Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD)

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT01510028
• Date of registration: 14/12/2011
• Prospective Registration: Yes
• Primary sponsor: Shire
• Public title: Multicenter Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy (MLD) IDEAMLD
• Scientific title: A Phase I/II Multicenter Open-label Dose Escalation Study of HGT-1110 Administered Intrathecally in Children With Metachromatic Leukodystrophy
• Date of first enrolment: February 2, 2012
• Target sample size: 24
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT01510028
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Argentina, Australia, Brazil, Denmark, France, Germany, Japan

Contacts

• Name: Study Director
• Affiliation: Shire

Key inclusion & exclusion 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.



Age minimum: N/A
Age maximum: 12 Years
Gender: All

Health Condition(s) or Problem(s) studied

Metachromatic Leukodystrophy (MLD)

Intervention(s)

Biological: Recombinant human arylsulfatase A

Primary Outcome(s)

Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [Time Frame: From start of study treatment up to Week 40]

Number of Participants With Cerebrospinal Fluid (CSF) Chemistry Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [Time Frame: From start of study treatment up to Week 40]

Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity [Time Frame: From start of study treatment up to Week 42]

Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [Time Frame: From start of study treatment up to Week 40]

Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Treatment Emergent Adverse Events (TEAE) [Time Frame: From start of study treatment up to Week 40]

Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs) [Time Frame: From start of study treatment up to Week 40]

Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum [Time Frame: Baseline up to Week 40]

Secondary Outcome(s)

Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of SHP611 [Time Frame: 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]

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Distal Latency at Week 40 [Time Frame: Baseline, Week 40]

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40 [Time Frame: Week 40]

Volume of Distribution (Vz/F) After Intrathecal Administration of SHP611 [Time Frame: 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]

Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-last) of SHP611 [Time Frame: 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]

Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of SHP611 [Time Frame: 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]

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Aspiration Risk at Week 40 [Time Frame: Week 40]

Concentration of SHP611 in Cerebrospinal Fluid [Time Frame: Baseline, 4, 8, 12, 16, 20, 24, 28, 32, 36, and 40 weeks]

Maximum Observed Serum Concentration (Cmax) of SHP611 [Time Frame: 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]

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Nerve Conduction Velocity at Week 40 [Time Frame: Baseline, Week 40]

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40 [Time Frame: Week 40]

Terminal Elimination Half Life (t1/2) of SHP611 [Time Frame: 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]

Total Body Clearance (CL/F) After Intrathecal Administration of SHP611 [Time Frame: 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]

Change From Baseline in Adaptive Behavior Composite Standard Score as Measured by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Week 40 [Time Frame: Baseline, Week 40]

Change From Baseline in Domain-specific Caregiver Observed Metachromatic Leukodystrophy (MLD) Functioning and Outcomes Reporting Tool (COMFORT) Scores at Week 40 [Time Frame: Baseline, Week 40]

Time to Reach Maximum Observed Drug Concentration (Tmax) of SHP611 in Plasma [Time Frame: 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]

Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40 [Time Frame: Baseline, Week 40]

First Order Rate Constant (Lambda z) Associated With the Terminal (Log-linear) Portion of the Curve for SHP611 [Time Frame: 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]

Number of Participants With Change in Nerve Conduction as Measured by Electroneurography (ENG) Assessments by Categorized Amplitude Values at Week 40 [Time Frame: Baseline, Week 40]

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40 [Time Frame: Week 40]

Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40 [Time Frame: Week 40]

Secondary ID(s)

2011-002044-28

HGT-MLD-070

U1111-1153-1422

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 15/10/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT01510028