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

Primary Purpose

Sanfilippo Syndrome Type A (MPS IIIA)

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

SOBI003

About this trial

This is an interventional treatment trial for Sanfilippo Syndrome Type A (MPS IIIA)

Eligibility Criteria

12 Months - 72 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Childrens's Hospital and Research Center
University of North Carolina Hospitals
University Medical Center Hamburg-Eppendorf
Gazi University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Dose group 1

Dose group 2

Arm Description

SOBI003 dose 3 mg/kg once weekly for 24 weeks

SOBI003 dose 10 mg/kg once weekly for 24 weeks

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

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

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

The Observed Serum Concentration at the End of Infusion of SOBI003

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

The Time of the End of the Infusion of SOBI003

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

The Maximum Observed Serum Concentration of SOBI003

The Maximum Observed Serum Concentration of SOBI003 (Cmax)

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

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

The Minimum Observed Serum Concentration of SOBI003

The minimum observed serum concentration of SOBI003 (CTrough)

Clearance

Clearance (CL) of SOBI003

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

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

The Half-life

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

SOBI003 Concentration in Cerebrospinal Fluid

SOBI003 concentration in cerebrospinal fluid

Number of Patients Having Anti-drug Antibodies in Serum

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

Patients Having Anti-drug Antibodies in Cerebrospinal Fluid

Percent of patients having anti-drug antibodies in cerebrospinal fluid

Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid

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

Change From Baseline in Heparan Sulfate Levels in Serum

Change from baseline in Heparan sulfate levels in serum

Change From Baseline in Heparan Sulfate Levels in Urine

Change from baseline in Heparan sulfate levels in urine

Change From Baseline in Neurocognitive Development Quotient

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.

Change From Baseline in Age-equivalence Score

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.

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

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.

Change From Baseline in Gray Matter Volume

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).

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

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.

Change From Baseline in PedsQL™ Family Impact Module Total Score

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.

Full Information

NCT ID

NCT03423186

First Posted

January 29, 2018

Last Updated

November 18, 2021

Sponsor

Swedish Orphan Biovitrum

1. Study Identification

Unique Protocol Identification Number

NCT03423186

Brief Title

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

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Completed

Study Start Date

June 19, 2018 (Actual)

Primary Completion Date

October 25, 2019 (Actual)

Study Completion Date

October 25, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Swedish Orphan Biovitrum

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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).

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sanfilippo Syndrome Type A (MPS IIIA)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

The study was designed to include three arms, up to 20 mg/kg. After a company decision to end the development of the compound it was decided to not start a third cohort, but if stated safe the dose could increase up to 20 mg/kg in cohort 1 and 2.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dose group 1

Arm Type

Experimental

Arm Description

SOBI003 dose 3 mg/kg once weekly for 24 weeks

Arm Title

Dose group 2

Arm Type

Experimental

Arm Description

SOBI003 dose 10 mg/kg once weekly for 24 weeks

Intervention Type

Drug

Intervention Name(s)

SOBI003

Other Intervention Name(s)

Modified recombinant human sulphamidase

Intervention Description

Weekly i.v.infusion

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

From start of first infusion up to Week 24

Secondary Outcome Measure Information:

Title

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

Description

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

Time Frame

Weeks 1, 2, 3, 4, 8, 12, and 24

Title

The Observed Serum Concentration at the End of Infusion of SOBI003

Description

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

Time Frame

Weeks 1, 2, 3, 4, 8, 12, and 24

Title

The Time of the End of the Infusion of SOBI003

Description

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

Time Frame

Weeks 1, 2, 3, 4, 8, 12, and 24

Title

The Maximum Observed Serum Concentration of SOBI003

Description

The Maximum Observed Serum Concentration of SOBI003 (Cmax)

Time Frame

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

Title

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

Description

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

Time Frame

Weeks 1, 4, 12, and 24

Title

The Minimum Observed Serum Concentration of SOBI003

Description

The minimum observed serum concentration of SOBI003 (CTrough)

Time Frame

Weeks 1, 4, 12, and 24

Title

Clearance

Description

Clearance (CL) of SOBI003

Time Frame

Weeks 1, 4, 12, and 24

Title

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

Description

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

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

Title

The Half-life

Description

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

Time Frame

Weeks 1, 4, 12, and 24

Title

SOBI003 Concentration in Cerebrospinal Fluid

Description

SOBI003 concentration in cerebrospinal fluid

Time Frame

Weeks 12 and 24

Title

Number of Patients Having Anti-drug Antibodies in Serum

Description

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

Time Frame

Weeks 2,4,8,12 and 24

Title

Patients Having Anti-drug Antibodies in Cerebrospinal Fluid

Description

Percent of patients having anti-drug antibodies in cerebrospinal fluid

Time Frame

Weeks 12 and 24

Title

Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid

Description

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

Time Frame

Baseline, weeks 12, and 24

Title

Change From Baseline in Heparan Sulfate Levels in Serum

Description

Change from baseline in Heparan sulfate levels in serum

Time Frame

Weeks 2, 3, 4, 8, 12 and 24

Title

Change From Baseline in Heparan Sulfate Levels in Urine

Description

Change from baseline in Heparan sulfate levels in urine

Time Frame

Weeks 2, 3, 4, 8, 12 and 24

Title

Change From Baseline in Neurocognitive Development Quotient

Description

Time Frame

Week 24

Title

Change From Baseline in Age-equivalence Score

Description

Time Frame

Week 24

Title

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

Description

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.

Time Frame

Week 24

Title

Change From Baseline in Gray Matter Volume

Description

Time Frame

Week 24

Title

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

Description

Time Frame

Week 24

Title

Change From Baseline in PedsQL™ Family Impact Module Total Score

Description

Time Frame

Week 24

10. Eligibility

Sex

All

Minimum Age & Unit of Time

12 Months

Maximum Age & Unit of Time

72 Months

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paul Harmatz, MD

Organizational Affiliation

Childrens's Hospital and Research Center Oakland

Official's Role

Principal Investigator

Facility Information:

Facility Name

Childrens's Hospital and Research Center

City

Oakland

State/Province

California

ZIP/Postal Code

94609

Country

United States

Facility Name

University of North Carolina Hospitals

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Facility Name

University Medical Center Hamburg-Eppendorf

City

Hamburg

Country

Germany

Facility Name

Gazi University Hospital

City

Ankara

Country

Turkey

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Undecided

Citations:

PubMed Identifier

35835061

Citation

Harmatz P, Muenzer J, Ezgu F, Dalen P, Huledal G, Lindqvist D, Gelius SS, Wiken M, Onnestam K, Broijersen A. Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study. Mol Genet Metab. 2022 Aug;136(4):249-259. doi: 10.1016/j.ymgme.2022.06.008. Epub 2022 Jun 28.

Results Reference

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

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