Extension of Study HGT-SAN-055 Evaluating Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)

NCT01299727 | Terminated Phase 1 Results

• 2 other identifiers: HGT-SAN-0672010-021348-16
• Study Type: interventional
• Target: 12
• Locations: 2 countries
• Sites: 2

Brief Summary

Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a rare lysosomal storage disease (LSD) caused by loss in activity of 1 of 9 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 to 15 years of age on average. The purpose of this study is to collect long term safety and tolerability data in patients with MPS IIIA who previously received rhHNS in study HGT-SAN-055 (NCT01155778).

Conditions

Sanfilippo Syndrome

Keywords

Recombinant Human Heparan N-Sulfatase (rhHNS); Sanfilippo Syndrome Type A (MPS IIIA); Lysosomal storage disease (LSD); Mucopolysaccharidosis (MPS) III

Outcome Measures

Primary Outcomes (6)

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

  An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered study drug related. Treatment-emergent Adverse events (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (NCT01155778) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. TEAEs included participants with any AE, any drug-related AE, any surgery-related AE, any IDDD-related AE, and any IT administration process-related AE, any SAE, any serious drug-related AE.

  From start of study drug administration up to follow-up (Month 103)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity

  An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered study drug related. TEAEs were defined as all AEs from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (NCT01155778) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. Severity of an AE is determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities; Severe: Inability to carry out usual activities.

  From start of study drug administration up to follow-up (Month 103)

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

  Clinical laboratory assessments include hematology, serum chemistry including liver function tests, coagulation urinalysis and cerebrospinal fluid (CSF) were reported.

  From start of study drug administration up to follow-up (Month 103)

• Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as Treatment Emergent Adverse Events (TEAEs)

  Any change in ECG assessments which were deemed to be clinically significant findings and abnormalities were recorded as TEAEs.

  From start of study drug administration up to follow-up (Month 103)

• Number of Participants With Postive Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS)

  Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Participants with positive Anti-rhHNS antibody status in serum were reported.

  Month 103

• Number of Participants With Positive Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS)

  Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Participants with positive anti-rhHNS antibody in CSF were reported

  Month 103

Secondary Outcomes (7)

• Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID-III) at Month 103

  Baseline, Month 103

• Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID-III)/Kaufman Assessment Battery for Children Second Edition (KABC-II) Age-Equivalent Scores at Month 103

  Baseline, Month 103

• Change From Baseline in Developmental Quotient (DQ) Using Bayley Scales of Infant Development Third Edition (BSID-III) and Kaufman Assessment Battery for Children Second Edition (KABC-II) at Month 103

  Baseline, Month 103

• Change From Baseline in Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Month 103

  Baseline, Month 103

• Change From Baseline in Cerebrospinal Fluid (CSF) Total Heparan Sulfate Levels at Month 103

  Baseline, Month 103

Study Arms (3)

rhHNS-10 mg

EXPERIMENTAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Biological: rhHNS-10 mg

rhHNS-45 mg

EXPERIMENTAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Biological: rhHNS-45 mg

rhHNS-90 mg

EXPERIMENTAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Biological: rhHNS-90 mg

Interventions

rhHNS-10 mg BIOLOGICAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Also known as: Recombinant human heparan N-sulfatase

rhHNS-10 mg

rhHNS-45 mg BIOLOGICAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Also known as: Recombinant human heparan N-sulfatase

rhHNS-45 mg

rhHNS-90 mg BIOLOGICAL

Once per month via an Intrathecal Drug Delivery Device (IDDD) for a maximum of 8 years

Also known as: Recombinant human heparan N-sulfatase

rhHNS-90 mg

Eligibility Criteria

• Age: 3 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient must have completed Study HGT SAN 055 and the opinion of the investigator, has no safety or medical issues that contraindicate participation.
• The patient, patient's parent(s), or legally authorized representative(s) has voluntarily signed an Institutional Review Board / Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient's, the patient's, patient's parents or legally authorized representative's consent and patient's assent, as appropriate, must be obtained prior to any study specific procedures.
• The patient has received at least 5 of the 6 planned infusions of rhHNS in the HGT-SAN-055 study.
• Patients must be medically stable, in the opinion of the Investigator, to accommodate the protocol requirements, including travel, assessments, and IDDD surgery (if necessary for replacement purposes), without placing an undue burden on the patient/patient's family.

You may not qualify if:

• Subjects will be excluded from the study if there is evidence of any of the following criteria at screening or at anytime during the study:
• The patient has experienced an adverse reaction to study drug in Study HGT-SAN-55 that contraindicates further treatment with rhHNS.
• The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS drug product.
• The patient has significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific integrity or interpretation of study assessments, as determined by the Investigator.
• The patient has significant MPS IIIA behavioral-related issues, as determined by the Investigator, which would preclude performance of study neurocognitive and developmental testing procedures.
• The 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, such as condoms, barrier method, oral contraception, etc.
• 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 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 and the dose and regimen of which cannot be kept constant throughout the study.
• 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 (eg, device re-implantation if applicable), 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 (other than rhHNS) 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.

Sponsors & Collaborators

• Shire: lead

Study Sites (2)

Emma Children's Hospital, Academic Medical Center

Amsterdam, Netherlands

Location

St. Mary's Hospital

Manchester, United Kingdom

Location

Related Publications (3)

• Wijburg FA, Heap F, Rust S, de Ruijter J, Tump E, Marchal JP, Nestrasil I, Shapiro E, Jones SA, Alexanderian D. Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A. Mol Genet Metab. 2021 Dec;134(4):317-322. doi: 10.1016/j.ymgme.2021.09.003. Epub 2021 Sep 14.

  PMID: 34600820 DERIVED

• King B, Marshall N, Beard H, Hassiotis S, Trim PJ, Snel MF, Rozaklis T, Jolly RD, Hopwood JJ, Hemsley KM. Evaluation of enzyme dose and dose-frequency in ameliorating substrate accumulation in MPS IIIA Huntaway dog brain. J Inherit Metab Dis. 2015 Mar;38(2):341-50. doi: 10.1007/s10545-014-9790-8. Epub 2014 Nov 25.

  PMID: 25421091 DERIVED

• Langford-Smith A, Wilkinson FL, Langford-Smith KJ, Holley RJ, Sergijenko A, Howe SJ, Bennett WR, Jones SA, Wraith J, Merry CL, Wynn RF, Bigger BW. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol Ther. 2012 Aug;20(8):1610-21. doi: 10.1038/mt.2012.82. Epub 2012 May 1.

  PMID: 22547151 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis III; 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

Limitations and Caveats

The study was terminated as pre-specified efficacy criteria were not met. Data was not presented for efficacy parameters: ABR, Children's Sleep Habits Rating Scale, Infant Toddler QoL Questionnaire, SBRS.

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: February 16, 2011
• First Posted: February 18, 2011
• Study Start: March 1, 2011
• Primary Completion: April 12, 2019
• Study Completion: April 12, 2019
• Last Updated: June 14, 2021
• Results First Posted: April 21, 2020

Record last verified: 2021-05

Locations

NL (1); GB (1)