Treatment of Metachromatic Leukodystrophy MedDRA version: 19.0 Level: PT Classification code 10067609 Term: Metachromatic leukodystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Code: HGT-1110
Pharmaceutical Form: Solution for injection
INN or Proposed INN: N/A
Current Sponsor code: HGT-1110
Other descriptive name: Recombinant Human Arylsulfatase A (rhASA,
Concentrati
Sponsors
Shire Human Genetics Therapies Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For Cohorts 1-4: 1. Confirmed diagnosis of metachromatic leukodystrophy by both: • Arylsulfatase A deficiency by assay in leukocytes AND • Elevated sulfatide in urine 2. Appearance of the first symptoms of disease at or before 30 months of age. For Cohorts 1-3 only: 3. Ambulatory at the time of screening. The minimum level of function required to meet this criterion is defined as the ability to walk forward 10 steps with one hand held. 4. The patient is less than 12 years of age at the time of screening. For Cohorts 4 only: 3.1 Minimum motor function requirements: a. A total GMFM-88 (percent) score >= 40 at the screening examination and a total GMFM-88 (percent) score >=35 at the baseline examination AND b. GMFM-88 Dimension E: Walking, Running & Jumping, item 68 ("walk forward 10 steps with one hand held") score of at least 1 "initiates" at the screeening and baseline examinations (if applicable). 4.1 The patient is less than 8 years of age at the time of screening For Cohorts 1-4: 5. Neurological signs of MLD must be present at the screening examination. 6. The patient and his/her parent/representative(s) must have the ability to comply with the clinical protocol. 7. Patient’s parent(s) or legally authorized representative(s) must provide written informed consent prior to performing any study-related activities. Study-related activities are any procedures that would not have been performed during normal management of the patient. Are the trial subjects under 18? yes Number of subjects for this age range: 24 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Patients will be excluded from the study if there is evidence or history of any of the following criteria at screening: For Cohorts 1-4: 1. History of hematopoietic stem cell transplantation. 2. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions. 3. Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial. 4. The patient is enrolled in another clinical study that involves the use of any investigational product (drug or device) other than HGT-1110 or the IDDD used in this study within 30 days prior to study enrollment or at any time during the study. 5. The patient is pregnant or breastfeeding. 6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S IDDD Instructions for Use, including: a The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A- PORT Mini S device. b The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access Port, as judged by the Investigator. c The patient has a known or suspected local or general infection. d The patient is at risk of abnormal bleeding due to a medical condition or therapy. e The patient has one or more spinal abnormalities that could complicate safe implantation or fixation. f The patient has a functioning CSF shunt device. g The patient has shown an intolerance to an implanted device.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Every other week up to week 42 (AEs, vital signs, CSF analysis) Once a month (serum chemistry, anti-HGT-1110 Abs, hematology) Screening and Week 40 (12-lead ECG);Main Objective: Cohorts 1-3: to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks in children with metachromatic leukodystrophy Cohort 4: to determine the safety of HGT-1110 produced with a revised drug substance manufacturing process administered by IT injection for 38 weeks in children with MLD.;Secondary Objective: • To evaluate the effects of IT administration of HGT-1110 on gross motor function • To evaluate the effects of IT administration of HGT-1110 on the ability to swallow • To evaluate the effects of IT administration of HGT-1110 on nerve conduction capabilities • To evaluate the effects of IT administration of HGT 1110 on adaptive behavior • To evaluate the effects of IT administration of HGT 1110 on health status and the ability to carry out activities of daily life • To assess single and repeated-dose pharmacokinetics of HGT-1110 in serum • To assess concentrations of HGT-1110 in cerebrospinal fluid ;Primary end point(s): Safety will be measured by the following endpoints: • Reporting of treatment emergent adverse events • Change from baseline in clinical laboratory testing (serum chemistry including liver function tests, hematology, and urinalysis) • Change from baseline in 12–lead electrocardiograms, vital signs, physical examinations, and CSF chemistry (including cell counts, glucose, and protein) • Determination of the presence of anti-HGT 1110 antibodies in CSF and/or serum | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of this study are the following: • Change from baseline in motor function using the GMFM-88 total score (percent) • Change from baseline in the ability to swallow as measured by the Functional Endoscopic Evaluation of Swallowing (FEES) • Change from baseline in nerve conduction as measured by the electroneurography (ENG) assessments of NCV, compound motor action potential (CMAP), amplitude (AMP), and distal latency (DL) • Change from baseline in the adaptive behavior composite standard score as measured by the Vinelan Adaptive Behavior Scales, Second Edition (VABS II) • Change from baseline in the domain specific Caregiver Observed MLD Functioning and Outcomes Reporting Tool (COMFORT) scores • Single and repeated-dose pharmacokinetic (PK) parameter estimates for HGT 1110 in serum • Concentrations of HGT-1110 in CSF at selected time points after single and repeated investigational drug product administration ;Timepoint(s) of evaluation of this end point: GMFM: Assessed at 0, 16, 28 and 40 weeks ((For cohort 4: also assessed at screening. The week 0 [baseline] assessment must be performed to confirm eligibility before device implantation or first dose administration, whichever occurs first ). FEES: Assessed at 0, 16, 28 and 40 weeks ENG studies : Assessed at 0, 16, 28 and 40 weeks VABS-II: Assessed at 0, 16, 28 and 40 weeks COMFORT: Assessed at 0, 16, 28 and 40 weeks Serum PK: Assessed on Week 0 and Week 38. Blood will be drawn for pharmacokinetic assessments within 1 hour prior to IT injection and then at 0.5, 1, 2, 4, 8, 12, 24 and 48 hours following completion of IT injection. CSF analysis: Assessed every other week for 40 weeks | — |
Countries
Australia, Brazil, Denmark, France, Germany, Japan
Contacts
Public ContactMelanie Ivarsson
Shire Human Genetic Therapies Inc.
Outcome results
None listed