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

NCT01510028 | Completed Phase 1 Results DMC

• 3 other identifiers: HGT-MLD-0702011-002044-28U1111-1153-1422
• Study Type: interventional
• Target: 24
• Locations: 5 countries
• Sites: 5

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).

Conditions

Metachromatic Leukodystrophy (MLD)

Keywords

Intrathecal Drug Delivery Device (IDDD); Recombinant human arylsulfatase A (rhASA); Metachromatic Leukodystrophy (MLD)

Outcome Measures

Primary Outcomes (7)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Type and Severity

  An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Drug-related and device-related types of TEAEs were analyzed and reported. The severity of AEs was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 grading scale. Severity of all AEs or SAEs was recorded as grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or fatal. Here SDI refers to surgical device implantation.

  From start of study treatment up to Week 42

• Number of Participants With Clinical Laboratory Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

  Clinical laboratory test included serum chemistry, hematology and urinalysis. Clinical laboratory abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

  From start of study treatment up to Week 40

• Number of Participants With Vital Sign Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

  Vital sign assessments included blood pressure, heart rate, respiratory rate and body temperature. Vital sign abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date. Vital sign abnormalities included pyrexia which was considered as TEAE and was reported.

  From start of study treatment up to Week 40

• Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as Treatment Emergent Adverse Events (TEAEs)

  12-lead ECG was recorded and measured with the participant in rested supine position for at least 10 minutes. ECG abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

  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)

  Complete physical examination included evaluation of the port and catheter track. Height or length and weight were recorded and used to calculate growth. Body weight and height measurements were used to calculate the body mass index (BMI). Head circumference was measured in uniform manner for all participants. Clinical significance was defined as any variation in physical findings that had medical relevance resulting in an alteration in medical care. Clinically significant abnormalities related to physical examination were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

  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)

  CSF chemistry assessments (including cell counts, glucose and protein) was measured. CSF chemistry abnormalities were recorded and reported as TEAE. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as all AEs that occurred at or after the first dose of the investigational product or device implant surgery (whichever occurred earlier) and through the last follow-up date.

  From start of study treatment up to Week 40

• Number of Participants With Positive Anti-SHP611 Antibodies in Cerebrospinal Fluid (CSF) and or Serum

  Number of participants with positive anti-SHP611 antibody results in serum and in CSF were reported. A participant was considered positive if they had at least 1 positive result during the study.

  Baseline up to Week 40

Secondary Outcomes (21)

• Change From Baseline in Motor Function Using Gross Motor Function Measure 88 (GMFM-88) Total Score at Week 40

  Baseline, Week 40

• Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing (FEES) for Texture Utilized at Week 40

  Week 40

• Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Laryngeal Penetration) at Week 40

  Week 40

• Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Feeding Assessment (Aspiration Through Vocal Cords) at Week 40

  Week 40

• Number of Participants With Shift in Functional Endoscopic Evaluation of Swallowing for Dose Residue Clear After Subsequent Swallowing at Week 40

  Week 40

Study Arms (4)

Cohort 1 (10 mg)

EXPERIMENTAL

6 patients treated with HGT-1110 10 mg EOW by IT injection

Biological: Recombinant human arylsulfatase A

Cohort 2 (30 mg)

EXPERIMENTAL

6 patients treated with HGT-1110 30 mg EOW by IT injection

Biological: Recombinant human arylsulfatase A

Cohort 3 (100 mg)

EXPERIMENTAL

6 patients treated with HGT-1110 100 mg EOW by IT injection

Biological: Recombinant human arylsulfatase A

Cohort 4 (100 mg)

EXPERIMENTAL

6 patients treated with HGT-1110 100 mg EOW by IT injection

Biological: Recombinant human arylsulfatase A

Interventions

Recombinant human arylsulfatase A BIOLOGICAL

6 patients treated with HGT-1110 EOW by IT injection

Also known as: HGT-1110, rhASA

Cohort 1 (10 mg); Cohort 2 (30 mg); Cohort 3 (100 mg); Cohort 4 (100 mg)

Eligibility Criteria

• Age: Up to 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• For Cohorts 1-4:
• Confirmed diagnosis of metachromatic leukodystrophy by both:
• Arylsulfatase A (ASA) deficiency by assay in leukocytes AND
• Elevated sulfatide in urine
• Appearance of the first symptoms of disease at or before 30 months of age.
• For Cohorts 1-3 only:
• 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.
• The patient is less than 12 years of age at the time of screening.
• For Cohort 4 only:
• Minimum motor function requirements:
• A total GMFM-88 (percent) score ≥40 at the screening examination and a total GMFM-88 (percent) score ≥35 at the baseline examination, AND
• 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).
• The patient is less than 8 years of age at the time of screening.
• For Cohorts 1-4:
• Neurological signs of MLD must be present at the screening examination.

You may not qualify if:

• 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:
• History of hematopoietic stem cell transplantation (HSCT).
• 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.
• Any other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial.
• 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.
• The patient is pregnant or breastfeeding.
• The patient has a condition that is contraindicated as described in the SOPH-A-PORT
• Mini S IDDD Instructions for Use (IFU), including:
• The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT Mini S device.
• 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.
• The patient has a known or suspected local or general infection.
• The patient is at risk of abnormal bleeding due to a medical condition or therapy.
• The patient has one or more spinal abnormalities that could complicate safe implantation or fixation.
• The patient has a functioning CSF shunt device.

Sponsors & Collaborators

• Shire: lead

Study Sites (5)

The Children's Hospital at Westmead

Westmead, 2145, Australia

Location

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Hopital de Bicetre

Le Kremlin-Bicêtre, Île-de-France Region, 94275, France

Location

Center for Pediatric Clinical Studies

Tübingen, Baden-Wurttemberg, 72076, Germany

Location

Osaka University Hospital

Suita, 565-0871, Japan

Location

Related Publications (1)

• 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.

  PMID: 32792226 DERIVED

MeSH Terms

Conditions

Leukodystrophy, Metachromatic

Condition Hierarchy (Ancestors)

Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 14, 2011
• First Posted: January 13, 2012
• Study Start: February 2, 2012
• Primary Completion: January 20, 2017
• Study Completion: January 20, 2017
• Last Updated: June 14, 2021
• Results First Posted: October 15, 2018

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); DK (1); JP (1); DE (1); FR (1)