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NCT Number: NCT03423186

A Study to Assess the Safety and Tolerability of SOBI003 in Pediatric MPS IIIA Patients

MPS IIIA, also known as Sanfilippo A, is an inherited lysosomal storage disease (LSD). MPS IIIA is caused by a deficiency in sulfamidase, one of the enzymes involved in the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS). The natural course of MPS IIIA is characterized by devastating neurodegeneration with initially mild somatic involvement. The aims of the present study is to assess the dose related safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of SOBI003, a chemically modified recombinant human (rh) Sulfamidase developed as an enzyme replacement therapy (ERT).

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Key information

Conditions

Sanfilippo Syndrome Type A (MPS IIIA) Carbohydrate Metabolism, Inborn Errors Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Genetic Diseases, Inborn Lysosomal Storage Diseases Metabolic Diseases Metabolism, Inborn Errors Mucinoses Mucopolysaccharidoses Mucopolysaccharidosis III Nutritional and Metabolic Diseases Skin and Connective Tissue Diseases

Age range

12 month–72 month

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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About this study

This is an open-label, non-controlled, parallel, sequential ascending multiple-dose, multicenter study to assess the dose related safety, tolerability, PK and PD of SOBI003 in pediatric MPS IIIA patients. Patients between 1 and 6 years of age who have not received previous treatment for MPS IIIA with an ERT, gene- or stem cell therapy will be eligible to participate in the study. The study is planned to consist of 3 dose cohorts, each comprising 3 patients. Treatment initiations will be staggered within each cohort in order to be able to observe, interpret and treat possible adverse reactions. SOBI003 is administered as weekly i.v. infusions over a period of 24 weeks. Upon completion of the 24-week treatment period with satisfactory tolerability, the patient is offered to receive continued SOBI003 treatment by participation in an extension study.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Informed consent obtained from the patient's legally authorized representative(s)
  • Patients with MPS IIIA, as confirmed by both:
  • A documented deficiency in sulfamidase enzyme activity in concordance with a diagnosis of MPS IIIA, and
  • Normal enzyme activity level of at least one other sulfatase measured in leukocytes
  • Chronological age of ≥12 and ≤72 months (i.e., 1 to 6 years) at the time of the first SOBI003 infusion and a developmental age ≥12 months at screening as assessed by the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
  • Medically stable patient who is expected to be able to comply with study procedures

Exclusion criteria

  • At least one S298P mutation in the SGSH gene
  • Contraindications for anesthetic procedures, surgical procedure (venous access port) MRI scans and/or lumbar punctures
  • History of poorly controlled seizures
  • Patients is currently receiving psychotropic or other medications which in the investigator's opinion, would be likely to substantially confound test results
  • Significant non-MPS IIIA-related central nervous system (CNS) impairment or behavioral disturbances, which in the investigator's opinion, would confound the scientific integrity or interpretation of study assessments
  • Prior administration of stem cell or gene therapy, or ERT for MPS IIIA
  • Concurrent or prior (within 30 days of enrolment into this study) participation in a study involving invasive procedures

Treatment and study plan

SOBI003

Drug

Weekly i.v.infusion

Other names: Modified recombinant human sulphamidase

Primary outcomes

  1. Safety as Measured by Adverse Events Frequencies (by Type and Severity)

    Time frame: From start of first infusion up to Week 24

    Number of adverse events, by type and severity, from start of infusion up to 24 weeks

Secondary outcomes

  1. The Observed Serum Concentration Immediately Before the Start of Infusion of SOBI003

    Time frame: Weeks 1, 2, 3, 4, 8, 12, and 24

    The observed serum concentration immediately before the start of infusion of SOBI003 (CPre-dose).

  2. The Observed Serum Concentration at the End of Infusion of SOBI003

    Time frame: Weeks 1, 2, 3, 4, 8, 12, and 24

    The observed serum concentration at the end of infusion of SOBI003 (CEnd of inf)

  3. The Time of the End of the Infusion of SOBI003

    Time frame: Weeks 1, 2, 3, 4, 8, 12, and 24

    The time of the end of infusion of SOBI003 (tEnd of inf)

  4. The Maximum Observed Serum Concentration of SOBI003

    Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Weeks 1, 4, 12, and 24

    The Maximum Observed Serum Concentration of SOBI003 (Cmax)

  5. The Time at Which the Maximum Serum Concentration of SOBI003 is Observed

    Time frame: Weeks 1, 4, 12, and 24

    The time after start of infusion at which the maximum serum concentration is observed (tmax)

  6. The Minimum Observed Serum Concentration of SOBI003

    Time frame: Weeks 1, 4, 12, and 24

    The minimum observed serum concentration of SOBI003 (CTrough)

  7. Clearance

    Time frame: Weeks 1, 4, 12, and 24

    Clearance (CL) of SOBI003

  8. Area Under the Serum Concentration-time Curve From Time 0 to 168 Hours

    Time frame: 0,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Weeks 1, 4,12, and 24

    Area under the serum concentration-time curve from time 0 to 168 hours (AUC 0-168h)

  9. The Half-life

    Time frame: Weeks 1, 4, 12, and 24

    The half-life of SOBI003 in serum (T1/2)

  10. SOBI003 Concentration in Cerebrospinal Fluid

    Time frame: Weeks 12 and 24

    SOBI003 concentration in cerebrospinal fluid

  11. Number of Patients Having Anti-drug Antibodies in Serum

    Time frame: Weeks 2,4,8,12 and 24

    Number of patients in each dose group having anti-drug antibodies in serum

  12. Patients Having Anti-drug Antibodies in Cerebrospinal Fluid

    Time frame: Weeks 12 and 24

    Percent of patients having anti-drug antibodies in cerebrospinal fluid

  13. Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid

    Time frame: Baseline, weeks 12, and 24

    Change from baseline, in percent, of Heparan Sulfate levels in cerebrospinal fluid

  14. Change From Baseline in Heparan Sulfate Levels in Serum

    Time frame: Weeks 2, 3, 4, 8, 12 and 24

    Change from baseline in Heparan sulfate levels in serum

  15. Change From Baseline in Heparan Sulfate Levels in Urine

    Time frame: Weeks 2, 3, 4, 8, 12 and 24

    Change from baseline in Heparan sulfate levels in urine

  16. Change From Baseline in Neurocognitive Development Quotient

    Time frame: Week 24

    Quotient between age equivalent score and age, 0 - 100%, where high values are desirable. The age equivalent score represent the age of the typical and normal individual who would achieve the same result as the one who was tested.

    The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition.

    The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior.

    The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development.

  17. Change From Baseline in Age-equivalence Score

    Time frame: Week 24

    The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested.

    The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition.

    The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior.

    The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development.

  18. Change From Baseline in Age-equivalence Score as Assessed by VABS-II

    Time frame: Week 24

    The age equivalent score represent the age in months of the typical and normal individual who would achieve the same result as the one who was tested.

    The age equivalent scores are assessed by Vineland™ Adaptive Behavior Scales, Expanded Interview Form, Second edition (VABS-II). The Vineland is designed to measure adaptive behavior of individuals from birth to age 90.

    The Vineland-II contains 5 domains each with 2-3 subdomains. The main domains are: Communication, Daily Living Skills, Socialization, Motor Skills, and Maladaptive Behavior.

  19. Change From Baseline in Gray Matter Volume

    Time frame: Week 24

    Grey matter contains most of the brain's neuronal cell bodies. The grey matter includes regions of the brain involved in muscle control, and sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control. The gray matter volume will be measured by volumetric magnetic resonance imaging (MRI).

  20. Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Total Score

    Time frame: Week 24

    Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. Lower scores indicate better functioning. Min score = 0, and max score = 144.

  21. Change From Baseline in PedsQL™ Family Impact Module Total Score

    Time frame: Week 24

    Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The measure includes a scale, from where the categorical score "4", "3", "2", "1", and "0" was reversed and linearly transformed to a 0-100 scale to 4=0, 3=25, 2=50, 1=75 and 0=100, where 100 = minimum and 0 = maximum. The Total Score is the sum of all 36 items in the test divided by the number of items answered. Higher scores indicate better functioning.

Sponsors and collaborators

Lead sponsor

Swedish Orphan Biovitrum

Industry

Registry information

Official study title

An Open, Non-controlled, Parallel, Ascending Multiple-dose, Multicenter Study to Assess Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SOBI003 in Pediatric MPS IIIA Patients

Important dates

Study start
2018
Primary completion
2019
Study completion
2019
First posted
Feb 6, 2018
Registry last updated
Nov 19, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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