Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)

NCT00418561 | Completed Phase 1 Results DMC

• 2 other identifiers: rhASA-012006-005341-11
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

Objectives: The overall objective is to evaluate the safety, efficacy and pharmacokinetics (PK) of rhASA treatment in patients with late infantile MLD. Methodology: This is a single center, open-label study of patients with late infantile MLD. Twelve patients will be enrolled in this study receiving a total of thirteen intravenous infusions of Metazym. One infusion will be given every other week for a period of half a year. After the half year the subjects will continue treatment every other week until safety data is available. Safety (AE/SAE) will be monitored at every visit during this period.

Conditions

Metachromatic Leukodystrophy (MLD)

Keywords

rhASA; MLD; Metazym

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  An adverse event (AE) is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a participant, participating in a clinical study with study drug, regardless of causal relationship. TEAEs were AEs occurred after study drug administration that were absent before treatment or that worsened relative to pre-treatment state, up to Week 28 until evaluation (when last cohort had 26-week evaluation and data management performed within 4 weeks) completed.

  From study drug administration up to Week 28

• Change From Baseline in Gross Motor Function Measure (GMFM) at Week 26

  GMFM was measured using GMFM-88 item scores and summed to calculate a total GMFM-88 score. For each GMFM-88 item, the score was between 0 (minimal) to 3 (maximum). The total GMFM-88 score was between 0 (minimal) and 264 (maximum). The decrease in GMFM score over time indicates worsening of disease over time. Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported.

  Baseline, Week 26

• Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatide at Week 26

  Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported.

  Baseline, Week 26

• Number of Participants With Shift From Baseline to Week 26 in Sulfatide Levels in Urine

  Number of participants with shifts between negative (value=0) and positive (value=1) values in urine sulfatide levels from baseline at Week 26 is reported.

  Baseline up to Week 26

• Change From Baseline in Mullen's Scales of Early Learning at Week 26

  Mullen's Scales of Early Learning is used to assess performance and learning ability in young children. The scale consisted of 144 items that had specific scoring criteria for each item. The scores were converted to T-scores with a decrease in score indicating worsening of disease. Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported.

  Baseline, Week 26

• Maximum Plasma Drug Concentration (Cmax) of Recombinant Human Arylsulphatase A (rhASA)

  Pre-dose and post-dose at 20, 40, 90 minutes, 3, 6 and 8 hours on Day 0, 40 minutes post-dose at Week 4, Pre-dose and post-dose at 20, 40, 90 minutes, 3, 6 and 8 hours at Week 8

• Arylsulfatase A (ASA) Activity in Leukocytes

  Pre-dose and post-dose at 24 hours on Day 0 and at Weeks 8 and 26

Secondary Outcomes (4)

• Change From Baseline in Nerve Conduction Velocity at Week 26

  Baseline, Week 26

• Number of Participants Who Had Undergone Nerve Biopsy and Had a Normal Nerve at Both Baseline and Week 26

  Baseline, Week 26

• Number of Participants With Shift From Baseline to Week 26 in Magnetic Resonance Imaging (MRI)-Loes Scores

  Baseline up to Week 26

• Change From Baseline in Paediatric Evaluation of Disability Inventory (PEDI) Scores at Week 26

  Baseline, Week 26

Other Outcomes (10)

• Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Biochemistry

  Baseline up to Week 26

• Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Coagulation

  Baseline up to Week 26

• Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Genotyping

  Baseline up to Week 26

Study Arms (3)

Cohort 1

EXPERIMENTAL

Metazym (Recombinant human arylsulfatase A (rhASA)): 25 U/kg as a single dose - hereafter 50 U/kg

Biological: rhASA - Dose Level 1

Cohort 2

EXPERIMENTAL

100 U/kg Metazym (Recombinant human arylsulfatase A (rhASA))

Biological: rhASA - Dose Level 2

Cohort 3

EXPERIMENTAL

200 U/kg Metazym (Recombinant human arylsulfatase A (rhASA))

Biological: rhASA - Dose Level 3

Interventions

rhASA - Dose Level 1 BIOLOGICAL

Intravenous infusion 25 U/kg as a single dose - hereafter 50 U/kg every other week for 26 weeks

Also known as: HGT-1111, metazym

Cohort 1

rhASA - Dose Level 2 BIOLOGICAL

Intravenous infusion 100 U/kg every other week for 26 weeks

Also known as: HGT-1111, metazym

Cohort 2

rhASA - Dose Level 3 BIOLOGICAL

Intravenous infusion 200 U/kg every other week for 26 weeks

Also known as: HGT-1111, metazym

Cohort 3

Eligibility Criteria

• Age: 1 Year - 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Subject's legally authorized guardian(s) must provide signed, informed consent prior to performing any study-related activities (Trial-related activities are any procedures that would not have been performed during normal management of the subject).
• The patient must have a confirmed diagnosis of MLD as defined by:
• ASA activity \< 10 nmol/h/mg in leukocytes Presence of elevated sulfatide in urine
• The patient must have a confirmed nerve conduction velocity \< 2 standard deviations (from the appropriate age level)
• The patient must have a residual level of voluntary function (as judged by the investigator), including presence of residual cognitive function (attention, executive and visual functions) as well as the presence of residual voluntary motor function in one upper or lower limb as a minimum.
• The patient must have an age at the time of screening ≥ 1 year and \< 6 years
• The patient must have had onset of symptoms before the age of 4 years
• The subject and his/her guardian(s) must have the ability to comply with the clinical protocol
• The patients' medical record must document that the legal guardian(s) has had independent counselling or a consultation regarding stem cell transplantation in order to assure that the guardian(s) is fully informed regarding the risks and benefits of this alternative

You may not qualify if:

• Lack of voluntary function
• Presence of severe pseudo-bulbar signs (weakness and disco-ordination of tongue and swallowing muscles leading to severe difficulty with swallowing)
• Spasticity so severe to inhibit transportation
• Known multiple sulfatase deficiency
• Presence of major congenital abnormality
• Presence of known chromosomal abnormality and syndromes affecting psychomotor development
• History of stem cell transplantation
• Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition
• Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
• Use of any investigational product within 30 days prior to study enrolment or currently enrolled in another study which involves clinical investigations
• Received ERT with rhASA from any source
• Planned or anticipated initiation of antispastic treatment after trial initiation

Sponsors & Collaborators

• Shire: lead

Study Sites (1)

Rigshospitalet

Hvidovre, DK-2650, Denmark

Location

Related Publications (2)

• Dali CI, Barton NW, Farah MH, Moldovan M, Mansson JE, Nair N, Duno M, Risom L, Cao H, Pan L, Sellos-Moura M, Corse AM, Krarup C. Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy. Ann Clin Transl Neurol. 2015 May;2(5):518-33. doi: 10.1002/acn3.193. Epub 2015 Mar 27.

  PMID: 26000324 RESULT

• I Dali C, Groeschel S, Moldovan M, Farah MH, Krageloh-Mann I, Wasilewski M, Li J, Barton N, Krarup C. Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study. Ann Clin Transl Neurol. 2021 Jan;8(1):66-80. doi: 10.1002/acn3.51254. Epub 2020 Dec 17.

  PMID: 33332761 DERIVED

MeSH Terms

Conditions

Leukodystrophy, Metachromatic

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Limitations and Caveats

ASA activity in leukocytes could not be included in basic results format as the results were presented graphically. Due to quick disappearance of rhASA from plasma, rhASA levels were not possible to report.

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2007
• First Posted: January 5, 2007
• Study Start: January 22, 2007
• Primary Completion: March 27, 2008
• Study Completion: March 27, 2008
• Last Updated: June 25, 2021
• Results First Posted: August 13, 2015

Record last verified: 2021-06

Locations

DK (1)