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CompletedNCT03505099SPR1NTUpdated Jan 26, 2026Results posted

Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2

A Phase 3 interventional study of onasemnogene abeparvovec-xioi in Spinal Muscular Atrophy, sponsored by Novartis Gene Therapies. Completed at 16 sites in 6 countries. Open to participants aged Up to 42 Days. Per ClinicalTrials.gov, last updated 2026-01-26.

Sponsored by Novartis Gene Therapies · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
30
Allocation
Not applicable
Ages
Up to 42 Days
Sex
All
01

Study summary

To evaluate the safety and efficacy of intravenous onasemnogene abeparvovec-xioi in pre-symptomatic patients with SMA and 2 or 3 copies SMN2

Read the detailed description

Phase 3, open-label, single-arm study of a single, one-time dose of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy who meet enrollment criteria and are genetically defined by bi-allelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not be included in the efficacy analysis sets.

The study includes a screening period, a gene replacement therapy period, and a follow-up period. During the screening period (Days -30 to -2), patients whose parent(s)/legal guardian(s) provide informed consent will undergo screening procedures to determine eligibility for study enrollment. Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 2). On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will receive a single, one-time intravenous (IV) infusion of onasemnogene abeparvovec-xioi, and will undergo in-patient safety monitoring for a minimum of 24 hours post infusion. Patients may be discharged 24 hours (48 hours in Japan) after the infusion, based on Investigator judgment. During the outpatient follow-up period (Days 3 to End of Study at 18 or 24 of age, dependent upon respective SMN2 copy number), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Study when the patient reaches 18 months of age (SMN2 = 2) or 24 months of age (SMN2 = 3). After the End of Study visit, eligible patients will be invited to rollover into a long-term follow up study.

02

Conditions studied

  • Spinal Muscular Atrophy

Keywords

  • gene therapy
03

Who can participate

Ages eligible
Up to 42 Days
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Age ≤6 weeks (≤42 days) at time of dose
  • Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
  • Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of CMAP data will be conducted
  • Gestational age of 35 to 42 weeks

  • Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

    • Patients with pre-symptomatic SMA Type 1 as determined by the following features:

      a. 2 copies of SMN2 (n ≥14)

    • Patients with pre-symptomatic SMA Type 2 as determined by the following features:

      1. 3 copies of SMN2 (n ≥12)

Exclusion criteria

Exclusion Criteria:

  • Weight at screening visit \<2 kg
  • Hypoxemia (oxygen saturation \<96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation \<92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
  • Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA
  • Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory support at any time and for any duration prior to screening or during the screening period
  • Patients with signs of aspiration/inability to tolerate nonthickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
  • Clinically significant abnormal laboratory values (gamma-glutamyl transferase [GGT], Alanine transaminase [ALT], and aspartate aminotransferase [AST], or total bilirubin > 2 × the upper limit of normal [ULN], creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] \< 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
  • Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
  • Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards

  • Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C)

    • Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA. Positive results warrant confirmed negative Zika virus RNA testing in the patient prior to enrollment.
  • Serious nonrespiratory tract illness requiring systemic treatment and/or hospitalization within 2 Weeks prior to screening
  • Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 Weeks prior to dosing

  • Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Investigator or Sponsor medical monitor, creates unnecessary risks for gene replacement therapy such as:

    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalciuria
    • Symptomatic cardiomyopathy
  • Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  • Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
  • Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 4 Weeks prior to gene replacement therapy

  • AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay

    • Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may receive retesting inside the 30-Day screening period and will be eligible to participate if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the \<6 Week age requirement at the time of dosing is still met
  • Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to dosing
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrollment
30 participants (actual)

Study arms

  • Experimental
    onasemnogene abeparvovec-xioi

    One-time intravenous infusion of onasemnogene abeparvovec-xioi at 1.1 X 10\^14 vg/kg

    Biological: onasemnogene abeparvovec-xioi

Interventions

  • Biologicalonasemnogene abeparvovec-xioi

    A non-replicating recombinant 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.

    Also known as: Zolgensma

05

What researchers measure

Primary outcomes

  1. Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds

    Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 26, confirmed by video recording, as a participant who sits for at least 30 seconds without assistance from another person or object. The participant was allowed to use their upper extremities.

    Time frame: From Day 1 up to 18 months of age visit

  2. Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds

    Defined by the BSID GM subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported.

    Time frame: From Day 1 up to 24 months of age visit

Secondary outcomes

  1. Cohort 1: Event-free Survival at 14 Months of Age

    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.

    Time frame: From Day 1 up to 14 months of age

  2. Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support

    The ability to maintain weight at or above the third percentile without the need for non-oral or mechanical feeding support was defined by meeting the following criteria at each visit up to 18 months of age: * Did not receive nutrition through mechanical support (i.e., feeding tube) * Maintained weight (≥ third percentile for age and sex as defined by World Health Organization \[WHO\] guidelines) consistent with the participant's age at the assessment.

    Time frame: From Day 1 up to 18 months of age

  3. Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone

    Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps.

    Time frame: From Day 1 up to 24 months of age visit

06

Results

Posted Jan 11, 2022
Limitations and caveats
Link to the full study results: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17902

Participant flow

A total of 30 participants took part in the trial at 16 sites in the United States, the United Kingdom, Belgium, Canada, Australia and Japan between April 2018 and June 2021.

Participant flow — Overall Study
MilestoneCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
Started1415
Received avxs-1011415
Completed1415
Not completed00

Outcome measures

PrimaryCohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds

Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 26, confirmed by video recording, as a participant who sits for at least 30 seconds without assistance from another person or object. The participant was allowed to use their upper extremities.

Time frame:
From Day 1 up to 18 months of age visit
Reported as:
Count of participants · Participants
Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds
ParticipantsCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds14
PrimaryCohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds

Defined by the BSID GM subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported.

Time frame:
From Day 1 up to 24 months of age visit
Reported as:
Count of participants · Participants
Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds
ParticipantsCohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds15
Statistical analysis
  • Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2 · Fisher Exact · p = <0.0001 · Difference of proportion: 76.5 · 95% CI 50.95 to 92.21
SecondaryCohort 1: Event-free Survival at 14 Months of Age

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.

Time frame:
From Day 1 up to 14 months of age
Reported as:
Count of participants · Participants
Cohort 1: Event-free Survival at 14 Months of Age
ParticipantsCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
Cohort 1: Event-free Survival at 14 Months of Age14
Statistical analysis
  • Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2 · Fisher Exact · p = <0.0001 · Difference of proportion: 73.9 · 95% CI 44.67 to 91.61
SecondaryCohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support

The ability to maintain weight at or above the third percentile without the need for non-oral or mechanical feeding support was defined by meeting the following criteria at each visit up to 18 months of age: * Did not receive nutrition through mechanical support (i.e., feeding tube) * Maintained weight (≥ third percentile for age and sex as defined by World Health Organization \[WHO\] guidelines) consistent with the participant's age at the assessment.

Time frame:
From Day 1 up to 18 months of age
Reported as:
Count of participants · Participants
Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support
ParticipantsCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support13
SecondaryCohort 2: Number of Participants Who Achieved the Ability to Walk Alone

Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps.

Time frame:
From Day 1 up to 24 months of age visit
Reported as:
Count of participants · Participants
Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone
ParticipantsCohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone14
Statistical analysis
  • Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2 · Fisher Exact · p = <0.0001 · Difference of proportion: 72.3 · 95% CI 44.90 to 90.11

Adverse events

Collected over Cohort 1: Treatment-emergent adverse events (TEAEs) were collected from Day 1 up to the 18 months of age visit. Serious adverse events (SAEs) were collected from signing of informed consent to 30 days after the last study visit (up to a maximum of approximately 20 months). Cohort 2: TEAEs were collected from Day 1 up to the 24 months of age visit. SAEs were collected from signing of informed consent to 30 days after the last study visit (up to a maximum of approximately 26 months).. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN20/14 (0%)5/14 (35.7%)14/14 (100%)
Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN20/15 (0%)3/15 (20%)15/15 (100%)
Most frequent serious events
Most frequent serious events
EventCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
Middle ear effusionEar and labyrinth disorders1/140/15
Inguinal herniaGastrointestinal disorders1/140/15
Croup infectiousInfections and infestations1/140/15
PyelonephritisInfections and infestations1/140/15
HypercalcaemiaMetabolism and nutrition disorders1/140/15
Sleep apnoea syndromeRespiratory, thoracic and mediastinal disorders1/140/15
Ear infectionInfections and infestations0/141/15
PharyngitisInfections and infestations0/141/15
LethargyNervous system disorders0/141/15
Most frequent other events
Showing 10 of 129
Most frequent other events
EventCohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
PyrexiaGeneral disorders7/1411/15
Upper respiratory tract infectionInfections and infestations5/149/15
TeethingGastrointestinal disorders2/145/15
ConstipationGastrointestinal disorders4/141/15
DiarrhoeaGastrointestinal disorders3/144/15
Aspartate aminotransferase increasedInvestigations3/144/15
CoughRespiratory, thoracic and mediastinal disorders1/144/15
Gastrooesophageal reflux diseaseGastrointestinal disorders3/143/15
VomitingGastrointestinal disorders3/142/15
Viral upper respiratory tract infectionInfections and infestations3/141/15

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2Total
<=18 years141529
Between 18 and 65 years000
>=65 years000
Sex: Female, Male
Sex: Female, Male(Participants)Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2Total
Female10919
Male4610
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2Total
Hispanic or Latino426
Not Hispanic or Latino101323
Unknown or Not Reported000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2Total
Asian224
American Indian or Alaska Native011
Black or African American101
White71017
Other426
SMN2 gene modifier mutation (c.859G>C) Present
SMN2 gene modifier mutation (c.859G>C) Present(Participants)Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2Total
Count of participants000
07

Study locations

16 sites
  • David Geffen School of Medicine at UCLA
    Los Angeles, California 90095, United States
  • Children's Hospital Colorado
    Aurora, Colorado 80045, United States
  • Nemours Children's Hospital
    Orlando, Florida 32827, United States
  • Massachusetts General Hospital
    Boston, Massachusetts 02114, United States
  • Helen DeVos Children's Hospital
    Grand Rapids, Michigan 49503, United States
  • St. Louis Children's Hospital
    St Louis, Missouri 63110, United States
  • Columbia University Medical Center
    New York, New York 10032, United States
  • Nationwide Children's Hospital
    Columbus, Ohio 43205, United States
  • Clinic for Special Children
    Strasburg, Pennsylvania 17579, United States
  • Children's Medical Center Dallas
    Dallas, Texas 75235, United States
  • University Hospital and UW Health Clinics
    Madison, Wisconsin 53792, United States
  • Sydney Children's Hospital
    Randwick, New South Wales 2145, Australia
  • Centre Hospitalier Régional Hôpital La Citadelle
    Liège, 4000, Belgium
  • Canada Childrens Hospital of Eastern Ontario
    Ottawa, Ontario K1H8L1, Canada
  • Tokyo Women's Medical
    Tokyo, Japan
  • Great Ormond Street Hospital for Children NHS Foundation Trust
    London, WC1N 3JH, United Kingdom
08

References and documents

Publications

  • Strauss KA, Farrar MA, Muntoni F, Saito K, Mendell JR, Servais L, McMillan HJ, Finkel RS, Swoboda KJ, Kwon JM, Zaidman CM, Chiriboga CA, Iannaccone ST, Krueger JM, Parsons JA, Shieh PB, Kavanagh S, Wigderson M, Tauscher-Wisniewski S, McGill BE, Macek TA. Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nat Med. 2022 Jul;28(7):1390-1397. doi: 10.1038/s41591-022-01867-3. Epub 2022 Jun 17. PubMed 35715567 ↗
  • Strauss KA, Farrar MA, Muntoni F, Saito K, Mendell JR, Servais L, McMillan HJ, Finkel RS, Swoboda KJ, Kwon JM, Zaidman CM, Chiriboga CA, Iannaccone ST, Krueger JM, Parsons JA, Shieh PB, Kavanagh S, Tauscher-Wisniewski S, McGill BE, Macek TA. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med. 2022 Jul;28(7):1381-1389. doi: 10.1038/s41591-022-01866-4. Epub 2022 Jun 17. PubMed 35715566 ↗
  • 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. PubMed 34383289 ↗

Study documents

  • Study protocol · Jul 28, 2020
  • Statistical analysis plan · Jul 2, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

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Registry details

Key details

Study ID
NCT03505099
Lead sponsor
Novartis Gene Therapies
Collaborators
PRA Health Sciences
Responsible party
Sponsor
First posted
Apr 23, 2018
Start date
Apr 2, 2018
Primary completion
Jun 15, 2021
Completion
Jun 15, 2021
Results posted
Jan 11, 2022
Last update
Jan 26, 2026

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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