Safety, Tolerability, Ascending Dose and Dose Frequency Study of rhHNS Via an IDDD in MPS IIIA Patients

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier:
NCT01155778
First received: June 24, 2010
Last updated: September 28, 2012
Last verified: September 2012
  Purpose

Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA. In these patients abnormal behaviors include, but are not limited to, aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average.

The purpose of this study is to determine the safety and tolerability of rhHNS via ascending doses administered via an a surgically implanted intrathecal drug delivery device (IDDD) intrathecal (IT) route once monthly for 6 months in patients with MPS IIIA.


Condition Intervention Phase
Sanfilippo Syndrome Type A (MPS IIIA)
Biological: Recombinant human heparan N-sulfatase
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Safety, Tolerability, Ascending Dose and Dose Frequency Study of Recombinant Human Heparan N-Sulfatase (rhHNS) Intrathecal Administration Via an Intrathecal Drug Delivery Device in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

Resource links provided by NLM:


Further study details as provided by Shire Human Genetic Therapies, Inc.:

Primary Outcome Measures:
  • Safety [ Time Frame: Duration of study-~9 months for each patient ] [ Designated as safety issue: Yes ]
    Measured by adverse events (by type and severity), changes in clinical laboratory testing , electrocardiograms, CSF chemistries, and anti-rhHNS antibodies.


Secondary Outcome Measures:
  • To determine (by dose group) the effects of IT administration of rhHNS, as measured by (1) change from baseline values, and (2) comparison to values obtained in a natural history study of untreated patients with MPS IIIA Surrogate Endpoint Trial [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    • Neurocognitive/behavioral tests
    • Gross and fine motor skills assessment
    • QoL
    • rhHNS levels, inflammatory cytokines, heparan sulfate levels (including derivatives) and biomarkers
    • MRI


Enrollment: 12
Study Start Date: June 2010
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Recombinant human heparan N-sulfatase
rhHNS, HGT-1410
Biological: Recombinant human heparan N-sulfatase
10 mg monthly via an IDDD
Other Name: rhHNS
Biological: Recombinant human heparan N-sulfatase
45 mg monthly via an IDDD
Other Name: rhHNS
Biological: Recombinant human heparan N-sulfatase
90 mg monthly via an IDDD
Other Name: rhHNS

Detailed Description:

Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes. MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase). In the absence of this enzyme, intermediates of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser accumulation outside the brain. MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 4.5 years for the majority of patients. Patients present a wide spectrum and severity of clinical symptoms. The central nervous system (CNS) is the most severely affected organ system in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and intellectual development. In addition, there are abnormal behaviors including but not limited to aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.Overall, individuals with MPS IIIA have a marked developmental delay and significantly reduced lifespan of 15 years of age on average.

No effective, disease-modifying therapies are currently approved as treatments for this devastating and disabling disease.

Shire Human Genetic Therapies (Shire HGT) is developing a sulfamidase enzyme replacement therapy (ERT)rhHNS for patients with MPS IIIA. rhHNS is being administered into the cerebrospinal fluid (CSF) via an surgically implanted intrathecal drug delivery device (IDDD), because when administered intravenously (IV) it does not cross the blood brain barrier (BBB).

This study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (10mg,45mg and 90mg monthly for 6 months) of rhHNS administered via an IDDD in patients with Sanfilippo syndrome Type A ages greater than or equal to 3 years of age.

Patients who have completed all study requirements in this study will be invited to participate in an open-label extension study that will be designed to evaluate long term safety and clinical outcomes of intrathecal administration of rhHNS.

  Eligibility

Ages Eligible for Study:   3 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study:

  • A documented deficiency in sulfamidase enzyme activity of greater than or equal to 10% of the lower limit of the normal range AND either
  • a normal enzyme activity level of at least 1 other sulfatase or 2 documented mutations

    •At least 3 years of age and have a developmental age above 1 year

  • Patients must be medically stable, in the opinion of the Investigator, 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 legal guardian must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

  • Significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments
  • MPS IIIA behavioral-related issues, as determined by the Investigator, that would preclude performance of study neurocognitive and developmental testing procedures.
  • Patient is pregnant, breast feeding, or is a female patient of childbearing potential who will not or cannot comply with the use of an acceptable method of birth control
  • The patient is blind and/or deaf.
  • The patient has any known or suspected hypersensitivity to anesthesia or is thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions.
  • The patient or the patient's family has a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
  • Complications resulting from prior lumbar punctures.
  • CNS shunt
  • Skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
  • History of poorly controlled seizure disorder.
  • Patient is currently receiving psychotropic or other medications
  • The patient cannot sustain absence from aspirin, non-steroidal medications, or medications that affect blood clotting within 1 week prior to a relevant study-related procedure or has ingested such medications within 1 week before any procedures in which any change in clotting activity would be deleterious.
  • The patient has received treatment with any investigational drug or a device intended as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently enrolled in another study that involves an investigational drug or device (screening through safety follow-up contact).
  • The patient has received a hematopoietic stem cell or bone marrow transplant.
  • The patient's parent(s), or patient's legal guardian(s) is/are unable to provide consent or the patient cannot provide assent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01155778

Locations
Netherlands
Emma Children's Hospital, Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
United Kingdom
St. Mary's Hospital
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Shire Human Genetic Therapies, Inc.
Investigators
Study Director: Patrick Haslett, M.D. Shire Human Genetic Therapies, Inc.
  More Information

No publications provided by Shire Human Genetic Therapies, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shire Human Genetic Therapies, Inc.
ClinicalTrials.gov Identifier: NCT01155778     History of Changes
Other Study ID Numbers: HGT-SAN-055, 2009-015984-15
Study First Received: June 24, 2010
Last Updated: September 28, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Shire Human Genetic Therapies, Inc.:
Sanfilippo Syndrome Type A (MPS IIIA)
Recombinant Human Heparan N-Sulfatase (rhHNS)
Lysosomal Storage Disease (LSD)
Intrathecal Drug Delivery Device (IDDD)

Additional relevant MeSH terms:
Mucopolysaccharidosis III
Syndrome
Carbohydrate Metabolism, Inborn Errors
Connective Tissue Diseases
Disease
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Metabolism, Inborn Errors
Mucinoses
Mucopolysaccharidoses
Pathologic Processes

ClinicalTrials.gov processed this record on October 20, 2014