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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 Infantil

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 Summary:

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)


Sponsor: Shire

Current Primary Outcome:

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From study drug administration up to Week 28 ]
    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.
  • Change From Baseline in Gross Motor Function Measure (GMFM) at Week 26 [ Time Frame: Baseline, 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.
  • Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatide at Week 26 [ Time Frame: Baseline, 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.<

    Original Primary Outcome:

    • To evaluate the safety profile of Metazym
    • 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


    Current Secondary Outcome:

    • Change From Baseline in Nerve Conduction Velocity at Week 26 [ Time Frame: Baseline, 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.

    • 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 [ Time Frame: Baseline up to Week 26 ]
      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.
    • Change From Baseline in Paediatric Evaluation of Disability Inventory (PEDI) Scores at Week 26 [ Time Frame: Baseline, 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).


    Original Secondary Outcome:

    • Efficacy of Metazym on the biochemical level, by assessing sulfatide concentrations in urine and cerebrospinal fluid, and changes in cerebrospinal fluid biomarkers
    • Efficacy of Metazym on functional capacity (disability level), by assessing gross and fine motor function, adaptive and cognitive development


    Information By: Shire

    Dates:
    Date Received: January 4, 2007
    Date Started: January 2007
    Date Completion:
    Last Updated: March 24, 2016
    Last Verified: March 2016