<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03837184</url>
  </required_header>
  <id_info>
    <org_study_id>AVXS-101-CL-306</org_study_id>
    <secondary_id>194664</secondary_id>
    <secondary_id>201900208</secondary_id>
    <secondary_id>COAV101A12304</secondary_id>
    <nct_id>NCT03837184</nct_id>
  </id_info>
  <brief_title>Single-Dose Gene Replacement Therapy Using for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies</brief_title>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Gene Therapies</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>PRA Health Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 3, open-label, single-arm, single-dose, trial of onasemnogene&#xD;
      abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy&#xD;
      (SMA) Type 1 and who are genetically defined by a biallelic pathogenic mutation of the&#xD;
      survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene&#xD;
      (SMN2). The primary objective of the study is to evaluate the efficacy of onasemnogene&#xD;
      abeparvovec-xioi by assessing the proportion of symptomatic SMA Type 1 participants who&#xD;
      achieve the ability to sit unaided for at least 10 seconds up to and including the 18 months&#xD;
      of age trial visit. At least 6 participants aged &lt; 6 months (&lt; 180 days) at the time of gene&#xD;
      replacement therapy (Day 1) will be enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 3, open-label, single-arm, single-dose trial of onasemnogene abeparvovec-xioi&#xD;
      (gene replacement therapy) in participants with SMA Type 1 with one or 2 copies of SMN2. At&#xD;
      least 6 participants &lt; 6 months (&lt; 180 days) of age at the time of gene replacement therapy&#xD;
      (Day 1) will be enrolled.&#xD;
&#xD;
      The trial includes 3 trial periods: screening, gene replacement therapy, and follow-up.&#xD;
      During the screening period (Days -30 to -2), participants whose parent(s)/legal guardian(s)&#xD;
      provide informed consent will undergo screening procedures to determine eligibility for trial&#xD;
      enrollment. participants who meet the entry criteria will enter the in-patient gene&#xD;
      replacement therapy period (Day -1 to Day 3). On Day -1, participants will be admitted to the&#xD;
      hospital for pre-treatment baseline procedures. On Day 1, participants will receive a&#xD;
      one-time intravenous (IV) infusion of the equivalent of onasemnogene abeparvovec-xioi cohort&#xD;
      2 dose received in the AVXS-101-CL-101 trial over approximately 60 minutes and will undergo&#xD;
      in-patient safety monitoring over the next 48 hours. Participants may be discharged 48 hours&#xD;
      after gene replacement therapy, based on Investigator judgment. During the outpatient&#xD;
      follow-up period (Days 4 to End of Trial at 18 months of age), participants will return at&#xD;
      regularly scheduled intervals for efficacy and safety assessments until the participant&#xD;
      reaches 18 months of age.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 31, 2019</start_date>
  <completion_date type="Actual">June 29, 2021</completion_date>
  <primary_completion_date type="Actual">June 29, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds</measure>
    <time_frame>From Baseline up to 18 Months of Age Visit</time_frame>
    <description>Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Event-free Survival at 14 Months of Age</measure>
    <time_frame>From Baseline up to 14 Months of Age</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Spinal Muscular Atrophy Type I</condition>
  <arm_group>
    <arm_group_label>Onasemnogene Abeparvovec-xioi</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a single dose of onasemnogene abeparvovec-xioi, administered intravenously.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Onasemnogene Abeparvovec-xioi</intervention_name>
    <description>Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB). Onasemnogene abeparvovec-xioi will be administered as a one-time intravenous infusion over approximately 60 minutes. Dosage will be determined by the participants weight.</description>
    <arm_group_label>Onasemnogene Abeparvovec-xioi</arm_group_label>
    <other_name>Zolgensma</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants with SMA Type 1 as determined by diagnosis of SMA based on gene mutation&#xD;
             analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2&#xD;
             copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G&gt;C)]&#xD;
&#xD;
          -  Participants must be &lt; 6 months (&lt; 180 days) of age at the time of onasemnogene&#xD;
             abeparvovec-xioi infusion&#xD;
&#xD;
          -  Participants must have a swallowing evaluation test performed prior to administration&#xD;
             of gene replacement therapy&#xD;
&#xD;
          -  Up-to-date on childhood vaccinations as per local health authorities.&#xD;
&#xD;
          -  Parent(s)/legal guardian(s) willing and able to complete the informed consent process&#xD;
             and comply with trial procedures and visit schedule&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of&#xD;
             age&#xD;
&#xD;
          -  Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse&#xD;
             oximetry &lt; 95% saturation at screening:&#xD;
&#xD;
               1. Pulse oximetry saturation must not decrease ≥ 4 percentage points between&#xD;
                  screening and dosing with confirmatory oximetry reading&#xD;
&#xD;
               2. Participants may be put on non-invasive ventilatory support for less than 12&#xD;
                  hours per day at the discretion of their physician or trial staff&#xD;
&#xD;
          -  Use or requirement of non-invasive ventilatory support for greater than or equal to 12&#xD;
             hours daily in the two weeks prior to dosing&#xD;
&#xD;
          -  Participant with signs of aspiration based on a swallowing test or whose&#xD;
             weight-for-age falls below the 3rd percentile based on World Health Organization (WHO)&#xD;
             Child Growth Standards and unwilling to use an alternative method to oral feeding&#xD;
&#xD;
          -  Active viral infection (includes human immunodeficiency virus [HIV] or positive&#xD;
             serology for hepatitis B, C, or E, or known Zika virus infection)&#xD;
&#xD;
          -  Serious non-respiratory tract illness requiring systemic treatment and/or&#xD;
             hospitalization within 2 weeks prior to screening&#xD;
&#xD;
          -  Upper or lower respiratory infection requiring medical attention, medical&#xD;
             intervention, or increase in supportive care of any manner within 4 weeks prior to&#xD;
             screening&#xD;
&#xD;
          -  Severe non-pulmonary/respiratory tract infection (eg, pyelonephritis, or meningitis)&#xD;
             within 4 weeks before administration of gene replacement therapy or concomitant&#xD;
             illness that, in the opinion of the Principal Investigator, creates unnecessary risks&#xD;
             for gene replacement such as:&#xD;
&#xD;
               1. Major renal or hepatic impairment&#xD;
&#xD;
               2. Known seizure disorder&#xD;
&#xD;
               3. Diabetes mellitus&#xD;
&#xD;
               4. Idiopathic hypocalcuria&#xD;
&#xD;
               5. Symptomatic cardiomyopathy&#xD;
&#xD;
          -  Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or&#xD;
             their excipients, or human, animal biological raw materials (human transferrin, human&#xD;
             insulin, trypsin derived from porcine spleen, bovine derived protein (FBS, bovine&#xD;
             milk-derived Benzonase, casamino acid, bovine pancreas), HEK 293 cells, Cosmic Calf&#xD;
             Serum, HyQtase) used in manufacturing of onasemnogene abeparvovec-xioi product&#xD;
&#xD;
          -  Concomitant use of any of the following: drugs for treatment of myopathy or&#xD;
             neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive&#xD;
             therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive&#xD;
             therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids,&#xD;
             cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin,&#xD;
             rituximab)&#xD;
&#xD;
          -  Anti-AAV9 antibody titer &gt; 1:50 as determined by Enzyme-linked Immunosorbent Assay&#xD;
             (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9&#xD;
             antibody titer &gt; 1:50, he or she may receive retesting within 30 days of the screening&#xD;
             period and will be eligible to participate if the Anti-AAV9 antibody titer upon&#xD;
             retesting is ≤ 1:50&#xD;
&#xD;
          -  Clinically significant abnormal laboratory values (gamma-glutamyl transpeptidase&#xD;
             [GGT], ALT, AST, total bilirubin &gt; 2x the ULN, creatinine ≥ 1.0 mg/dL, hemoglobin&#xD;
             [Hgb] &lt; 8 or &gt; 18 g/dL; white blood cell [WBC] &gt; 20,000 per cmm) prior to gene&#xD;
             replacement therapy. Patients with an elevated bilirubin level that is unequivocally&#xD;
             the result of neonatal jaundice shall not be excluded&#xD;
&#xD;
          -  Participation in recent SMA treatment clinical trial (with the exception of&#xD;
             observational cohort studies or non-interventional studies) or receipt of an&#xD;
             investigational or commercial compound, product or therapy administered with the&#xD;
             intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening&#xD;
             for this trial. Oral beta-agonists must be discontinued at least 30 days prior to&#xD;
             dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory&#xD;
             (bronchodilator) management is acceptable and not a contraindication at any time prior&#xD;
             to screening for this trial&#xD;
&#xD;
          -  Expectation of major surgical procedures during the trial assessment period (e.g.,&#xD;
             spinal surgery or tracheostomy)&#xD;
&#xD;
          -  Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or&#xD;
             inability to travel for repeat visits&#xD;
&#xD;
          -  Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential&#xD;
             or to refrain from posting confidential trial results/observations on social media&#xD;
             sites&#xD;
&#xD;
          -  Parent(s)/legal guardian(s) refuses to sign consent form&#xD;
&#xD;
          -  Participants &lt; 35 weeks gestational age at time of birth&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Days</minimum_age>
    <maximum_age>6 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tokyo Women's Medical University</name>
      <address>
        <city>Tokyo</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pusan National University Yangsan Hospital</name>
      <address>
        <city>Yangsan</city>
        <state>Gyeongsangnam-do</state>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Taiwan</country>
  </location_countries>
  <link>
    <url>https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17903</url>
    <description>Novartis Clinical Trial Results</description>
  </link>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>February 8, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <results_first_submitted>December 14, 2021</results_first_submitted>
  <results_first_submitted_qc>December 14, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">January 11, 2022</results_first_posted>
  <last_update_submitted>November 18, 2022</last_update_submitted>
  <last_update_submitted_qc>November 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Spinal Muscular Atrophy</keyword>
  <keyword>SMN2</keyword>
  <keyword>Onasemnogene Abeparvovec-xioi</keyword>
  <keyword>Gene replacement therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscular Atrophy</mesh_term>
    <mesh_term>Muscular Atrophy, Spinal</mesh_term>
    <mesh_term>Spinal Muscular Atrophies of Childhood</mesh_term>
    <mesh_term>Atrophy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>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.&#xD;
This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.</ipd_description>
    <ipd_url>https://www.clinicalstudydatarequest.com/.</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 11, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/84/NCT03837184/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 30, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/84/NCT03837184/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 2 participants took part in the trial at a single site in Taiwan between May 2019 and June 2021.</recruitment_details>
      <pre_assignment_details>A total of 5 participants were screened, of which 3 were screen failures and 2 were enrolled and received study drug.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>AVXS-101</title>
          <description>Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>AVXS-101</title>
          <description>Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>SMN2 gene modifier mutation (c.859G&gt;C) Present</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds</title>
        <description>Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds.</description>
        <time_frame>From Baseline up to 18 Months of Age Visit</time_frame>
        <population>Intent-to-Treat (ITT) population - Symptomatic participants with biallelic deletion mutations of survival of motor neuron 1 (SMN1) (exon 7/8 common homozygous deletions) and 2 copies of survival of motor neuron 2 (SMN2) without the known gene modifier mutation (c.859G&gt;C) who received an IV infusion of AVXS-101 at less than 180 days of age.</population>
        <group_list>
          <group group_id="O1">
            <title>AVXS-101</title>
            <description>Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds</title>
          <description>Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds.</description>
          <population>Intent-to-Treat (ITT) population - Symptomatic participants with biallelic deletion mutations of survival of motor neuron 1 (SMN1) (exon 7/8 common homozygous deletions) and 2 copies of survival of motor neuron 2 (SMN2) without the known gene modifier mutation (c.859G&gt;C) who received an IV infusion of AVXS-101 at less than 180 days of age.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Event-free Survival at 14 Months of Age</title>
        <description>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.</description>
        <time_frame>From Baseline up to 14 Months of Age</time_frame>
        <population>ITT population - Symptomatic participants with biallelic deletion mutations of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene modifier mutation (c.859G&gt;C) who received an IV infusion of AVXS-101 at less than 180 days of age.</population>
        <group_list>
          <group group_id="O1">
            <title>AVXS-101</title>
            <description>Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.</description>
          </group>
        </group_list>
        <measure>
          <title>Event-free Survival at 14 Months of Age</title>
          <description>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.</description>
          <population>ITT population - Symptomatic participants with biallelic deletion mutations of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene modifier mutation (c.859G&gt;C) who received an IV infusion of AVXS-101 at less than 180 days of age.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From Day 1 up to 18 Months of Age Visit (total duration of approximately 12-18 months depending on age at dosing).</time_frame>
      <group_list>
        <group group_id="E1">
          <title>AVXS-101</title>
          <description>Participants received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (23.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Congenital, familial and genetic disorders</title>
            <event_list>
              <event>
                <sub_title>Cleft Palate</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gastrointestinal hypomotility</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Upper gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hiatus hernia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gingivitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Urinary tract infection/</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Glucose urine present</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Failure to thrive</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Glycosuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory distress</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rhonchi</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Tachypnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dermatitis diaper</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Depending on local requirements, Sponsor's consent necessary before publication of study, or Sponsor can review results communications before public release with a right to request changes to communications regarding trial results between 40 to 60 and up to 90 or 120 days, as applicable, from the time submitted to Sponsor for review to remove references to Sponsor's Confidential Information or delay results communications to permit Sponsor to obtain appropriate Intellectual Property protection.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>EMEA Medical Information</name_or_title>
      <organization>Novartis Gene Therapies EU Limited</organization>
      <phone>+353 (1) 566-2364</phone>
      <email>medinfoemea.gtx@novartis.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03837184
org study id: AVXS-101-CL-306
secondary id: 194664
secondary id: 201900208
secondary id: COAV101A12304
nct id: NCT03837184
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a Phase 3, open-label, single-arm, single-dose, trial of onasemnogene
      abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy
      (SMA) Type 1 and who are genetically defined by a biallelic pathogenic mutation of the
      survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene
      (SMN2). The primary objective of the study is to evaluate the efficacy of onasemnogene
      abeparvovec-xioi by assessing the proportion of symptomatic SMA Type 1 participants who
      achieve the ability to sit unaided for at least 10 seconds up to and including the 18 months
      of age trial visit. At least 6 participants aged < 6 months (< 180 days) at the time of gene
      replacement therapy (Day 1) will be enrolled.
This is a Phase 3, open-label, single-arm, single-dose trial of onasemnogene abeparvovec-xioi
      (gene replacement therapy) in participants with SMA Type 1 with one or 2 copies of SMN2. At
      least 6 participants < 6 months (< 180 days) of age at the time of gene replacement therapy
      (Day 1) will be enrolled.

      The trial includes 3 trial periods: screening, gene replacement therapy, and follow-up.
      During the screening period (Days -30 to -2), participants whose parent(s)/legal guardian(s)
      provide informed consent will undergo screening procedures to determine eligibility for trial
      enrollment. participants who meet the entry criteria will enter the in-patient gene
      replacement therapy period (Day -1 to Day 3). On Day -1, participants will be admitted to the
      hospital for pre-treatment baseline procedures. On Day 1, participants will receive a
      one-time intravenous (IV) infusion of the equivalent of onasemnogene abeparvovec-xioi cohort
      2 dose received in the AVXS-101-CL-101 trial over approximately 60 minutes and will undergo
      in-patient safety monitoring over the next 48 hours. Participants may be discharged 48 hours
      after gene replacement therapy, based on Investigator judgment. During the outpatient
      follow-up period (Days 4 to End of Trial at 18 months of age), participants will return at
      regularly scheduled intervals for efficacy and safety assessments until the participant
      reaches 18 months of age.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants Who Achieved Sitting Alone for at Least 10 Seconds
time frame: From Baseline up to 18 Months of Age Visit
description: Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight unsupported for at least 10 seconds.
measure: Event-free Survival at 14 Months of Age
time frame: From Baseline up to 14 Months of Age
description: 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.
arm group label: Onasemnogene Abeparvovec-xioi
arm group type: Experimental
description: Participants will receive a single dose of onasemnogene abeparvovec-xioi, administered intravenously.
intervention type: Biological
intervention name: Onasemnogene Abeparvovec-xioi
description: Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB). Onasemnogene abeparvovec-xioi will be administered as a one-time intravenous infusion over approximately 60 minutes. Dosage will be determined by the participants weight.
arm group label: Onasemnogene Abeparvovec-xioi
other name: Zolgensma
criteria: 
gender: All
minimum age: 0 Days
maximum age: 6 Months
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
country: Japan
country: Korea, Republic of
country: Taiwan
url: https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17903
description: Novartis Clinical Trial Results
responsible party type: Sponsor
mesh term: Muscular Atrophy
mesh term: Muscular Atrophy, Spinal
mesh term: Spinal Muscular Atrophies of Childhood
mesh term: Atrophy
sharing ipd: Yes
ipd description: 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/.
ipd url: https://www.clinicalstudydatarequest.com/.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 