Clinical Trial Results:
Phase IIIb, open-label, single-arm, multi-center study to evaluate the safety, tolerability and efficacy of OAV101 administered intrathecally (1.2 x 10^14 vector genomes) to participants 2 to <18 years of age with spinal muscular atrophy (SMA) who have discontinued treatment with nusinersen (Spinraza®) or risdiplam (Evrysdi®)
Summary
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EudraCT number |
2021-006709-31 |
Trial protocol |
ES FR DE BE NL IT |
Global end of trial date |
29 Nov 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
31 May 2025
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First version publication date |
31 May 2025
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Other versions |
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 |
COAV101B12302
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT05386680 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
Novartis Campus, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
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Scientific contact |
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.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-002168-PIP01-17 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Nov 2024
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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 |
29 Nov 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to characterize the safety and tolerability of OAV101B (administered by lumbar intrathecal injection) over a 52-week period in participants with SMA aged 2 to <18 years who had discontinued treatment with nusinersen or risdiplam.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Jan 2023
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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 |
Australia: 1
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Country: Number of subjects enrolled |
Belgium: 2
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Country: Number of subjects enrolled |
Canada: 1
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Japan: 4
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Country: Number of subjects enrolled |
Netherlands: 6
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
27
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EEA total number of subjects |
18
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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) |
25
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Adolescents (12-17 years) |
2
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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 |
- | ||||||||||
Pre-assignment
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Screening details |
The study aimed to enroll approximately 28 participants across each of 2 age brackets (2 to <6 years, and 6 to <18 years). | ||||||||||
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 | ||||||||||
Arms
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Arm title
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OAV101 1.2x10^14 vg - All participants | ||||||||||
Arm description |
Intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes, one time dose | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
onasemnogene abeparvovec-xioi
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Investigational medicinal product code |
OAV101
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intrathecal use
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Dosage and administration details |
administered at a dose 1.2 x 10^14 vector genomes as a one-time injection
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Baseline characteristics reporting groups
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Reporting group title |
OAV101 1.2x10^14 vg - All participants
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Reporting group description |
Intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes, one time dose | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
OAV101 1.2x10^14 vg - All participants
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Reporting group description |
Intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes, one time dose |
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End point title |
Overview of treatment-emergent adverse events by age subgroup [1] | ||||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.
disc. = discontinuation
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End point type |
Primary
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End point timeframe |
Adverse events were reported from single dose of study treatment plus 52 weeks, up to a maximum time period of 52 weeks.
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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: not applicable for single arm study |
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No statistical analyses for this end point |
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End point title |
Treatment-emergent adverse events related to treatment by system organ class, preferred term, age subgroup (>= 10%) [2] | ||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.
adm. = administration
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End point type |
Primary
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End point timeframe |
Adverse events were reported from single dose of study treatment plus 52 weeks, up to a maximum time period of 52 weeks.
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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: not applicable for single arm study |
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No statistical analyses for this end point |
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End point title |
Adverse events of special interest by system organ class, preferred term, age subgroup [3] | ||||||||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments.
An adverse event of special interest (AESI) is primarily defined by using standard Medical Dictionary for Regulatory Activities (MedDRA) queries, and identified as follows: Hepatotoxicity, Transient thrombocytopenia, Thrombotic microangiopathy, Cardiac adverse events, signs and symptoms that may be suggestive dorsal root ganglia toxicity, and new malignancies.
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End point type |
Primary
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End point timeframe |
Adverse events were reported from single dose of study treatment plus 52 weeks, up to a maximum time period of 52 weeks.
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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: not applicable for single arm study |
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in the HFMSE total score - Mean (SD) | ||||||||
End point description |
The Hammersmith Functional Motor Scale Expanded (HFMSE) is a SMA-specific 33-item assessment that is administered by qualified clinical evaluators. Each motor skill item is scored on a 3-point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 66. A higher score indicates a higher ability level.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in the RULM total Score - Mean (SD) | ||||||||
End point description |
The Revised Upper Limb Model (RULM) is a validated, SMA-specific assessment that measures motor performance in the upper limbs from childhood through adulthood in ambulatory and never ambulatory individuals with SMA. The revised version of the test consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). These item scores are summed to give a total score ranging from 0 to 37 points with lower scores reflecting poorer ability.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in Assessment of Caregiver Experience in ACEND instrument score - Mean (SD) | ||||||||
End point description |
The Assessment of Caregiver Experience in Neuromuscular Disease (ACEND) instrument quantifies the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. The total score is on a scale of 0 to 100 with a higher score indicating that caregivers experienced less intense caregiving impact.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in the HFMSE total score - LS Means | ||||||||
End point description |
The Hammersmith Functional Motor Scale Expanded (HFMSE) is a SMA-specific 33-item assessment that is administered by qualified clinical evaluators. Each motor skill item is scored on a 3-point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 66. A higher score indicates a higher ability level.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in the RULM total Score - LS Means | ||||||||
End point description |
The Revised Upper Limb Model (RULM) is a validated, SMA-specific assessment that measures motor performance in the upper limbs from childhood through adulthood in ambulatory and never ambulatory individuals with SMA. The revised version of the test consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). These item scores are summed to give a total score ranging from 0 to 37 points with lower scores reflecting poorer ability.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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No statistical analyses for this end point |
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End point title |
Change from baseline at Week 52 visit in Assessment of Caregiver Experience in ACEND instrument score - LS Means | ||||||||
End point description |
The Assessment of Caregiver Experience in Neuromuscular Disease (ACEND) instrument quantifies the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. The total score is on a scale of 0 to 100 with a higher score indicating that caregivers experienced less intense caregiving impact.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 52
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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 |
Adverse events were reported from single dose of study treatment plus 52 weeks, up to a maximum time period of 52 weeks.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
27.1
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Reporting groups
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Reporting group title |
Overall
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Reporting group description |
Overall | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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17 May 2023 |
The purpose of this amendment was to expand the age group for inclusion in the study from 2 to 12 years of age, to 2 to <18 years of age to cover the full pediatric age range and for consistency with the study population age range of Novartis Phase III study (COAV101B2301) in treatment naïve participants aged 2 to <18 years.
In addition, the risk language has been revised to include the theoretical risk of tumorigenicity due to the very low potential incorporation of AAV vector DNA into chromosomal DNA that has been noted based on published literature for AAV-based therapies; also, the liver safety monitoring for elevated levels has been updated to apply more stringent monitoring to ensure a timely follow-up and to align with FDA guidance for drug induced liver toxicity. |
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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 |