mu A Fn Brno
Brno, Czechia, 61300
Denmark
Rigshospitalet
Copenhagen, Denmark, 2100
France
Hôpital de Bicêtre
Le Kremlin Bicetre, Ile-de-France, France, 94275
Hopital Femme Mere Enfant
Bron Cedex, France, 69 677
Hopital Gui de Chauliac - CHRU de Montpellier
Montpellier, France, 34000
CHU de Nantes
Nantes Cedex 1, France, 44093
CHR Orleans - Hopital La Source
Orleans, France, 45067
Germany
Center for Pediatric Clinical Studies (CPCS)
Tubingen, Baden-Wuerttemberg, Germany, 72076
Klinikum Oldenburg
Oldenburg, Germany, 26133
Marien-Hospital Wesel gGmbh
Wesel, Germany, 46483
Japan
Kitakyushu Municipal Yahata Hospital
Fukuoka, Japan, 805-8534
Kurashiki Central Hospital
Okayama Prefecture, Japan, 710-8602
Osaka University Hospital
Osaka, Japan, 565-0871
Sponsors and Collaborators
Shire
Investigators
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Study Director: Study Director Shire

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01887938     History of Changes
Other Study ID Numbers: HGT-MLD-071
2012-003775-20 ( EudraCT Number )
First Posted: June 27, 2013    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 2019
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: No
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