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

NCT ID: NCT00418561

Last Updated: 2021-06-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-22
• Study Completion Date: 2008-03-27

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.

Detailed Description

Test product, dose, mode of administration, batch No.: The lowest dose level will be evaluated as a single dose of 25 U/kg. The three upper dose levels will be evaluated as repeated doses. Patients in each cohort will receive one dose of enzyme every other week for a period of eight weeks, a total of five doses. Dosing will be performed as follows: Cohort 1: 25 U/kg as a single dose - hereafter 50 U/kg; Cohort 2: 100 U/kg; Cohort 3: 200 U/kg. Patients receiving the lowest dose as a single dose will receive the next dose level as a repeated dose. After twenty six weeks 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. The dose will be adjusted monthly to account for changes in body weight. The infusion length will be dependent on the dose. Doses of 25 U/kg, 50 U/kg and 100 U/kg will be diluted in 50 ml isotonic sodium chloride and infused over 30 minutes. Infusion of 200 U/kg will be administered in the same manner except for an infusion time of 60 minutes.

Duration of treatment: Half a year (26 weeks)

Conditions

Metachromatic Leukodystrophy (MLD)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1

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

Group Type: EXPERIMENTAL

rhASA - Dose Level 1

Intervention Type: BIOLOGICAL

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

Cohort 2

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

Group Type: EXPERIMENTAL

rhASA - Dose Level 2

Intervention Type: BIOLOGICAL

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

Cohort 3

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

Group Type: EXPERIMENTAL

rhASA - Dose Level 3

Intervention Type: BIOLOGICAL

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

Interventions

rhASA - Dose Level 1

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

Intervention Type: BIOLOGICAL

rhASA - Dose Level 2

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

Intervention Type: BIOLOGICAL

rhASA - Dose Level 3

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

Intervention Type: BIOLOGICAL

Other Intervention Names

HGT-1111; metazym; HGT-1111; metazym; HGT-1111; metazym

Eligibility Criteria

Inclusion Criteria

1. 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).

2. 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

3. The patient must have a confirmed nerve conduction velocity < 2 standard deviations (from the appropriate age level)

4. 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.

5. The patient must have an age at the time of screening ≥ 1 year and < 6 years

6. The patient must have had onset of symptoms before the age of 4 years

7. The subject and his/her guardian(s) must have the ability to comply with the clinical protocol

8. 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

1. Lack of voluntary function

2. Presence of severe pseudo-bulbar signs (weakness and disco-ordination of tongue and swallowing muscles leading to severe difficulty with swallowing)

3. Spasticity so severe to inhibit transportation

4. Known multiple sulfatase deficiency

5. Presence of major congenital abnormality

6. Presence of known chromosomal abnormality and syndromes affecting psychomotor development

7. History of stem cell transplantation

8. Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition

9. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial

10. Use of any investigational product within 30 days prior to study enrolment or currently enrolled in another study which involves clinical investigations

11. Received ERT with rhASA from any source

12. Planned or anticipated initiation of antispastic treatment after trial initiation

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shire

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Takeda

Locations

Rigshospitalet

Hvidovre, , Denmark

Countries

Denmark

References

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.

Reference Type: RESULT

PMID: 26000324 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33332761 (View on PubMed)

Other Identifiers

2006-005341-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

rhASA-01

Identifier Type: -

Identifier Source: org_study_id