Clinical trial NCT01510028: Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)
Official title: A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metachromatic Leukodystrophy (MLD)
Keywords: Intrathecal Drug Delivery Device (IDDD)
Recombinant human arylsulfatase A (rhASA)
Metachromatic Leukodystrophy (MLD)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2012-01-13
Enrollment: 24
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety of ascending doses of HGT-1110 administered by intrathecal (IT) injection for 38 weeks (20 injections) in children with metachromatic leukodystrophy (MLD).

Detailed description: Metachromatic leukodystrophy (MLD) is an inherited, autosomal recessive disorder of lipid metabolism characterized by deficient activity of the lysosomal enzyme, arylsulfatase A (ASA). MLD is a rare disease that occurs in most parts of the world. The estimated overall incidence of the disease in the western world is approximately 1 in 100,000 live births that varies by geographic location. There are no approved therapies for MLD.

This is a multicenter, open-label, dose-escalation study designed to evaluate the safety of up to 3 dose levels (10, 30, or 100 mg) of HGT-1110 administered via an intrathecal drug delivery device (IDDD) every other week (EOW) for a total of 38 weeks (20 injections, Weeks 0 to 38) to children with MLD. The study also includes the assessment of HGT-1110 drug product produced with a revised drug substance manufacturing process (referred to as Process B) in a fourth cohort (Cohort 4). Approximately 24 patients will be enrolled and will receive treatment of HGT-1110. Patients will be sequentially enrolled into 4 dose cohorts, approximately 6 patients each. Patient enrollment will be staggered in this study to facilitate adequate safety monitoring per dose cohort.

Eligibility criteria: Inclusion

For Cohorts 1-4:

1. Confirmed diagnosis of metachromatic leukodystrophy by both:

   * Arylsulfatase A (ASA) 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 Cohort 4 only:

   3.1 Minimum motor function requirements:
   1. A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND
   2. 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 screening 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.

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 (HSCT).
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 (IFU), including:

1. The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
2. 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.
3. The patient has a known or suspected local or general infection.
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy.
5. The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
6. The patient has a functioning CSF shunt device.
7. The patient has shown an intolerance to an implanted device.

Primary outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity
timeFrame: From start of study treatment up to Week 42
measure: Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study treatment up to Week 40
measure: Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study treatment up to Week 40
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study treatment up to Week 40
measure: Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE)
timeFrame: From start of study treatment up to Week 40
measure: Number of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study treatment up to Week 40
measure: Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum
timeFrame: Baseline up to Week 40
Secondary outcomes:
measure: Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40
timeFrame: Baseline, Week 40
measure: Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40
timeFrame: Week 40
measure: Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40
timeFrame: Week 40
measure: Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40
timeFrame: Week 40
measure: Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40
timeFrame: Week 40
measure: Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40
timeFrame: Week 40
measure: Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40
timeFrame: Baseline, Week 40
measure: Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40
timeFrame: Baseline, Week 40
measure: Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40
timeFrame: Baseline, Week 40
measure: Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40
timeFrame: Baseline, Week 40
measure: Maximum Observed Serum Concentration (Cmax) of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Terminal Elimination Half Life (t1/2) of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Total Body Clearance (CL/F) After Intrathecal Administration of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611
timeFrame: Baseline: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose; Week 38: Predose, 0.5, 1, 2, 4, 8, 12, 24, 48 hours postdose
measure: Concentration of SHP611 in Cerebrospinal Fluid
timeFrame: Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
city: København
country: Denmark
facility: Rigshospitalet
city: Le Kremlin Bicetre
country: France
facility: Hopital de Bicetre
state: Ile-de-France
city: Tubingen
country: Germany
facility: Center for Pediatric Clinical Studies
state: Baden-Wuerttemberg
city: Suita
country: Japan
facility: Osaka University Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: I Dali C, Sevin C, Krageloh-Mann I, Giugliani R, Sakai N, Wu J, Wasilewski M. Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial. Mol Genet Metab. 2020 Sep-Oct;131(1-2):235-244. doi: 10.1016/j.ymgme.2020.07.002. Epub 2020 Jul 16.