Clinical Trial Results:
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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Summary
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EudraCT number |
2018-000504-42 |
Trial protocol |
ES |
Global end of trial date |
10 Mar 2022
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Results information
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Results version number |
v4(current) |
This version publication date |
18 Jul 2023
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First version publication date |
04 Oct 2022
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Other versions |
v1 , v2 , v3 |
Version creation reason |
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Summary report(s) |
Results Extension Notification |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ABT-003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04088734 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ultragenyx Pharmaceutical Inc.
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Sponsor organisation address |
60 Leveroni Court, Novato, United States, California 94949
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Public contact |
Ultragenyx Pharmaceutical, Inc., Patient Advocacy, +1 415 756-8657, Trialrecruitment@ultragenyx.com
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Scientific contact |
Medical Information, Ultragenyx Pharmaceutical, Inc., +1 888 756-8657, medinfo@ultragenyx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002206-PIP02-19 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Mar 2022
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Mar 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To evaluate the safety and efficacy of ABO-102 (also known as UX111) in patients with middle and advanced phases of mucopolysaccharidosis (MPS) IIIA disease.
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Protection of trial subjects |
All parents and/or legal guardians of the participant will be provided with an Information Sheet and/or Consent Form describing this study and providing sufficient information for participants to make an informed decision about the participation of their represented participant in this study. Where required, consent will be sought from the parents and/or legal guardian of the participant. The Informed Consent Forms (ICFs) and Patient Informed Consent Forms (PICFs) will include all elements required by ICH, Good Clinical Practice (GCP) and applicable regulatory requirements.
The Information Sheet and/or Consent Form will be submitted with the protocol for review and approval by the relevant Ethical Review Board for the study in each country. The formal consent of a participant, using the Informed Consent Form approved by the relevant Ethical Review Board, must be obtained before that participant undergoes any study procedure. The consent form must be signed by the participant’s parent/legal guardian, and the Investigator-designated research professional obtaining the consent. Where required by the relevant Ethical Review Board, a witness may sign the consent form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Sep 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
Australia: 1
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Worldwide total number of subjects |
5
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EEA total number of subjects |
3
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
5
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||
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Pre-assignment
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Screening details |
The screening evaluations will take place over two visits (preferentially two weeks apart). Each screening visit may take place over multiple consecutive days if deemed necessary by the Principal Investigator to accommodate all the clinical assessments that need to be performed. | ||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
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Arms
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Arm title
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scAAV9.U1a.hSGSH, 3x1013 vg/kg | ||||||||||
Arm description |
An intravenous injection of ABO-102 (scAAV9.U1a.hSGSH) via peripheral limb vein at a dose of 3.0 x 1013 vg/kg | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
ABO-102
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
3 x 1013 vg/kg of ABO-102 delivered one time through a venous catheter inserted into a peripheral limb vein.
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Baseline characteristics reporting groups
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Reporting group title |
scAAV9.U1a.hSGSH, 3x1013 vg/kg
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Reporting group description |
An intravenous injection of ABO-102 (scAAV9.U1a.hSGSH) via peripheral limb vein at a dose of 3.0 x 1013 vg/kg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
scAAV9.U1a.hSGSH, 3x1013 vg/kg
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Reporting group description |
An intravenous injection of ABO-102 (scAAV9.U1a.hSGSH) via peripheral limb vein at a dose of 3.0 x 1013 vg/kg | ||
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End point title |
Incidence, Type and Severity of Related Treatment-Emergent Adverse Events (TEAEs) by Time Frame [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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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End point type |
Primary
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End point timeframe |
From the first dose of study drug to <30 days postdose, Day 30, 60, 90, 180 and Month 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame [2] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life threatening
c. Requires inpatient hospitalization or prolongation of existing hospitalization
d. Results in persistent disability/incapacity
e. Is a congenital anomaly/birth defect
f. 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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End point type |
Primary
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End point timeframe |
From signing of informed consent through Day 60, 90, 180 and up to Day 454 (> 12 months)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline (BL) in Multiples of Normal of Liver and Spleen Volumes After Treatment [3] | ||||||||||||||||||||
End point description |
As Measured by Magnetic Resonance Imaging (MRI).
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).
[1] Baseline value of multiple of normal is calculated using the baseline values of the Liver volume/Spleen Volume/Height and Weight.
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End point type |
Primary
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End point timeframe |
Baseline, Day 30, 180, Month 12
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistics are presented in the data table per protocol. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Change From BL in Cerebrospinal Fluid (CSF) Heparan Sulfate Levels After Treatment [4] | ||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline, Day 30, 180, Month 12
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistics are presented in the data table per protocol. |
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| Notes [5] - n=number of participants with an assessment; 99999=not applicable (1 participant analyzed) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Plasma Heparan Sulfate After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [6] - n=number of participants at given time point |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Urine Glycosaminoglycans After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [7] - n=participants with an assessment at given time point; 99999=not applicable (1 participant analyzed) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Urine Heparan Sulfate After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [8] - n=participants with an assessment at given time point; 99999=not applicable (1 participant analyzed) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Cerebrospinal Fluid (CSF) N-Sulfoglucosamine Sulfohydrolase (SGSH) Enzyme Activity Levels After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, and Month 12
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| Notes [9] - n=participants with an assessment at given time point; 99999=not applicable (1 participant analyzed) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change from Baseline in Heparan N-sulfatase (type A) After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [10] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change from Baseline in Plasma SGSH After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [11] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Brain Volumes After Treatment | ||||||||||||||||||||||||||||||||||||||
End point description |
As measured by MRI
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End point type |
Secondary
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End point timeframe |
Basline, Month 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Brain Volumes After Treatment: Average Total Cortical Thickness | ||||||||
End point description |
As measured by MRI
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End point type |
Secondary
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End point timeframe |
Baseline, 12 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Sleep Pattern as Measured by the Modified Children's Sleep Habits Questionnaire (CSHQ) Subscore Total at Day 180 and Month 12 | ||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [12] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales Total Score | ||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [13] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Parent Quality of Life, Using the Parenting Stress Index, 4th Edition (PSI-4) Total Stress Raw Score | ||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [14] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in Gastrointestinal Symptoms Using the PedsQL™ Gastrointestinal Symptoms Scales Score | ||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [15] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Parent Global Impression (PGI) Total Score | ||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [16] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Clinical Global Impression Improvement Scale at Day 180 and Month 12 | ||||||||||||||||||||||||||||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Day 180, Month 12
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| Notes [17] - n=participants with an assessment |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline in Parent Symptoms Score Questionnaire | ||||||
End point description |
The Parent Symptoms Score Questionnaire contains 29 symptoms with an indicator of whether the symptom was present or absent.
Due to the inconsistent use of forms across visits and sites for this study, the data collected for this endpoint was incomplete, unreliable, and could not be evaluated.
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End point type |
Secondary
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End point timeframe |
Baseline, Day 180, Month 12
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| Notes [18] - See explanation in description above for reason this endpoint could not be evaluated. |
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| No statistical analyses for this end point | |||||||
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End point title |
Percent Change From Baseline in Body Mass Index After Treatment | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [19] - n=participants with an assessment at given time point |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Participants With Abnormalities in Standard Awake 45-Minutes-Electroencephalogram (EEG) Monitoring at Baseline and Day 180 | ||||||||||||||||||
End point description |
NCS=not clinically significant CS=clinically significant
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End point type |
Secondary
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End point timeframe |
Baseline, Day 180
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| Notes [20] - Participants with an assessment |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Change From Baseline in Vector Shedding Analysis in Plasma, Saliva, Stool and Urine | ||||||||||||||||||||||||||||||
End point description |
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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End point type |
Secondary
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End point timeframe |
Baseline, Day 30, Day 180, Month 12
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| Notes [21] - n=participants with an assessment at given time point; 99999=not applicable (1 participant analyzed) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All-Cause Mortality: From enrollment to the end of study; mean of 18 months. Adverse Events: from first dose of study drug up to Day 454.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Total
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Reporting group description |
An intravenous injection of ABO-102 (scAAV9.U1a.hSGSH) via peripheral limb vein at a dose of 3.0 x 1013 vg/kg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Apr 2018 |
• Added clarification to Secondary Outcome and Statistical Analysis that the Vineland Adaptive Behavior Scale II will be used
• Clarified sample types for lab work to include:
o Screening, Pre-infusion, Days 7, 14, 30, 90, 180, Months 12, 18, 24 visits: Aspartate aminotransferase (AST), alanine transaminase (ALT), serum/plasma gamma-glutamyl transpeptidase (serum/plasma GGT), Serum/plasma total bilirubin
o Day 1: Serum/plasma total bilirubin
o Days 45, 60, 75, 120, 150, 2-weeks post steroid taper visits: AST, ALT, serum/plasma GGT
• Clarified for Screening, Day 30, 180, Month 12 visit regarding abdominal magnetic resonance imaging (MRI) to measure liver and spleen volumes
• Clarified Section 6.3.1 Day of Gene Transfer (Day 0) instructions
• Section 6.4.1.1, added clarification regarding tapering instructions
• Added assessment at Day 30 for amylase levels
• Section 7.4.1, deleted ‘recession’
• Section 7.4.3: Updated with new data available
• Updated References |
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25 Feb 2019 |
• Separated signature pages for Sponsor and Principal Investigator
• Added tables to describe document history
• Clarified clinical phase of study
• Clarified study population and updated inclusion/exclusion criteria
• Updated primary, secondary and exploratory outcomes
• Reorganized the introduction sections according to a new template
• Removed age criteria
• Added inclusion criterion: Cognitive Development Quotient (DQ) lower than 60
• Added exclusion criteria:
• Participants with 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 a positive response for the ELISPOT for T-cell responses to AAV9
• 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 enzyme replacement therapy (ERT) clinical trial
• Deleted exclusion criteria:
• Prior treatment with n-sulfoglucosamine sulfohydrolase (SGSH) ERT
• Updated Primary and Secondary Outcome Measures and added Exploratory Measures
• Remove the Dose Limiting Toxicity section
• Included a section with Dosing New Participants, to clarify that patients will be treated with a 14-day interval
• Modify the Stopping Rules, to indicate that study will be halted if 2 or more SAEs (not Grade III AEs) are reported.
• Deleted neurocognitive assessment using Leiter scale
• Inclusion of a neurocognitive validity form
• Inclusion of the Vineland, Bayley, Mullen and Kaufman (depending on developmental age) scale neurocognitive assessment for all participants participating.
• Added Pediatric Quality of Life Inventory (PedsQL™), Parenting Stress Index, 4th Edition (PSI-4) and Children’s Sleep Habits Questionnaire (CSHQ) clinical questionnaire |
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25 Feb 2019 |
(continued)
• Added Sanfilippo Behavior Rating Scale (SBRS) Scales assessment, Parent Global Impression Score, Clinical Global Impression Improvement Scale and Parent Symptom Score Questionnaire
• Included diffusion tensor imaging (DTI) analysis on the brain MRI images.
• Changed the patient weight for dosing to the one obtained in Screening visit 2.
• Included four audiometry clinical assessments (Screening, Month 6, 12 and 24).
• Provided more detailed information about the vital sign collection after treatment
• Changed some study visit windows to allow more flexibility.
• Included new clinical biomarkers such as plasma and CSF cytokines, GM2/GM3.
• Added CSF biobanking
• Included new gene therapy biomarkers such as neutralizing antibodies against the adeno-associated Virus 9 (AAV9) capsid.
• Included a participant questionnaire to collect information on the quality of the service provided by vendors interacting with participants.
• Reorganized the safety sections according to a new template
• Limited the SAEs to those who are following the regulatory definition by International Conference on Harmonization (ICH) and not all grade 3, 4 or 5.
• Replaced terminology of ‘subject’ with ‘participant’
• Added 60-minute electroencephalogram (EEG) at Months, 6, 2, 18, and 24 |
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05 Mar 2020 |
• Added inclusion criterion: ‘Age range of 2 years up to 18 years (excluded)’.
• Updated the version of CTCAE to be referenced for AEs, to v4.03.
• Revised the following secondary outcome to exploratory outcome:
• Change from baseline in the Sanfilippo Behavior Rating Scale [Time Frame: Month 6, 12, 18, 24]
• Removed brain MRI assessment and brain DTI analysis at Days 30 and 180.
• Clarification of the scale to be used for the two arms in the study above and below 18 months of chronological age.
• Removed medical history assessment at Visits 2 and 3.
• Added urine pregnancy test (if applicable) at Day 0, Months 12 and 24.
• Added troponin in the panel of labs, to be assessed at Visit 1, Days -1 and 1, and at Visits 4 to 12.
• ELISpot assessment: removed from Day 7 and added at Days 45, 75, 120, and at 2-weeks post-steroid, if needed based on previous results.
• Corrected several inconsistencies between the schedule of evaluations table and Section 5, study procedures.
• Revised the electroencephalogram (EEG) assessment from 60-minute EEG to 45-minute EEG.
• Clarified that audiometry evaluations will start with tympanometry and otoacoustic emissions (OAE). In case relevant alterations are detected, an auditory brainstem response (ABR) along all frequencies will be assessed.
• Added the acceptable method of contraception for the study and instructions on reporting of pregnancy during the study.
• Specified the prohibited medications for the study and instructions on capturing concomitant medication/therapy.
• Specified that the blood sample schedule and collection allows for a maximum blood volume of 35 ml per study visit, with flexibility to the sites to reduce volume as per site policy if needed and that additional ad-hoc analysis on blood samples collected at any particular visit may be performed at the discretion of the principal investigator (PI). |
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05 Mar 2020 |
(continued)
• Specified the order of certain scales to be administered and the provision for use of an external qualified and trained rater, if the family signed the consent annex.
• Added that prophylactic enteral prednisone or prednisolone will not be provided by the Sponsor; the standard of care at the site/country should be used for prophylaxis.
• Revised the wording on long-term monitoring to include the long-term follow-up study designed to enroll participants who complete the current study.
• Provided rationale on the choice of primary and secondary outcomes.
• Clarified the definitions and reporting of AEs, SAEs and serious adverse reactions (SAR).
• Clarified the stopping/discontinuation rules for the study (Section 7.2).
• Added that the date of birth and age of the participant at screening will be collected to ensure that the appropriate age-based assessments are performed throughout the study. Demographic data including age, gender, race and date of birth will be collect at Visit 1.
• Clarified the Data Safety Monitoring Board (DSMB) roles and requirements, including an update to the minimum number of members required, from 3 to 4 members.
• Several editorial changes for clarity and correction of errors throughout the protocol.
• Clarified the EEG roles and requirements, including an update to the minimum number of members required, from 3 to 4 members.
• Several editorial changes for clarity and correction of errors throughout the protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
