Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of rhHNS Administration Via an IDDD in Pediatric Patients With Early Stage MPS IIIA Disease

NCT02060526 | Completed Phase 2 Results DMC

• 2 other identifiers: HGT-SAN-0932013-003450-24
• Study Type: interventional
• Target: 21
• Locations: 8 countries
• Sites: 10

Brief Summary

Sanfilippo syndrome Type A, or Mucopolysaccharidosis (MPS) IIIA, is a rare lysosomal storage disease caused by deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, there is an accumulation of the glycosaminoglycan, heparan sulfate, resulting in progressive neurodegeneration. Symptoms are usually first noted in the 1st or 2nd year of life, although definitive diagnosis is often delayed, with an average age of diagnosis of 4.5 years. The disease is characterized by developmental delays initially, followed by neurological developmental arrest, then regression. These developmental deficits are typically associated with severe behavioral disturbances. Patients have a significantly reduced lifespan, with few surviving beyond the 2nd or 3rd decade. The purpose of this study is to evaluate the safety and efficacy of recombinant human heparan-N-sulfatase (rhHNS) in pediatric patients with Early Stage Mucopolysaccharidosis Type III A Disease.

Conditions

Sanfilippo Syndrome

Keywords

sulfoglucosamine sulfohydrolase (SGSH); recombinant human heparan N-sulfatase (rhHNS); Hunter's Syndrome; Shire HGT; Lysosomal Storage Disease (LSD); Sanfilippo Syndrome Type A (Sanfilippo A); enzyme replacement therapy (ERT)

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Overall Response Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III)

  The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which was computed as a ratio and expressed as a percentage using the age equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range: 0, 100). The BSID--III DQ score is based on the cognitive domain. A positive value indicates improvement in health and cognition. Overall response was the maximum decline in the DQ of 10 points or less over 48 weeks. Number of participants with the overall response were reported here.

  Baseline (Week 0) up to Week 48

Secondary Outcomes (10)

• Number of Participants With Serious Adverse Events (SAE)

  Baseline (Week 0) up to Week 52

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

  Baseline (Week 0) up to Week 52

• Number of Participants With Positive Anti-recombinant Human Heparan-N-Sulfatase (rhHNS) Antibody in Serum at Week 48

  Baseline (Week 0) up to Week 48

• Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score at Week 48

  Baseline (Week 0), Week 48

• Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Third Edition (BSID-III) at Week 48

  Baseline (Week 0), Week 48

Study Arms (3)

45 mg Q2W

ACTIVE COMPARATOR

rhHNS 45 mg administered intrathecally Q2W (once every 2 weeks ie, every 14 days), for 48 weeks via the surgically implanted IDDD (or LP)

Drug: Recombinant human heparan N-sulfatase [rhHNS]

45 mg Q4W

ACTIVE COMPARATOR

rhHNS 45 mg administered intrathecally Q4W (once every 4 weeks ie, every 28 days), for 48 weeks via the surgically implanted IDDD (or LP)

Drug: Recombinant human heparan N-sulfatase [rhHNS]

Placebo

PLACEBO COMPARATOR

The comparator group will receive no treatment with rhHNS.

Drug: Recombinant human heparan N-sulfatase [rhHNS]

Interventions

Recombinant human heparan N-sulfatase [rhHNS] DRUG

Recombinant human heparan N-sulfatase \[rhHNS\]

45 mg Q2W; 45 mg Q4W; Placebo

Eligibility Criteria

• Age: 12 Months - 48 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Each patient must meet the following criteria to be enrolled in this study.
• Documented MPS IIIA diagnosis
• Age ≥12 months and ≤48 months
• The patient has a DQ score ≥60%
• The patient is medically stable, in the opinion of the Investigator, and able to accommodate the protocol requirements, including travel, assessments, and IDDD surgery, without placing an undue burden on the patient/patient's family
• The patient's parent(s) or legally authorized representative(s) must have voluntarily signed and dated an Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's parent(s), or legally authorized representative(s). Consent of the patient's parent(s) or legally authorized representative(s) must be obtained prior to the start of any study procedures.

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from the study.
• The presence of significant non-MPS IIIA related CNS impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator.
• The presence of at least one S298P mutation in SGSH, associated with attenuated disease OR there is documentation of the S298P mutation in a sibling affected by MPS IIIA, provided parental consent is obtained to use this information.
• The presence of relatively attenuated MPS IIIA disease in an older sibling, defined as preservation of any speech beyond the age of 10 years.
• Visual or hearing impairment sufficient, in the clinical judgment of the investigator, to preclude cooperation with neurodevelopmental testing. Use of hearing aids is permitted.
• In the opinion of the Investigator, the patient is assessed as having an unacceptably high risk for anesthesia due to airway compromise, drug hypersensitivity, or other conditions (such as neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns).
• The patient has a history of poorly controlled seizure disorder.
• The patient is currently receiving psychotropic or other medications, which in the Investigator's opinion would be likely to substantially confound test results.
• The patient has a history of bleeding disorder or is unable to abstain from medications that, in the opinion of the investigator, place them at risk of bleeding following surgery or LP.
• The patient participated in a clinical trial of another investigational medicinal product, within the 30 days prior to the study (or within 5 elimination half lives of the investigational product), or is currently enrolled in another study that involves an investigational drug or device. NOTE: Nutritional supplements, including genistein are permitted if they are taken or administered outside the context of a formal investigation.
• The patient has received a hematopoietic stem cell or bone marrow transplant, or gene therapy.
• The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S-IDDD
• The patient's parent(s) or patient's legally authorized representative(s) is/are unable to understand the nature, scope, and possible consequences of the study, or do/does not agree to comply with the protocol defined schedule of assessments.
• The patient is unable to comply with the protocol (eg, has a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, or otherwise unlikely to complete the study) or is, in the opinion of the Investigator, otherwise unsuited for the study.
• The patient has any item (braces, tattoos, etc.) which would exclude the patient from being able to undergo MRI according to local Institutional Policy, or the patient has any other situation that would exclude the patient from undergoing any other procedure required in this study.

Sponsors & Collaborators

• Shire: lead

Study Sites (10)

Los Angeles Biomedical Research

Torrance, California, 90502, United States

Location

University of Minnesota Department of Pediatrics

Minneapolis, Minnesota, 55455, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27514, United States

Location

Hospital Universitario Austral A Unidad de Investigacion

Buenos Aires, Argentina

Location

Chu Bicetre

Le Kremlin-Bicêtre, Paris, 94270, France

Location

Universitätsklinikum Hamburg Eppendorf

Hamburg, 20246, Germany

Location

U.O.S Malattie Metaboliche Rare Clinical Pediatrica

Monza, Italy

Location

Academisch Medisch Centrum

Amsterdam, 22660, Netherlands

Location

Hospital Vall D'Hebron

Barcelona, 08035, Spain

Location

Great Ormond Street Hospital

London, WC1N 3JH, United Kingdom

Location

Related Publications (1)

• Wijburg FA, Whitley CB, Muenzer J, Gasperini S, Del Toro M, Muschol N, Cleary M, Sevin C, Shapiro E, Bhargava P, Kerr D, Alexanderian D. Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Mol Genet Metab. 2019 Feb;126(2):121-130. doi: 10.1016/j.ymgme.2018.10.006. Epub 2018 Oct 24.

  PMID: 30528227 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis III; Mucopolysaccharidosis II; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System

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 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2014
• First Posted: February 12, 2014
• Study Start: February 26, 2014
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: June 8, 2021
• Results First Posted: March 3, 2017

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

ES (1); FR (1); GB (1); IT (1); AR (1); NL (1); DE (1); US (3)