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

Primary Purpose

Metachromatic Leukodystrophy (MLD)

Status

Completed

Phase

Phase 1

Locations

Denmark

Study Type

Interventional

Intervention

rhASA - Dose Level 1

rhASA - Dose Level 2

rhASA - Dose Level 3

About this trial

This is an interventional treatment trial for Metachromatic Leukodystrophy (MLD) focused on measuring rhASA, MLD, Metazym

Eligibility Criteria

1 Year - 5 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Rigshospitalet

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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

Arylsulfatase A (ASA) Activity in Leukocytes

Secondary Outcome Measures

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.

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

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).

Full Information

NCT ID

NCT00418561

First Posted

January 4, 2007

Last Updated

June 23, 2021

Sponsor

Shire

1. Study Identification

Unique Protocol Identification Number

NCT00418561

Brief Title

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

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)

Study Type

Interventional

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Completed

Study Start Date

January 22, 2007 (Actual)

Primary Completion Date

March 27, 2008 (Actual)

Study Completion Date

March 27, 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Shire

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metachromatic Leukodystrophy (MLD)

Keywords

rhASA, MLD, Metazym

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Factorial Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

13 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

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

Intervention Type

Biological

Intervention Name(s)

rhASA - Dose Level 1

Other Intervention Name(s)

HGT-1111, metazym

Intervention Description

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

Intervention Type

Biological

Intervention Name(s)

rhASA - Dose Level 2

Other Intervention Name(s)

HGT-1111, metazym

Intervention Description

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

Intervention Type

Biological

Intervention Name(s)

rhASA - Dose Level 3

Other Intervention Name(s)

HGT-1111, metazym

Intervention Description

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

Primary Outcome Measure Information:

Title

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Description

Time Frame

From study drug administration up to Week 28

Title

Change From Baseline in Gross Motor Function Measure (GMFM) at Week 26

Description

Time Frame

Baseline, Week 26

Title

Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatide at Week 26

Description

Time Frame

Baseline, Week 26

Title

Number of Participants With Shift From Baseline to Week 26 in Sulfatide Levels in Urine

Description

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

Title

Change From Baseline in Mullen's Scales of Early Learning at Week 26

Description

Time Frame

Baseline, Week 26

Title

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

Title

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 Outcome Measure Information:

Title

Change From Baseline in Nerve Conduction Velocity at Week 26

Description

Time Frame

Baseline, Week 26

Title

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

Time Frame

Baseline, Week 26

Title

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

Description

Time Frame

Baseline up to Week 26

Title

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

Description

Time Frame

Baseline, Week 26

Other Pre-specified Outcome Measures:

Title

Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Biochemistry

Description

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.

Time Frame

Baseline up to Week 26

Title

Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Coagulation

Description

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.

Time Frame

Baseline up to Week 26

Title

Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Genotyping

Description

Number of participants with at least 1 shift from baseline to Week 26 are reported. Abbreviations: CSF=Cerebrospinal fluid; NFP=Neurofilament proteins.

Time Frame

Baseline up to Week 26

Title

Number of Participants With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Hematology

Description

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.

Time Frame

Baseline up to Week 26

Title

Number of Participants With Abnormal Findings in Urine Analysis

Description

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.

Time Frame

Baseline up to Week 26

Title

Number of Participants With Clinically Significant Abnormal Electrocardiogram (ECG) Findings

Description

Abnormal ECG findings were considered as clinically significant at the discretion of investigator.

Time Frame

Baseline up to Week 26

Title

Change From Baseline in Chitotriosidase at Week 26

Time Frame

Baseline, Week 26

Title

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

Title

Change From Baseline in Amplitude at Week 26

Description

Abbreviations: MN=Median Nerve; PN=Peroneal Nerve; SN=Sural Nerve; Dig.=Digit; APB=abductor pollicis brevis; EDB=extensor digitorum brevis.

Time Frame

Baseline, Week 26

Title

Physical Examination Results

Description

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.

Time Frame

Baseline up to Week 26

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

Facility Name

Rigshospitalet

City

Hvidovre

ZIP/Postal Code

DK-2650

Country

Denmark

12. IPD Sharing Statement

Citations:

PubMed Identifier

26000324

Citation

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.

Results Reference

result

PubMed Identifier

33332761

Citation

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.

Results Reference

derived

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

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