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

Shire13 enrolled

Overview

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.

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)

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 1 YearMax age: 5 Years

Medical Language ↔ Plain English

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 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: 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

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 26

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

Time frame: 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

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

Secondary Outcomes

Change From Baseline in Nerve Conduction Velocity at Week 26

An electrophysiological evaluation using standard electrophysiological and electromyography to measure the speed and extent of nerve conduction and units are expressed in meters per second. Abbreviations: MN=Median Nerve; PN=Peroneal Nerve; SN=Sural Nerve; Dig.=Digit; FH=fibular hemimelia; L LM=left lateral medial; R LM=right lateral medial; MC=medial collateral.

Time frame: Baseline, Week 26

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

Time frame: Baseline, Week 26

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

Loes scoring system is used to grade the demyelinating abnormalities on brain MRI. A total of 17 locations of the brain were scored from 0 (normal appearance) to 2 (dense appearance). The total score ranged from 0 to 34 with a score of 14 or greater being considered severe. Number of participants with any shift of score between 0 to 2 for each of the 17 locations (Parieto Occipital \[PO\]-Periventricular \[P\], Central \[C\], Subcortical \[Sc\]; Anterior Temporal \[AT\]-P, C, Sc; Frontal \[F\]-P, C, Sc; Corpus Callosum \[CC\]-Splenium \[S\], Genus \[G\]; Projection Fibers \[PF\]-Capsular interna \[CI\] ant, CI post, Brainstem \[B\]; Cerebellum \[Cb\]-Cortex, Atrophy; Basal Ganglia \[BG\]-BG, Thalamus \[T\]; Cerebral Atrophy \[CA\]-CA), are only reported.

Time frame: Baseline up to Week 26

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

PEDI is used for the clinical evaluation of functional capabilities, performance and changes in functional skills in children with disabilities. It consisted of 20 items scored on a scale from 0 (total assistance) to 5 (independent). Total score ranged from 0-100 with higher scores indicating better functioning. None, child, rehab, extensive are items in 3 domains (self-care, mobility and social functioning).

Time frame: Baseline, Week 26

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes