Late Infantile Metachromatic Leukodystrophy
Conditions
Keywords
Metazyme, Late Infantile Metachromatic Leukodystrophy
Brief summary
This is a multi-center, open-label, extension study of patients with late infantile MLD who have previously completed clinical study HGT-MLD-048 (NCT00633139), defined as the completion of all Week 52 procedures. This group of patients will be offered ongoing treatment with HGT-1111 in this protocol. One infusion will be given every other week until the product is commercially available, the patient discontinues, or the study is terminated by the Sponsor, provided no safety issues have emerged.
Detailed description
The primary objective of this study is to provide ongoing treatment of HGT-1111 to patients who have completed study HGT-MLD-048 (previously study rhASA-03 - NCT00633139) until HGT-1111 is commercially available or the study is terminated by the Sponsor, provided no safety concerns have emerged. The secondary objective of this study is to monitor disease progression and the safety profile of HGT-1111 administered to patients who have completed study HGT-MLD-048 (NCT00633139).
Interventions
DRUGHGT-1111
Patients currently dosed with 100 U/kg or 200 U/kg will continue this treatment. Patients dosed with 50 U/kg will be equally randomized to treatment on 100 U/kg or 200 U/kg. The dose will be adjusted every 6-week to account for changes in body weight.The infusion length will be dependent on the dose. Infusion of 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.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 6 Years
Healthy volunteers
No
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. Completion of study HGT-MLD-048 (NCT00633139) 3. The subject and his/her guardian(s) must have the ability to comply with the protocol
Exclusion criteria
1. Spasticity so severe to inhibit transportation 2. 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 3. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days of Exposure to HGT-1111 | Baseline until end of study (Week 139) | End of study was defined as until HGT-1111 was commercially available, the participant's participation was discontinued, or the study was terminated by the Sponsor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Level of Cerebrospinal Fluid (CSF) Sulfatide | Baseline until end of study (Week 139) | Level of CSF sulfatide measured at 6-month intervals in HGT-MLD-049 (NCT00681811). |
| Level of White Matter Metabolites | Baseline until end of study (Week 139) | Level of white matter metabolites \[N-acetyl Aspartate (NAA)\] measured at 6-month intervals in HGT-MLD-049 (NCT00681811). |
| Score of Gross Motor Function Measurement (GMFM) | Baseline until end of study (Week 139) | Gross motor function was measured using GMFM-88 at 6-month intervals. The GMFM-88 item scores were 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) to 264 (maximum). Decrease in GMFM score indicates disease progression. |
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 who completed Study HGT-MLD-048 (NCT00633139) participated in this study.
Participants by arm
| Arm | Count |
|---|---|
| 100 U/kg HGT1111 Participants received 100 U/kg of HGT1111 IV infusion every other week. | 6 |
| 200 U/kg Participants received 200 U/kg of HGT1111 IV infusion every other week. | 5 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Non-compliance | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | 200 U/kg | 100 U/kg HGT1111 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 49.99 months STANDARD_DEVIATION 8.752 | 53.14 months STANDARD_DEVIATION 10.526 | 51.71 months STANDARD_DEVIATION 9.42 |
| Region of Enrollment Denmark | 5 Participants | 6 Participants | 11 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 5 / 5 |
| serious Total, serious adverse events | 2 / 6 | 4 / 5 |
Outcome results
Primary
Days of Exposure to HGT-1111
End of study was defined as until HGT-1111 was commercially available, the participant's participation was discontinued, or the study was terminated by the Sponsor.
Time frame: Baseline until end of study (Week 139)
Population: Safety population was defined as all enrolled participants who received at least one study infusion (or any portion of a dose) of HGT-1111.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 U/kg HGT-1111 (Month 6) | Days of Exposure to HGT-1111 | 644.7 Days | Standard Deviation 276.11 |
| 200 U/kg HGT-1111 (Month 6) | Days of Exposure to HGT-1111 | 544.8 Days | Standard Deviation 397.27 |
Secondary
Level of Cerebrospinal Fluid (CSF) Sulfatide
Level of CSF sulfatide measured at 6-month intervals in HGT-MLD-049 (NCT00681811).
Time frame: Baseline until end of study (Week 139)
Population: Safety population. Number of participants analysed signifies participants who were evaluable for the respective arms under this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 U/kg HGT-1111 (Month 6) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 685.0 nanomole per liter (nmol/L) | Standard Deviation 522.79 |
| 200 U/kg HGT-1111 (Month 6) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 732.5 nanomole per liter (nmol/L) | Standard Deviation 545.06 |
| 100 U/kg HGT-1111 (Month 12) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 745.0 nanomole per liter (nmol/L) | Standard Deviation 525.12 |
| 200 U/kg HGT-1111 (Month 12) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 1150.0 nanomole per liter (nmol/L) | Standard Deviation 676.39 |
| 100 U/kg HGT-1111 (Month 18) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 700.0 nanomole per liter (nmol/L) | Standard Deviation 526.78 |
| 200 U/kg HGT-1111 (Month 18) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 850.0 nanomole per liter (nmol/L) | Standard Deviation 491.81 |
| 100 U/kg HGT-1111 (Month 24) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 900.0 nanomole per liter (nmol/L) | — |
| 200 U/kg HGT-1111 (Month 24) | Level of Cerebrospinal Fluid (CSF) Sulfatide | 837.5 nanomole per liter (nmol/L) | Standard Deviation 441.94 |
Secondary
Level of White Matter Metabolites
Level of white matter metabolites \[N-acetyl Aspartate (NAA)\] measured at 6-month intervals in HGT-MLD-049 (NCT00681811).
Time frame: Baseline until end of study (Week 139)
Population: Safety population. Number of participants analysed signifies participants who were evaluable for the respective arms under this outcome measure. No participants were analysed after Month 18, hence, data were not available after Month 18.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 U/kg HGT-1111 (Month 6) | Level of White Matter Metabolites | 0.528 nmol/L | Standard Deviation 0.176 |
| 200 U/kg HGT-1111 (Month 6) | Level of White Matter Metabolites | 0.385 nmol/L | Standard Deviation 0.237 |
| 100 U/kg HGT-1111 (Month 12) | Level of White Matter Metabolites | 0.598 nmol/L | Standard Deviation 0.208 |
| 200 U/kg HGT-1111 (Month 12) | Level of White Matter Metabolites | 0.470 nmol/L | Standard Deviation 0.198 |
| 100 U/kg HGT-1111 (Month 18) | Level of White Matter Metabolites | 0.510 nmol/L | Standard Deviation 0.141 |
| 200 U/kg HGT-1111 (Month 18) | Level of White Matter Metabolites | 0.805 nmol/L | Standard Deviation 0.445 |
Secondary
Score of Gross Motor Function Measurement (GMFM)
Gross motor function was measured using GMFM-88 at 6-month intervals. The GMFM-88 item scores were 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) to 264 (maximum). Decrease in GMFM score indicates disease progression.
Time frame: Baseline until end of study (Week 139)
Population: Safety population. Number of participants analysed signifies participants who were evaluable for the respective arms under this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 100 U/kg HGT-1111 (Month 6) | Score of Gross Motor Function Measurement (GMFM) | 16.8 scores on a scale | Standard Deviation 11.3 |
| 200 U/kg HGT-1111 (Month 6) | Score of Gross Motor Function Measurement (GMFM) | 9.2 scores on a scale | Standard Deviation 11.71 |
| 100 U/kg HGT-1111 (Month 12) | Score of Gross Motor Function Measurement (GMFM) | 15.6 scores on a scale | Standard Deviation 15.84 |
| 200 U/kg HGT-1111 (Month 12) | Score of Gross Motor Function Measurement (GMFM) | 8.7 scores on a scale | Standard Deviation 9.29 |
| 100 U/kg HGT-1111 (Month 18) | Score of Gross Motor Function Measurement (GMFM) | 16.8 scores on a scale | Standard Deviation 13.6 |
| 200 U/kg HGT-1111 (Month 18) | Score of Gross Motor Function Measurement (GMFM) | 9.0 scores on a scale | Standard Deviation 5.66 |
| 100 U/kg HGT-1111 (Month 24) | Score of Gross Motor Function Measurement (GMFM) | 14.5 scores on a scale | Standard Deviation 10.61 |
| 200 U/kg HGT-1111 (Month 24) | Score of Gross Motor Function Measurement (GMFM) | 13.0 scores on a scale | Standard Deviation 11.31 |