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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire
ClinicalTrials.gov Identifier:
NCT00418561
First received: January 4, 2007
Last updated: July 16, 2015
Last verified: February 2014
  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 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Shire:

Primary Outcome Measures:
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From study drug administration up to Week 28 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Shift From Baseline to Week 26 in Sulfatide Levels in Urine [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mullen's Scales of Early Learning at Week 26 [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change From Baseline in Nerve Conduction Velocity at Week 26 [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
  • Number of Participants With Shift From Baseline to Week 26 in Magnetic Resonance Imaging (MRI)-Loes Scores [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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).


Other Outcome Measures:
  • Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Biochemistry [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]

    Number of participants with at least 1 shift from baseline to Week 26, are reported.

    Abbreviations: ALT=Alanine transaminase; CK=Creatine kinase; AP=Amyloid P component; LDH=Lactate dehydrogenase.


  • Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Coagulation [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]
    Number of participants with at least 1 shift from baseline to Week 26 are reported. The shift reported below for Cohort 1 was from low level at baseline to low level at Week 26.

  • Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Genotyping [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]

    Number of participants with at least 1 shift from baseline to Week 26 are reported.

    Abbreviations: CSF=Cerebrospinal fluid; NFP=Neurofilament proteins.


  • Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Hematology [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]

    Number of participants with at least 1 shift from baseline to Week 26 are reported.

    Abbreviations: Abs=Absolute count; ERCS=Erythrocytes; MCHC=Mean corpuscular hemoglobin concentration; MCH=Mean cell hemoglobin.


  • Number of Participants With Abnormal Findings in Urine Analysis [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]
    The parameters analyzed in urine were albumin/protein, glucose, leucocytes, acetoacetate/ketones, nitrite and pH. Urine analysis findings were considered abnormal as judged by the investigator.

  • Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]
    Abnormal ECG findings were considered as clinically significant at the discretion of investigator.

  • Change From Baseline in Chitotriosidase at Week 26 [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Change From Baseline in Neurofilament Proteins (NFP), Glial Fibrillary Acidic Protein (GFAP) and Tauprotein in Cerebrospinal Fluid (CSF) at Week 26 [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
  • Change From Baseline in Amplitude at Week 26 [ Time Frame: Baseline, Week 26 ] [ Designated as safety issue: No ]
    Abbreviations: MN=Median Nerve; PN=Peroneal Nerve; SN=Sural Nerve; Dig.=Digit; APB=abductor pollicis brevis; EDB=extensor digitorum brevis.

  • Physical Examination Results [ Time Frame: Baseline up to Week 26 ] [ Designated as safety issue: Yes ]
    Physical examination included general appearance, skin, head, ears, eyes, nose and throat, lymph nodes, heart, lungs, abdomen, extremities/joints, hip, neurological, mental status and, if appropriate, breasts, external genitalia, pelvic and rectal, and in addition weight, height and head circumference were recorded.


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
Experimental: rhASA Drug: rhASA
intravenous infusion 25 U/kg,50 U/kg, 100U/kg or 200 U/kg every other week for 26 weeks
Other Names:
  • metazym
  • HGT-1111

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:

  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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
Denmark
Rigshospitalet
Hvidovre, Denmark, DK-2650
Sponsors and Collaborators
Shire
Investigators
Principal Investigator: Allan M Lund, MD Rigshospitalet, Denmark
  More Information

No publications provided

Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT00418561     History of Changes
Other Study ID Numbers: rhASA-01, 2006-005341-11
Study First Received: January 4, 2007
Results First Received: July 16, 2015
Last Updated: July 16, 2015
Health Authority: Denmark: Danish Medicines Agency

Keywords provided by Shire:
Metazym
MLD
rhASA

Additional relevant MeSH terms:
Leukodystrophy, Metachromatic
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Demyelinating Diseases
Genetic Diseases, Inborn
Hereditary Central Nervous System Demyelinating Diseases
Leukoencephalopathies
Lipid Metabolism Disorders
Lipid Metabolism, Inborn Errors
Lipidoses
Lysosomal Storage Diseases
Lysosomal Storage Diseases, Nervous System
Metabolic Diseases
Metabolism, Inborn Errors
Nervous System Diseases
Sphingolipidoses
Sulfatidosis

ClinicalTrials.gov processed this record on September 01, 2015