Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD) - Full Text View

Sponsored by:	Shire Human Genetic Therapies, Inc.
Information provided by:	Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier:	NCT00418561

Purpose

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.

Condition	Intervention	Phase
Metachromatic Leukodystrophy	Drug: rhASA	Phase I

Genetics Home Reference related topics: cholesteryl ester storage disease Farber lipogranulomatosis leukoencephalopathy with vanishing white matter long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency megalencephalic leukoencephalopathy with subcortical cysts metachromatic leukodystrophy mitochondrial trifunctional protein deficiency primary carnitine deficiency

MedlinePlus related topics: Leukodystrophies

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Factorial Assignment, Safety Study
Official Title:	A Single Center, Open-Label, Non-Randomized, Uncontrolled, Multiple-Dose, Dose Escalation Study of the Safety, Pharmacokinetics and Efficacy of Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)

Further study details as provided by Shire Human Genetic Therapies, Inc.:

Primary Outcome Measures:

To evaluate the safety profile of Metazym [ Time Frame: One year ] [ Designated as safety issue: Yes ]
To determine the PK profile of Metazym in patients with late infantile MLD as measured by rhASA levels in plasma and ASA activity in leukocytes [ Time Frame: One year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Efficacy of Metazym on the biochemical level, by assessing sulfatide concentrations in urine and cerebrospinal fluid, and changes in cerebrospinal fluid biomarkers [ Time Frame: One year ] [ Designated as safety issue: No ]
Efficacy of Metazym on functional capacity (disability level), by assessing gross and fine motor function, adaptive and cognitive development [ Time Frame: One year ] [ Designated as safety issue: No ]

Enrollment:	12
Study Start Date:	January 2007
Study Completion Date:	March 2008
Primary Completion Date:	March 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
rhASA: Experimental	Drug: rhASA intravenous infusion 25 U/kg,50 U/kg, 100U/kg or 200 U/kg every other week for 26 weeks

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)

Eligibility

Ages Eligible for Study:	1 Year to 5 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

Patients will be excluded from this study if they do not meet the specific inclusion criteria, or if any of the following criteria apply:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00418561

Locations

Denmark
PhaseOneTrials A/S
Hvidovre, Denmark, DK-2650

Sponsors and Collaborators

Shire Human Genetic Therapies, Inc.

Investigators

Principal Investigator:

Allan M Lund, MD

Rigshospitalet, Denmark

More Information

Responsible Party:	Shire HGT ( Carol Cannon (U.S.) or Steve Moloney (EU) )
Study ID Numbers:	rhASA-01, EudraCT number: 2006-005341-11
Study First Received:	January 4, 2007
Last Updated:	December 3, 2008
ClinicalTrials.gov Identifier:	NCT00418561
Health Authority:	Denmark: Danish Medicines Agency

Keywords provided by Shire Human Genetic Therapies, Inc.:

Metazym
MLD
rhASA

Study placed in the following topic categories:

Lipid Metabolism, Inborn Errors
Sphingolipidoses
Leukodystrophy, Metachromatic
Metabolic Diseases
Demyelinating Diseases
Lysosomal Storage Diseases
Sphingolipidosis
Central Nervous System Diseases
Demyelinating diseases
Brain Diseases

Leukodystrophy
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metachromatic leukodystrophy
Brain Diseases, Metabolic, Inborn
Lipidoses
Metabolic disorder
Lipid Metabolism Disorders
Brain Diseases, Metabolic

Additional relevant MeSH terms:

Lysosomal Storage Diseases, Nervous System
Nervous System Diseases
Sulfatidosis
Hereditary Central Nervous System Demyelinating Diseases

ClinicalTrials.gov processed this record on January 14, 2009