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Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

Primary Purpose

Spinal Muscular Atrophy 1

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

AVXS-101

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy 1 focused on measuring Gene Transfer, Gene Therapy, Adeno-associated virus, Survival Motor Neuron, SMN, AAV9

Eligibility Criteria

undefined - 6 Months (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA as defined by the following features:
- Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2.
- Onset of disease at birth up to 6 months of age.
- Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints.

Exclusion Criteria:

Active viral infection (includes HIV or serology positive for hepatitis B or C)
Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry <95% saturation.
Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff.
Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer
Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay.
Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer.
Family does not want to disclose patient's study participation with primary care physician and other medical providers.
Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding.
Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded based on predicted mild phenotype.

Sites / Locations

Nationwide Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Arm Description

6.7 X 10^13 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=3)

2.0 X 10^14 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=12)

Outcomes

Primary Outcome Measures

Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment

Secondary Outcome Measures

Number of Participants Who Experienced Permanent Ventilation or Death

Permanent ventilation was defined as the requirement of ≥ 16-hour respiratory assistance, including non-invasive ventilatory support, per day continuously for ≥ 2 weeks in the absence of an acute reversible illness, excluding perioperative ventilation.

Percent Change From Baseline in Mean Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Score

Score ranges from 0 to 64, where 64 is the maximum possible score. A higher score is indicative of higher/better motor function. CHOP-INTEND assessments were discontinued once patients achieved higher functioning status, so the number of available data points decreased over time.

Number of Participants With Assessed Improvement in Motor Function

Improvement in motor function was determined by achievement of developmental milestones, specifically achievement of ability to sit unassisted for at least 30 seconds, determined by physical therapist and confirmed by an independent central video reviewer. Achievement of functional independent sitting was defined as the ability to maintain a sitting position independently for at least 30 seconds as confirmed per video evaluation by an expert central reviewer based on videos taken either at scheduled visits or provided by the parent/legal guardian.

Full Information

NCT ID

NCT02122952

First Posted

April 23, 2014

Last Updated

August 30, 2022

Sponsor

Novartis Gene Therapies

1. Study Identification

Unique Protocol Identification Number

NCT02122952

Brief Title

Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

Official Title

Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering AVXS-101

Study Type

Interventional

2. Study Status

Record Verification Date

August 2022

Overall Recruitment Status

Completed

Study Start Date

May 5, 2014 (Actual)

Primary Completion Date

December 15, 2017 (Actual)

Study Completion Date

December 15, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Gene Therapies

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this trial is to evaluate safety and efficacy of intravenous delivery of AVXS-101 as a treatment of spinal muscular atrophy Type 1 (SMN1).

Detailed Description

The study will evaluate safety and efficacy of gene therapy in spinal muscular atrophy Type 1 (SMA1) patients. SMA is caused by low levels of the survival motor neuron (SMN) protein, and affects all muscles in the body. There is no effective treatment for SMA and current drug therapy has been unsuccessful in stabilizing or reversing this disease. Only supportive care is currently possible. Open-label, dose-escalation clinical trial of AVXS-101 injected intravenously through a peripheral limb vein. Short-term safety will be evaluated over a two year period. Patients will be tested at baseline and return for follow up visits on days 7, 14, 21, 30, followed by once every month through 12 months post dose, and then every three months through two (2) years post infusion. Unscheduled visits may occur if the PI determines that they are necessary. The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age (a database lock will be performed at the time point at which all patients reach 13.6 months of age). A follow-up safety analysis will be completed at the time point at which the last patient reaches 24 months post-dose. Upon completion of the 2-year study period, patients will be monitored annually as per standard of care for up to 15 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Spinal Muscular Atrophy 1

Keywords

Gene Transfer, Gene Therapy, Adeno-associated virus, Survival Motor Neuron, SMN, AAV9

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

6.7 X 10^13 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=3)

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

2.0 X 10^14 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=12)

Intervention Type

Biological

Intervention Name(s)

AVXS-101

Other Intervention Name(s)

Zolgensma

Intervention Description

Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Primary Outcome Measure Information:

Title

Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Number of Participants Who Experienced Permanent Ventilation or Death

Description

Time Frame

Up to 13.6 months of age

Title

Percent Change From Baseline in Mean Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Score

Description

Time Frame

Baseline to 24 months post-dose

Title

Number of Participants With Assessed Improvement in Motor Function

Description

Time Frame

24 months post-dose

10. Eligibility

Sex

All

Maximum Age & Unit of Time

6 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA as defined by the following features: Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2. Onset of disease at birth up to 6 months of age. Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints. Exclusion Criteria: Active viral infection (includes HIV or serology positive for hepatitis B or C) Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry <95% saturation. Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff. Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab) Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer. Family does not want to disclose patient's study participation with primary care physician and other medical providers. Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding. Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded based on predicted mild phenotype.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jerry R Mendell, MD

Organizational Affiliation

The Research Institute at Nationwide Children's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

21811247

Citation

Bevan AK, Duque S, Foust KD, Morales PR, Braun L, Schmelzer L, Chan CM, McCrate M, Chicoine LG, Coley BD, Porensky PN, Kolb SJ, Mendell JR, Burghes AH, Kaspar BK. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther. 2011 Nov;19(11):1971-80. doi: 10.1038/mt.2011.157. Epub 2011 Aug 2.

Results Reference

background

PubMed Identifier

20639395

Citation

Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH, Kaspar BK. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet. 2010 Oct 15;19(20):3895-905. doi: 10.1093/hmg/ddq300. Epub 2010 Jul 16.

Results Reference

background

PubMed Identifier

20190738

Citation

Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.

Results Reference

background

PubMed Identifier

19098898

Citation

Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65. doi: 10.1038/nbt.1515. Epub 2008 Dec 21.

Results Reference

background

PubMed Identifier

34383289

Citation

Day JW, Mendell JR, Mercuri E, Finkel RS, Strauss KA, Kleyn A, Tauscher-Wisniewski S, Tukov FF, Reyna SP, Chand DH. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12. Erratum In: Drug Saf. 2022 Feb;45(2):191-192.

Results Reference

derived

PubMed Identifier

31277975

Citation

Lowes LP, Alfano LN, Arnold WD, Shell R, Prior TW, McColly M, Lehman KJ, Church K, Sproule DM, Nagendran S, Menier M, Feltner DE, Wells C, Kissel JT, Al-Zaidy S, Mendell J. Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatr Neurol. 2019 Sep;98:39-45. doi: 10.1016/j.pediatrneurol.2019.05.005. Epub 2019 May 13.

Results Reference

derived

PubMed Identifier

30879249

Citation

Dabbous O, Maru B, Jansen JP, Lorenzi M, Cloutier M, Guerin A, Pivneva I, Wu EQ, Arjunji R, Feltner D, Sproule DM. Survival, Motor Function, and Motor Milestones: Comparison of AVXS-101 Relative to Nusinersen for the Treatment of Infants with Spinal Muscular Atrophy Type 1. Adv Ther. 2019 May;36(5):1164-1176. doi: 10.1007/s12325-019-00923-8. Epub 2019 Mar 16.

Results Reference

derived

PubMed Identifier

30548438

Citation

Al-Zaidy S, Pickard AS, Kotha K, Alfano LN, Lowes L, Paul G, Church K, Lehman K, Sproule DM, Dabbous O, Maru B, Berry K, Arnold WD, Kissel JT, Mendell JR, Shell R. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019 Feb;54(2):179-185. doi: 10.1002/ppul.24203. Epub 2018 Dec 12.

Results Reference

derived

PubMed Identifier

29091557

Citation

Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L'Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-1722. doi: 10.1056/NEJMoa1706198.

Results Reference

derived

Links:

URL

http://www.nationwidechildrens.org/center-for-gene-therapy

Description

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital

URL

http://avexis.com/

Description

AveXis, Inc

URL

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17849

Description

Novartis Clinical Trial Results

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Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

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