Clinical Trial Results:
Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
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Summary
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EudraCT number |
2020-000095-38 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
12 Nov 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
02 Sep 2022
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First version publication date |
22 May 2020
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Other versions |
v1 |
Version creation reason |
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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 |
AVXS-101-CL-303
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03306277 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AveXis, Inc
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Sponsor organisation address |
2275 Half Day Road, Bannockburn, United States, IL 60015
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Public contact |
EMEA Medical Information, AveXis Eu Ltd , +353 (1) 566-2364, medinfo.emea@avexis.com
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Scientific contact |
EMEA Medical Information, AveXis Eu Ltd , +353 (1) 566-2364, medinfo.emea@avexis.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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Nov 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Nov 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Nov 2019
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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 |
• Determine efficacy by demonstrating achievement of developmental milestone of functional independent sitting for at least 30 seconds at the 18 months of age visit.
• Determine the efficacy based on survival at 14 months of age. Survival is defined by avoidance of combined endpoint of either (a) death or (b) permanent ventilation.
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Protection of trial subjects |
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements and the AveXis’ policy on Bioethics.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Oct 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Regulatory reason | ||
Long term follow-up duration |
15 Years | ||
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 |
United States: 22
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Worldwide total number of subjects |
22
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EEA total number of subjects |
0
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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) |
1
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Infants and toddlers (28 days-23 months) |
21
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Children (2-11 years) |
0
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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 |
22 participants were recruited at 12 study centres in the United States. | ||||||||||||||
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Pre-assignment
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Screening details |
A screening period of up to 30 days occurred before treatment. | ||||||||||||||
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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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AVXS-101 | ||||||||||||||
Arm description |
Single dose of AVXS-101 administered as an intravenous (IV) infusion. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
AVXS-101
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Investigational medicinal product code |
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Other name |
Onasemnogene Abeparvovec-xioi
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received a single dose of AVXS-101 as an intravenous (IV) infusion.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
AVXS-101
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Reporting group description |
Single dose of AVXS-101 administered as an intravenous (IV) infusion. | ||
Subject analysis set title |
PNCR (Historical Control)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Participants in historical control PNCR cohort received uniform standard of care treatment. Participants visited the study site at baseline and at 2, 4, 6, 9, 12 months and every 6 months thereafter.
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End point title |
Achievement of independent sitting for at least 30 seconds [1] | ||||||
End point description |
This endpoint is a co-primary endpoint.
Independent sitting is defined as sitting for at least 30 seconds at the 18 months of age visit.
A one-sided Exact Binomial Test was used to test the null hypothesis of p=0.1% at significance level of 0.025. The corresponding 97.5% confidence intervals was estimated by the exact method for binomial proportions. It was assumed that the true response rate for the primary endpoint was actually zero (or as low as 0.1%) in the population of historical control; the first co-primary efficacy endpoint hypothesis was that the AVXS-101 treated participants achieve a response rate greater than 0.1%.
The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the endpoint of survival assessed.
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End point type |
Primary
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End point timeframe |
At 18 months of age visit
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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: There are no statistical analyses associated with this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Event-free survival [2] | ||||||
End point description |
The endpoint is a co-primary endpoint.
Survival is defined by the avoidance of combined endpoint of either death or permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation is considered a surrogate for death. An acute reversible illness is defined as any condition other than SMA that results in increased medical intervention.
A two sample 2-sided Fischer's exact test was used to test the null hypothesis of p=historical at the significance level of 0.05.
The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the survival endpoint assessed.
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End point type |
Primary
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End point timeframe |
14 months of age
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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: There are no statistical analyses associated with this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Ability to thrive | ||||||
End point description |
This is a co-secondary endpoint.
Ability to thrive is defined as achieving all of the following at 18 months of age:
- does not receive nutrition through mechanical support or other non-oral method
- ability to tolerate thin liquids as demonstrated through a formal swallowing test
- maintains weight
The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed. Comparison to the historical was made using 0.1% as comparison, as the percentage of participants who maintained ability to thrive was essentially 0.
One-sided exact binomial tests were executed for secondary efficacy analyses on the Intent to Treat (ITT) population.
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End point type |
Secondary
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End point timeframe |
At 18 months of age
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| Notes [3] - Two participants discontinued the study prior to 18 months. |
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| No statistical analyses for this end point | |||||||
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End point title |
Ventilatory support independence | ||||||
End point description |
This is a co-secondary endpoint.
Ventilatory support independence is defined as requiring no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative ventilation, through assessment of actual usage data captured from the device (Phillips Trilogy).
The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed. Comparison to the historical was made using 0.1% as comparison, as the percentage of participants who maintained independence from ventilatory support was essentially 0.
One-sided exact binomial tests were executed for secondary efficacy analyses on the Intent to Treat (ITT) population.
Two participants had Trilogy data at or after 18 months of age.
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End point type |
Secondary
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End point timeframe |
At 18 months
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| Notes [4] - Two participants discontinued the study prior to 18 months. |
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| No statistical analyses for this end point | |||||||
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End point title |
Event-free Survival at 14 Months of Age Compared to Data From an Historical Control, Pediatric Neuromuscular Clinical Research Network (PNCR), Finkel et al, 2014 | |||||||||
End point description |
Data for the current study were compared to data from an historical control (PNCR. Finkel et al, 2014 - PubMed 25080519). Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age.
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End point type |
Other pre-specified
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End point timeframe |
14 months of age
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Statistical analysis title |
AVXS-101 versus PNCR | |||||||||
Statistical analysis description |
This comparison is made against the results from the age and gender-matched control participants selected from existing natural history data sets (PNCR) [Neurol. 2014; 83(9):810-817].
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Comparison groups |
AVXS-101 v PNCR (Historical Control)
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Number of subjects included in analysis |
45
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
P-value |
< 0.0001 | |||||||||
Method |
Fisher exact | |||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Up to 18 months of age
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
AVXS-101
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Reporting group description |
Single dose of AVXS-101 administered as an intravenous (IV) infusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 Oct 2017 |
Updated to include cardiac enzyme monitoring (CK-MB), added AVXS-101 dose determined through ddPCR with AveXis GMP product, and to require a total of 15 participants meeting the ITT criteria to be enrolled. |
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21 Dec 2017 |
Updated to clarify the data points which require review for the first three participants prior to continuing with enrollment. Additionally, a Day -1 CHOP-INTEND assessment was added. |
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04 Oct 2018 |
Updated to included updated and recent GLP toxicology data, to provide additional cardiac monitoring for patient safety, standardize infusion times within protocol, allow laboratory samples to be processed locally in certain instances, and to exclude participants from Bayley scales where English is not their first language to preserve the validity of the Bayley scales. |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/22467740 |
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