Late Infantile Metachromatic Leukodystrophy
Conditions
Keywords
Metazym, Late infantile, Metachromatic leukodystrophy, Long-term safety
Brief summary
This is a single center, open-label study of patients with late infantile MLD. All patients were previous treated 26 weeks in the phase I trial (EudraCT number: 2006-005341-11, NCT00418561). All patients will be offered continuing treatment in this study and will in this protocol receive 13 infusions, whereby the patients total have had 27 infusions of Metazym. One infusion will be given every other week. After a total of 52 weeks of treatment the subjects will continue treatment in a compassionate use protocol. Safety (AE/SAE) will be monitored at every visit.
Interventions
BIOLOGICALRecombinant human Arylsulfatase A (rhASA)
intravenous infusion, every other week for 26 weeks
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 5 Years
Healthy volunteers
No
Inclusion criteria
The patients from the Phase I trial must meet the following criteria to be enrolled in the study. * 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 subject and his/her guardian(s) must have the ability to comply with the clinical protocol
Exclusion criteria
* Spasticity so severe to inhibit transportation * Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition that, in the opinion of the Investigator, would preclude participation in the trial * 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 other than rhASA within 30 days prior to study enrolment or currently enrolled in another study which involves clinical investigations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relative Changes (%) in Gross Motor Function Measurement (GMFM) | Baseline, 52 Weeks | Change (percent change) in GMFM is measured from baseline to end of study (Week 52). GMFM is measured using GMFM-88. The GMFM-88 item scores can be summed to calculate a total GMFM-88 score. For each GMFM-88 item, the score is between 0 (minimal) to 3 (maximum). The total GMFM-88 score is between 0 (minimal) to 264 (maximum). Relative changes in GMFM are calculated as percentage change from baseline divided by the age difference in months between first and last visit. The GMFM score decreases over time, which, indicates that the disease worsened over time. Score over time (SOT), data mentioned over mean represents the adjusted mean. |
| Relative Change in Mullen's Scales of Early Learning | Baseline, 52 Weeks | Changes in Mullen's Scales of Early Learning are measured from baseline to end of study (Week 52) using Mullen's Scales of Early Learning. T scores, percentile ranks, and age equivalents can be computed for the four scales separately (visual reception, fine motor, expressive language, and receptive language). Relative change is calculated as percentage change from baseline divided by the age-difference in months between first and last visit. When Mullen's score decreases over time, it indicates the disease worsened over time. Data mentioned over mean represents the adjusted mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrospinal Fluid (CSF) Sulfatide | Baseline, 52 Weeks | Changes in CSF sulfatide from baseline to end of study (Week 52). Data mentioned over mean represents the adjusted mean. |
Countries
Denmark
Participant flow
Recruitment details
Children with an established diagnosis of late metachromatic leukodystrophy (MLD) due to arylsulfatase A (ASA) deficiency were recruited.
Pre-assignment details
All participants that completed study recombinant human arylsulfatase A (rhASA-01) (NCT00418561) except 1 participant who did not complete (at week 18) the rhASA-01 (NCT00418561) participated in HGT-MLD-048/rhASA-03 (NCT00633139).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants received a single dose of rhASA at 25 U/kg IV infusion in rhASA-01 (NCT00418561) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52. | 4 |
| Cohort 2 Participants received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52. | 5 |
| Cohort 3 Participants received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52. | 4 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Non compliance | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 1 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 4 Participants | 4 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 41.80 months STANDARD_DEVIATION 10.13 | 30.75 months STANDARD_DEVIATION 7.27 | 36.25 months STANDARD_DEVIATION 9.32 | 36.69 months STANDARD_DEVIATION 9.59 |
| Region of Enrollment Denmark | 5 Participants | 4 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 2 / 4 | 2 / 5 | 3 / 4 |
Outcome results
Primary
Relative Change in Mullen's Scales of Early Learning
Changes in Mullen's Scales of Early Learning are measured from baseline to end of study (Week 52) using Mullen's Scales of Early Learning. T scores, percentile ranks, and age equivalents can be computed for the four scales separately (visual reception, fine motor, expressive language, and receptive language). Relative change is calculated as percentage change from baseline divided by the age-difference in months between first and last visit. When Mullen's score decreases over time, it indicates the disease worsened over time. Data mentioned over mean represents the adjusted mean.
Time frame: Baseline, 52 Weeks
Population: ITT population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Relative Change in Mullen's Scales of Early Learning | -2.82 Relative % change in Mullen's SOT |
| Cohort 2 | Relative Change in Mullen's Scales of Early Learning | -2.97 Relative % change in Mullen's SOT |
| Cohort 3 | Relative Change in Mullen's Scales of Early Learning | -6.98 Relative % change in Mullen's SOT |
p-value: 0.275ANCOVA
Primary
Relative Changes (%) in Gross Motor Function Measurement (GMFM)
Change (percent change) in GMFM is measured from baseline to end of study (Week 52). GMFM is measured using GMFM-88. The GMFM-88 item scores can be summed to calculate a total GMFM-88 score. For each GMFM-88 item, the score is between 0 (minimal) to 3 (maximum). The total GMFM-88 score is between 0 (minimal) to 264 (maximum). Relative changes in GMFM are calculated as percentage change from baseline divided by the age difference in months between first and last visit. The GMFM score decreases over time, which, indicates that the disease worsened over time. Score over time (SOT), data mentioned over mean represents the adjusted mean.
Time frame: Baseline, 52 Weeks
Population: Intent to Treat (ITT) population included all the participants in the study.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Relative Changes (%) in Gross Motor Function Measurement (GMFM) | -2.98 Relative % change in total GMFM-88 SOT |
| Cohort 2 | Relative Changes (%) in Gross Motor Function Measurement (GMFM) | -5.42 Relative % change in total GMFM-88 SOT |
| Cohort 3 | Relative Changes (%) in Gross Motor Function Measurement (GMFM) | -5.28 Relative % change in total GMFM-88 SOT |
p-value: 0.4013ANCOVA
Secondary
Change in Cerebrospinal Fluid (CSF) Sulfatide
Changes in CSF sulfatide from baseline to end of study (Week 52). Data mentioned over mean represents the adjusted mean.
Time frame: Baseline, 52 Weeks
Population: ITT population
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Change in Cerebrospinal Fluid (CSF) Sulfatide | 8.60 %change in CSF sulfatide |
| Cohort 2 | Change in Cerebrospinal Fluid (CSF) Sulfatide | -1.53 %change in CSF sulfatide |
| Cohort 3 | Change in Cerebrospinal Fluid (CSF) Sulfatide | -2.77 %change in CSF sulfatide |
p-value: 0.1363ANCOVA