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Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1 (STR1VE)

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ClinicalTrials.gov Identifier: NCT03306277
Recruitment Status : Completed
First Posted : October 11, 2017
Results First Posted : July 16, 2020
Last Update Posted : June 14, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Gene Therapies )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions SMA - Spinal Muscular Atrophy
Gene Therapy
Intervention Biological: Onasemnogene Abeparvovec-xioi
Enrollment 22
Recruitment Details 22 participants were recruited across 16 study centers in the United States.
Pre-assignment Details A screening period of up to 30 days occurred before treatment.
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Period Title: Overall Study
Started 22
Completed 19
Not Completed 3
Reason Not Completed
Death             1
Adverse Event             1
Withdrawal by Subject             1
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Overall Number of Baseline Participants 22
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
<=18 years
22
 100.0%
Between 18 and 65 years
0
   0.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 22 participants
3.7  (1.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Female
12
  54.5%
Male
10
  45.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Hispanic or Latino
4
  18.2%
Not Hispanic or Latino
18
  81.8%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
   9.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
3
  13.6%
White
11
  50.0%
More than one race
0
   0.0%
Unknown or Not Reported
6
  27.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 22 participants
22
Patient reported hospitalizations  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 22 participants
Yes 17
No 5
Weight at baseline  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 22 participants
5.8  (1.1)
Height/length at baseline  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 22 participants
61.3  (4.3)
1.Primary Outcome
Title Achievement of Independent Sitting for at Least 30 Seconds
Hide Description

Independent sitting is defined as sitting up straight with head erect for at least 30 seconds.

This endpoint is a co-primary endpoint. 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 event-free survival assessed.

Time Frame Up to 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description:

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Overall Number of Participants Analyzed 22
Measure Type: Count of Participants
Unit of Measure: Participants
13
  59.1%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Onasemnogene Abeparvovec-xioi
Comments This comparison is made to an assumed rate of zero 0 (or as low as 0.1%). By definition, children with spinal muscular atrophy Type 1 are never able to sit independently.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Exact Binomial Test
Comments [Not Specified]
2.Primary Outcome
Title Event-free Survival
Hide Description

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.

The endpoint is a co-primary endpoint. 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.

Time Frame 14 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description:

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Overall Number of Participants Analyzed 22
Measure Type: Count of Participants
Unit of Measure: Participants
20
  90.9%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Onasemnogene Abeparvovec-xioi
Comments 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].
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
3.Secondary Outcome
Title Ability to Thrive
Hide Description

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

This is a co-secondary endpoint. 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.

Time Frame 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description:

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Overall Number of Participants Analyzed 22
Measure Type: Count of Participants
Unit of Measure: Participants
9
  40.9%
4.Secondary Outcome
Title Ventilatory Support Independence
Hide Description

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 BiPAP device). This endpoint is derived solely from the Phillips Trilogy BiPAP device.

This is a co-secondary endpoint. 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.

Time Frame Up to 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description:

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Overall Number of Participants Analyzed 22
Measure Type: Count of Participants
Unit of Measure: Participants
18
  81.8%
Time Frame Up to 18 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Onasemnogene Abeparvovec-xioi
Hide Arm/Group Description

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Onasemnogene Abeparvovec-xioi: Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

All-Cause Mortality
Onasemnogene Abeparvovec-xioi
Affected / at Risk (%)
Total   1/22 (4.55%)    
Hide Serious Adverse Events
Onasemnogene Abeparvovec-xioi
Affected / at Risk (%) # Events
Total   10/22 (45.45%)    
Cardiac disorders   
Cyanosis * 1  1/22 (4.55%)  1
Gastrointestinal disorders   
Dysphagia * 1  1/22 (4.55%)  1
Infections and infestations   
Bronchiolitis * 1  2/22 (9.09%)  2
Pneumonia * 1  2/22 (9.09%)  2
Respiratory syncytial virus bronchiolitis * 1  2/22 (9.09%)  2
Bacterial tracheitis * 1  1/22 (4.55%)  1
Device related infection * 1  1/22 (4.55%)  1
Pneumonia bacterial * 1  1/22 (4.55%)  1
Rhinovirus infection * 1  1/22 (4.55%)  2
Sepsis * 1  1/22 (4.55%)  1
Upper respiratory tract infection * 1  1/22 (4.55%)  1
Investigations   
Alanine aminotransferase increased * 1  1/22 (4.55%)  1
Aspartate aminotransferase increased * 1  1/22 (4.55%)  1
Human metapneumovirus test positive * 1  1/22 (4.55%)  1
Transaminases increased * 1  1/22 (4.55%)  1
Metabolism and nutrition disorders   
Abnormal weight gain * 1  1/22 (4.55%)  1
Failure to thrive * 1  1/22 (4.55%)  1
Feeding disorder * 1  1/22 (4.55%)  1
Nervous system disorders   
Hydrocephalus * 1  1/22 (4.55%)  1
Product Issues   
Device malfunction * 1  1/22 (4.55%)  1
Respiratory, thoracic and mediastinal disorders   
Respiratory distress * 1  4/22 (18.18%)  7
Respiratory failure * 1  2/22 (9.09%)  2
Acute respiratory failure * 1  1/22 (4.55%)  1
Atelectasis * 1  1/22 (4.55%)  2
Pneumonia aspiration * 1  1/22 (4.55%)  1
Respiratory arrest * 1  1/22 (4.55%)  1
1
Term from vocabulary, MedDRA (20.1)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Onasemnogene Abeparvovec-xioi
Affected / at Risk (%) # Events
Total   22/22 (100.00%)    
Blood and lymphatic system disorders   
Thrombocytopenia * 1  2/22 (9.09%)  2
Cardiac disorders   
Pericardial effusion * 1  2/22 (9.09%)  2
Congenital, familial and genetic disorders   
Pectus excavatum * 1  3/22 (13.64%)  3
Asphyxiating thoracic dystrophy * 1  2/22 (9.09%)  2
Cryptorchism * 1  2/22 (9.09%)  2
High arched palate * 1  2/22 (9.09%)  2
Gastrointestinal disorders   
Constipation * 1  9/22 (40.91%)  11
Teething * 1  5/22 (22.73%)  6
Diarrhoea * 1  4/22 (18.18%)  4
Gastroesophageal reflux disease * 1  4/22 (18.18%)  4
Vomiting * 1  4/22 (18.18%)  8
Abdominal distension * 1  2/22 (9.09%)  2
Dysphagia * 1  2/22 (9.09%)  2
Haematochezia * 1  2/22 (9.09%)  2
General disorders   
Pyrexia * 1  12/22 (54.55%)  26
Infections and infestations   
Upper respiratory tract infection * 1  11/22 (50.00%)  28
Conjunctivitis * 1  3/22 (13.64%)  3
Otitis media * 1  3/22 (13.64%)  4
Respiratory syncytial virus bronchiolitis * 1  2/22 (9.09%)  3
Gastroenteritis * 1  2/22 (9.09%)  2
Nasopharyngitis * 1  2/22 (9.09%)  2
Injury, poisoning and procedural complications   
Contusion * 1  4/22 (18.18%)  4
Arthropod bite * 1  3/22 (13.64%)  7
Investigations   
Aspartate aminotransferase increased * 1  6/22 (27.27%)  9
Alanine aminotransferase increased * 1  5/22 (22.73%)  8
Blood creatine phosphokinase MB increased * 1  2/22 (9.09%)  2
Gamma-glutamyltransferase increased * 1  2/22 (9.09%)  2
Lymphocyte count decreased * 1  2/22 (9.09%)  2
Weight decreased * 1  2/22 (9.09%)  2
Metabolism and nutrition disorders   
Feeding disorder * 1  3/22 (13.64%)  4
Weight gain poor * 1  2/22 (9.09%)  2
Musculoskeletal and connective tissue disorders   
Scoliosis * 1  9/22 (40.91%)  12
Deformity thorax * 1  2/22 (9.09%)  2
Joint contracture * 1  2/22 (9.09%)  2
Kyphosis * 1  2/22 (9.09%)  2
Torticollis * 1  2/22 (9.09%)  2
Nervous system disorders   
Muscle contractions involuntary * 1  2/22 (9.09%)  3
Respiratory, thoracic and mediastinal disorders   
Use of accessory respiratory muscles * 1  5/22 (22.73%)  7
Cough * 1  7/22 (31.82%)  10
Respiratory distress * 1  6/22 (27.27%)  10
Respiration abnormal * 1  5/22 (22.73%)  6
Nasal congestion * 1  3/22 (13.64%)  3
Sleep apnoea syndrome * 1  3/22 (13.64%)  3
Tachypnoea * 1  3/22 (13.64%)  3
Respiratory track congestion * 1  2/22 (9.09%)  2
Rhinorrhea * 1  2/22 (9.09%)  2
Upper respiratory tract congestion * 1  2/22 (9.09%)  2
Skin and subcutaneous tissue disorders   
Rash * 1  5/22 (22.73%)  5
Dermatitis atopic * 1  3/22 (13.64%)  3
Eczema * 1  3/22 (13.64%)  3
Dermatitis contact * 1  2/22 (9.09%)  3
Dermatitis diaper * 1  2/22 (9.09%)  4
Urticaria * 1  2/22 (9.09%)  2
Vascular disorders   
Diastolic hypertension * 1  2/22 (9.09%)  2
1
Term from vocabulary, MedDRA (20.1)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Sponsor can review results communications prior to public release and has right to request changes to communications regarding trial results for a period that is more or equal to 30 days but less than or equal to 150 days from the time submitted to the Sponsor for review in order to either delete references to Sponsor's Confidential Information or delay such results communications to permit Sponsor to obtain appropriate Intellectual Property protection as set forth in the agreement.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: US Medical Information
Organization: AveXis, Inc
Phone: 833-828-3947
EMail: medinfo@avexis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Gene Therapies )
ClinicalTrials.gov Identifier: NCT03306277    
Other Study ID Numbers: AVXS-101-CL-303
2020-000095-38 ( EudraCT Number )
First Submitted: October 2, 2017
First Posted: October 11, 2017
Results First Submitted: June 25, 2020
Results First Posted: July 16, 2020
Last Update Posted: June 14, 2021