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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT04088734
Registration number
NCT04088734
Ethics application status
Date submitted
11/09/2019
Date registered
13/09/2019
Date last updated
25/07/2023
Titles & IDs
Public title
Gene Transfer Study of ABO-102 in Patients With Middle and Advanced Phases of MPS IIIA Disease
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Scientific title
A Phase I/II Open Label, Single-dose, Gene Transfer Study of scAAV9.U1a.hSGSH (ABO-102) in Patients With Middle and Advanced Phases of MPS IIIA Disease
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Secondary ID [1]
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UX111-CL201
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Secondary ID [2]
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ABT-003
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
MPS IIIA
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Sanfilippo Syndrome
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Sanfilippo A
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Mucopolysaccharidosis III
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Condition category
Condition code
Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - ABO-102
Experimental: ABO-102 - Dose of 3x10^13 vg/kg
Treatment: Drugs: ABO-102
Single dose of ABO-102 (scAAV9.U1a.hSGSH) administered by intravenous injection through a peripheral limb vein at a dose of 3 X 10^13 vg/kg
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Incidence, Type and Severity of Related Treatment-Emergent Adverse Events (TEAEs) by Time Frame
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Assessment method [1]
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An adverse event (AE) is any untoward medical occurrence or unintended change from the time informed consent form (ICF) is signed, including inter-current illness that occurs during the course of a clinical trial after treatment has started, whether considered related to treatment or not. TEAEs are those that occurred after the start of study drug. Related adverse events were categorized as possible, probable, or definitely.
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Timepoint [1]
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From the first dose of study drug to <30 days postdose, Day 30, 60, 90, 180 and Month 12
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Primary outcome [2]
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Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame
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Assessment method [2]
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An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent disability/incapacity
Is a congenital anomaly/birth defect
Other situations such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.
Relationship to study drug was defined as unrelated, unlikely, possible, probable, or definitely.
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Timepoint [2]
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From signing of informed consent through Day 60, 90, 180 and up to Day 454 (> 12 months)
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Primary outcome [3]
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Change From Baseline (BL) in Multiples of Normal of Liver and Spleen Volumes After Treatment
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Assessment method [3]
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As Measured by Magnetic Resonance Imaging (MRI). Baseline value of multiple of normal is calculated using the baseline values of the Liver volume/Spleen Volume/Height and Weight.
Body Surface Area (BSA) (m2)=( Height(cm) * Weight (kg)/3600)1/2.
Normal Liver Volume=(689.9 * BSA (m)) - 24.7.
Normal Spleen Volume (mL)=(4.6 * Weight (kg)) + 0.7.
Liver Volume (multiples of normal)=Subject Liver Volume (mL)/Normal Liver Volume (mL).
Spleen Volume (multiples of normal)=Subject Spleen Volume (mL)/Normal Spleen Volume (mL).
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Timepoint [3]
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Baseline, Day 30, 180, Month 12
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Primary outcome [4]
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Change From BL in Cerebrospinal Fluid (CSF) Heparan Sulfate Levels After Treatment
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Assessment method [4]
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Change from baseline in CSF heparan sulfate levels after treatment
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Timepoint [4]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [1]
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Change From Baseline in Plasma Heparan Sulfate After Treatment
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Assessment method [1]
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Timepoint [1]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [2]
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Change From Baseline in Urine Glycosaminoglycans After Treatment
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Assessment method [2]
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Timepoint [2]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [3]
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Change From Baseline in Urine Heparan Sulfate After Treatment
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Assessment method [3]
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Timepoint [3]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [4]
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Change From Baseline in CSF N-Sulfoglucosamine Sulfohydrolase (SGSH) Enzyme Activity Levels After Treatment
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Assessment method [4]
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Timepoint [4]
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Baseline, Day 30, Day 180, and Month 12
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Secondary outcome [5]
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Change From Baseline in Heparan N-Sulfatase (Type A) After Treatment
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Assessment method [5]
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Timepoint [5]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [6]
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Change From Baseline in Plasma SGSH After Treatment
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Assessment method [6]
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Timepoint [6]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [7]
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Change From Baseline in Brain Volumes After Treatment
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Assessment method [7]
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As measured by MRI
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Timepoint [7]
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Baseline, 12 months
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Secondary outcome [8]
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Change From Baseline in Brain Volumes After Treatment: Average Total Cortical Thickness
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Assessment method [8]
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As measured by MRI
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Timepoint [8]
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Baseline, 12 months
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Secondary outcome [9]
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Change From Baseline in Sleep Pattern as Measured by the Modified Children's Sleep Habits Questionnaire (CSHQ) Subscore Total After Treatment
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Assessment method [9]
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CSHQ is a caregiver-completed, 35-item questionnaire that assesses the frequency of behaviors associated with common pediatric sleep difficulties. Eight domains of sleep, including Bedtime Resistance, Sleep Onset Delay, Sleep Duration, Sleep Anxiety, Night Awakenings, Parasomnias, Sleep Disordered Breathing, and Daytime Sleepiness are assessed, producing eight individual subdomain scores and an overall CSHQ subscore total. CSHQ total score is calculated by adding all the 8 subscores, and ranges from 36 to 108. A higher score is indicative of more disturbed sleep.
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Timepoint [9]
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Baseline, Day 180, Month 12
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Secondary outcome [10]
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Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales Total Score
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Assessment method [10]
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PedsQL is a brief measure of health-related quality of life in children. The Peds QL Generic Core Scales was used in the study, consisting of 23 items applicable for healthy school and community populations, as well as pediatric populations with acute and chronic conditions. The four scales include Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Item scores are added together and averaged to produce a Core total score, where higher scores on a scale of 0-100 indicate better Health-related Quality of Life (HRQOL).
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Timepoint [10]
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Baseline, Day 180, Month 12
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Secondary outcome [11]
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Change From Baseline in Parent Quality of Life, Using the Parenting Stress Index, 4th Edition (PSI-4) Total Stress Raw Score
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Assessment method [11]
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The Parenting Stress Index, 4th Edition evaluates the magnitude and type of stress in a parent/child relationship. The short form version was used in the study, consisting of 36 items divided into three domains: Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI), and Difficult Child (DC), which combine together to form a Total Stress raw score. Total Stress raw scores can range from 36 - 180, with higher raw scores indicating higher levels of stress.
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Timepoint [11]
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Baseline, Day 180, Month 12
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Secondary outcome [12]
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Change From Baseline in Gastrointestinal Symptoms Using the PedsQL™ Gastrointestinal (GI) Symptoms Scales Score
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Assessment method [12]
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The PedsQL Gastrointestinal Symptoms Scale is a specific module of the PedsQL that measures gastrointestinal symptoms in patients with acute and chronic health conditions as well as healthy school and community populations. The Parent Report version was used on the study, consisting of 58 items across 10 dimensions, assessing parents' perceptions of their child's GI-specific symptoms. Item scores are added together and averaged to produce a GI symptoms scales score, where higher scores on a scale of 0-100 indicate better GI specific QOL.
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Timepoint [12]
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Baseline, Day 180, Month 12
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Secondary outcome [13]
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Change From Baseline in Parent Global Impression (PGI) Total Score
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Assessment method [13]
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The Parent Global Impression scale evaluates all aspects of a patients' health and assesses if there has been an improvement or decline in clinical status, as reported by the parent/caregiver. This study used a modified version with symptoms relevant to the patient population in the trial. Nine symptoms were scored at each visit, using a 7-point rating scale where 3 = much better, 2 = better, 1 = slightly better, 0 = same, -1 = slightly worse, -2 = worse, and -3 = much worse. The nine symptom scores are added together to produce a PGI total score, ranging from -27 to 27.
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Timepoint [13]
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Baseline, Day 180, Month 12
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Secondary outcome [14]
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Clinical Global Impression Improvement Scale at Day 180 and Month 12
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Assessment method [14]
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The Clinical Global Impression of Improvement scale is a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication, specifically looking at whether the patient has demonstrated improvement or not. Assessment of improvement was scored at each visit, using a 7-point rating scale where 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
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Timepoint [14]
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Day 180, Month 12
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Secondary outcome [15]
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Change From Baseline in Parent Symptoms Score Questionnaire
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Assessment method [15]
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The Parent Symptoms Score Questionnaire contains 29 symptoms with an indicator of whether the symptom was present or absent.
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Timepoint [15]
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Baseline, Day 180, Month 12
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Secondary outcome [16]
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Percent Change From Baseline in Body Mass Index After Treatment
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Assessment method [16]
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Timepoint [16]
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Baseline, Day 30, Day 180, Month 12
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Secondary outcome [17]
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Number of Participants With Abnormalities in Standard Awake 45-Minutes-Electroencephalogram (EEG) Monitoring at Baseline and Day 180
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Assessment method [17]
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NCS=not clinically significant CS=clinically significant
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Timepoint [17]
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Baseline, Day 180
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Secondary outcome [18]
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Change From Baseline in Vector Shedding Analysis in Plasma, Saliva, Stool and Urine
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Assessment method [18]
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Detection of the adeno-associated Virus 9 (AAV9) viral deoxyribonucleic acid (DNA) in plasma, saliva, urine and feces was analyzed. Per protocol, data were not collected for urine at Month 12.
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Timepoint [18]
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Baseline, Day 30, Day 180, Month 12
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Eligibility
Key inclusion criteria
- Diagnosis of MPS IIIA confirmed by the following methods:
1. No detectable or significantly reduced SGSH enzyme activity by leukocyte assay
and
2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations
in the SGSH gene
- Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of
Infant and Toddler Development - Third Edition)
- Must be ambulatory, though may receive assistance with ambulation
- Age range of 2 years up to 18 years (excluded)
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Minimum age
2
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Maximum age
18
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Inability to participate in the clinical evaluation as determined by Principal
Investigator
- Identification of two nonsense or null variants on genetic testing of the SGSH gene
- At least one S298P mutation in the SGSH gene
- Has evidence of an attenuated phenotype of MPS IIIA
- Presence of a concomitant medical condition that precludes lumbar puncture or use of
anesthetics
- Active viral infection based on clinical observations
- Concomitant illness or requirement for chronic drug treatment that in the opinion of
the PI creates unnecessary risks for gene transfer, or precludes the child from
participating in the protocol assessments and follow up
- Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as
determined by ELISA binding immunoassay
- Participants with a positive response for the ELISPOT for T-cell responses to AAV9
- Serology consistent with exposure to HIV, or serology consistent with active hepatitis
B or C infection
- Bleeding disorder or any other medical condition or circumstance in which a lumbar
puncture (for collection of CSF) is contraindicated according to local institutional
policy
- Visual or hearing impairment sufficient to preclude cooperation with
neurodevelopmental testing
- Any item (braces, etc.) which would exclude the participant from being able to undergo
MRI according to local institutional policy
- Any other situation that precludes the participant from undergoing procedures required
in this study
- Participants with cardiomyopathy or significant congenital heart abnormalities
- The presence of significant non-MPS IlIA related CNS impairment or behavioral
disturbances that would confound the scientific rigor or interpretation of results of
the study
- Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total
bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine,
hemoglobin, WBC count, platelet count, PT and aPTT
- Female participant who is pregnant or demonstrates a positive urine or beta-hCG result
at screening assessment (if applicable)
- Any vaccination with viral attenuated vaccines less than 30 days prior to the
scheduled date of treatment (and use of prednisolone)
- Previous treatment by Haematopoietic Stem Cell transplantation
- Previous participation in a gene/cell therapy or ERT clinical trial
- Participants who are anticipated to undergo a procedure involving anesthesia within 6
months post- drug administration
- Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
18/09/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
10/03/2022
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Sample size
Target
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Accrual to date
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Final
5
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Recruitment in Australia
Recruitment state(s)
SA
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Recruitment hospital [1]
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Adelaide Women's and Children's Hospital - North Adelaide
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Recruitment postcode(s) [1]
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5006 - North Adelaide
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Pennsylvania
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Country [2]
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Spain
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State/province [2]
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Santiago De Compostela
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Ultragenyx Pharmaceutical Inc
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Address
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Country
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Other collaborator category [1]
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Commercial sector/Industry
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Name [1]
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Abeona Therapeutics, Inc
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Address [1]
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Country [1]
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Ethics approval
Ethics application status
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Summary
Brief summary
Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral
limb vein
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04088734
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Trial related presentations / publications
Fu H, Cataldi MP, Ware TA, Zaraspe K, Meadows AS, Murrey DA, McCarty DM. Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery. Mol Ther Methods Clin Dev. 2016 Jun 8;3:16036. doi: 10.1038/mtm.2016.36. eCollection 2016.
Fu H, Meadows AS, Pineda RJ, Kunkler KL, Truxal KV, McBride KL, Flanigan KM, McCarty DM. Differential Prevalence of Antibodies Against Adeno-Associated Virus in Healthy Children and Patients with Mucopolysaccharidosis III: Perspective for AAV-Mediated Gene Therapy. Hum Gene Ther Clin Dev. 2017 Dec;28(4):187-196. doi: 10.1089/humc.2017.109. Epub 2017 Oct 24.
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Public notes
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Contacts
Principal investigator
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Medical Director
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Address
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Ultragenyx Pharmaceutical Inc
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04088734
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