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

NCT01155778 | Completed Phase 1 Results DMC

• 2 other identifiers: HGT-SAN-0552009-015984-15
• 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 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). 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. 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. 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 (or every two weeks) for 6 months in patients with MPS IIIA.

Conditions

Mucopolysaccharidosis (MPS)

Keywords

Mucopolysaccharidosis (MPS) IIIA; Recombinant Human Heparan N-Sulfatase (rhHNS); Sanfilippo Syndrome Type A (MPS IIIA); Lysosomal Storage Disease (LSD); Intrathecal Drug Delivery Device (IDDD)

Outcome Measures

Primary Outcomes (5)

• Number of Treatment Emergent Serious Adverse Events (SAE)

  An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for IDDD implantation to the last follow up contact, 30 (±7) days after the end of study (EOS) procedures.

  Baseline to week 30 (follow-up)

• Number of Treatment Emergent Adverse Events (TEAE)

  An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for IDDD implantation to the last follow up contact, 30 (±7) days after the end of study (EOS) procedures.

  Baseline to week 30 (follow-up)

• Summary of Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS) Dose Group

  Participants with positive, negative and missing status were reported.

  Baseline, Week 26

• Summary of Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS) Dose Group

  Participants with positive, negative and missing status were reported.

  Baseline, Week 26

• Number of Participants With Intrathecal Drug Device (IDDD) Failures at Week 26

  Participants with IDDD failures were reported.

  Week 26

Secondary Outcomes (20)

• 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 Week 22

  Baseline, Week 22

• Change From Baseline in Four Point Scoring System/Total Disability Score (FPSS/TDS) at Week 22 and Week 26 (EOS)

  Baseline, Week 22, Week 26

• Change From Baseline in Sanfilippo Behavioral Rating Scale (SBRS) at Week 22 and Week 26 (EOS)

  Baseline, Week 22, Week 26/EOS

• Change From Baseline in Developmental Quotient (DQ) Using Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Week 22

  Baseline, Week 22

• Change From Baseline in Movement Assessment Battery for Children Second Edition (MABC-2) at Week 26 (EOS)

  Baseline, Week 26/EOS

Study Arms (3)

10 mg rhHNS

EXPERIMENTAL

10 mg monthly via an IDDD (every 28 \[±7 days\]) for a total of 6 months

Biological: Recombinant human heparan N-sulfatase (rhHNS)

45 mg rhHNS

EXPERIMENTAL

45 mg monthly via an IDDD (every 28 \[±7 days\]) for a total of 6 months

Biological: Recombinant human heparan N-sulfatase (rhHNS)

90 mg rhHNS

EXPERIMENTAL

Given IDDD as a 45 mg dose every 14 \[±2 days\] for a monthly total of 90 mg for 6 months

Biological: Recombinant human heparan N-sulfatase (rhHNS)

Interventions

Recombinant human heparan N-sulfatase (rhHNS) BIOLOGICAL

10 mg rhHNS; 45 mg rhHNS; 90 mg rhHNS

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:

• Each patient had to meet the following criteria to be eligible for the study:
• a.) Patients had a documented deficiency in sulfamidase enzyme activity of ≤10% of the lower limit of the normal range as measured in fibroblasts or leukocytes.
• AND either b or c b.) Patients had a normal enzyme activity level of at least 1 other sulfatase (to rule out multiple sulfatase deficiency) as measured in fibroblasts or leukocytes.
• c.) Patients had 2 documented mutations.
• The patient was ≥3 years of age and had a developmental age ≥1 year.
• Patients must have been 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 after all relevant aspects of the study have been explained and discussed with the patient, the patient's parent(s), or legal guardian. The patients, patient's parents or legal guardian's consent and patient's assent as appropriate, must have been obtained.

You may not qualify if:

• Patients who met any of the following criteria were excluded from the study:
• The patient had 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 patient had MPS IIIA behavioral-related issues, as determined by the investigator, that would have precluded performance of study neurocognitive and developmental testing procedures
• The patient was pregnant, breast feeding, or was a female patient of childbearing potential who would not or could not comply with the use of an acceptable method of birth control such as condoms, barrier method, oral contraception, etc.
• The patient was blind and/or deaf.
• The patient had any known or suspected hypersensitivity to anesthesia or was thought to have an unacceptably high risk for anesthesia due to airway compromise or other conditions.
• The patient or the patient's family had a history of neuroleptic malignant syndrome, malignant hyperthermia, or other anesthesia-related concerns.
• The investigator may have chosen to exclude patients who have had complications resulting from prior lumbar punctures.
• The patient had a CNS shunt.
• The patient had skeletomuscular/spinal abnormalities or other contraindications for the surgical implantation of the IDDD.
• The patient had a history of poorly controlled seizure disorder.
• The patient was currently receiving psychotropic or other medications, which in the investigator's opinion, would have been likely to substantially confound test results and the dose and regimen of which cannot be kept constant throughout the study.
• The patient could not sustain absence from aspirin, non-steroidal medications, or medications that affected blood clotting within 1 week prior to a relevant study related procedure (eg, device implantation if applicable), or had ingested such medications within 1 week before any procedures in which any change in clotting activity would have been deleterious.
• The patient had 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 was enrolled in another study that involved an investigational drug or device (screening through safety follow-up contact).
• The patient received a hematopoietic stem cell or bone marrow transplant.

Sponsors & Collaborators

• Shire: lead

Study Sites (2)

Emma Children's Hospital, Academic Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

St. Mary's Hospital

Manchester, M13 9WL, United Kingdom

Location

Related Publications (3)

• Jones SA, Breen C, Heap F, Rust S, de Ruijter J, Tump E, Marchal JP, Pan L, Qiu Y, Chung JK, Nair N, Haslett PAJ, Barbier AJ, Wijburg FA. A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA. Mol Genet Metab. 2016 Jul;118(3):198-205. doi: 10.1016/j.ymgme.2016.05.006. Epub 2016 May 10.

  PMID: 27211612 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

Mucopolysaccharidoses; Mucopolysaccharidosis III; Lysosomal Storage Diseases

Condition Hierarchy (Ancestors)

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

Comparison to values obtained in a longitudinal, 12 month, natural history study of untreated participants with MPS IIIA was not reported as it was to be compared with another study protocol HGT-SAN-053 (NCT01047306).

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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2010
• First Posted: July 2, 2010
• Study Start: June 1, 2010
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2012
• Last Updated: June 14, 2021
• Results First Posted: December 12, 2018

Record last verified: 2021-05

Locations

NL (1); GB (1)