<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/NCT04488133</url>
  </required_header>
  <id_info>
    <org_study_id>232SM404</org_study_id>
    <secondary_id>2020-003492-18</secondary_id>
    <nct_id>NCT04488133</nct_id>
  </id_info>
  <brief_title>A Study of Nusinersen Among Participants With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec</brief_title>
  <acronym>RESPOND</acronym>
  <official_title>A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Biogen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Biogen</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to evaluate the clinical outcomes following treatment&#xD;
      with Nusinersen in participants with spinal muscular atrophy (SMA) who previously received&#xD;
      onasemnogene abeparvovec.&#xD;
&#xD;
      The secondary objectives of this study are to evaluate the safety and tolerability; and&#xD;
      clinical outcomes following treatment with Nusinersen in participants with SMA who previously&#xD;
      received onasemnogene abeparvovec.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 4, 2021</start_date>
  <completion_date type="Anticipated">October 7, 2025</completion_date>
  <primary_completion_date type="Anticipated">October 7, 2025</primary_completion_date>
  <phase>Phase 4</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>Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp (0 to 3), ability to kick in supine position (0 to 4), head control (0 to 2), rolling (0 to 3), sitting (0 to 4), crawling (0 to 4), standing (0 to 3), and walking (0 to 3). Total HINE score is the sum of points from each item and can range from 0 to 26, with higher scores depicting better level of ability.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect or is a medically important event.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Change from Baseline in Clinical Laboratory Parameters</measure>
    <time_frame>Up to Day 778</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Change from Baseline in Electrocardiograms (ECGs)</measure>
    <time_frame>Up to Day 778</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Change from Baseline in Vital Signs</measure>
    <time_frame>Up to Day 778</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>The motor milestones as defined by WHO criteria includes the following six test items: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>The CHOP INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. The total score ranges from 0-64, with higher scores depicting better response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>The HFMSE is a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale (HFMS) was expanded to include 13 additional items to improve sensitivity for the higher functioning ambulant population. Participants will be asked to complete a specific movement and are then graded on the quality and execution of that movement. Higher scores indicate higher levels of motor ability. The overall score is the sum of the scores for all activities, with a maximum score of 66 with higher scores depicting better ability to perform activities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in Revised Upper Limb Module (RULM) Score</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living. The RULM is scored from 0 to 37 points, with higher scores indicating better function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Death or Permanent Ventilation</measure>
    <time_frame>Up to Day 778</time_frame>
    <description>Permanent ventilation is defined as tracheostomy or ≥16 hours ventilation/day continuously for &gt;21 days in the absence of an acute reversible event.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">46</enrollment>
  <condition>Muscular Atrophy, Spinal</condition>
  <arm_group>
    <arm_group_label>Nusinersen 12 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive Nusinersen 12 milligrams (mg) via intrathecal (IT) injection as loading doses on Days 1, 15, 29, and 64 followed by maintenance doses, every 4 months, on Days 183, 302, 421, 540 and 659.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nusinersen</intervention_name>
    <description>Administered as specified in the treatment arm.</description>
    <arm_group_label>Nusinersen 12 mg</arm_group_label>
    <other_name>ISIS 396443</other_name>
    <other_name>BIIB058</other_name>
    <other_name>Spinraza</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
        For all participants:&#xD;
&#xD;
          -  Genetic documentation of 5q SMA homozygous gene survival motor neuron 1 (SMN1)&#xD;
             deletion or mutation, or compound heterozygous mutation&#xD;
&#xD;
          -  SMN2 copy number of ≥1&#xD;
&#xD;
          -  ≤36 months of age at the time of first Nusinersen dose&#xD;
&#xD;
          -  Must have previously received onasemnogene abeparvovec per the approved label or&#xD;
             local/regional regulations ≥2 months prior to first Nusinersen dose&#xD;
&#xD;
          -  Must have suboptimal clinical status per the Investigator&#xD;
&#xD;
        Additional Criteria for Subgroups A and B:&#xD;
&#xD;
          -  ≤9 months of age (270 days) at the time of first Nusinersen dose&#xD;
&#xD;
          -  SMN2 copy number of 2&#xD;
&#xD;
        Additional Criteria for Subgroup A:&#xD;
&#xD;
          -  SMA symptom onset ≤4 months (120 days) of age&#xD;
&#xD;
          -  Must have received intravenous (IV) onasemnogene abeparvovec at &gt;6 weeks to ≤6 months&#xD;
             (43 days to 180 days) of age&#xD;
&#xD;
          -  Must have received IV onasemnogene abeparvovec after SMA symptom onset&#xD;
&#xD;
        Additional Criteria for Subgroup B:&#xD;
&#xD;
          -  Must have received IV onasemnogene abeparvovec at ≤6 weeks (42 days) of age&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
        For all participants:&#xD;
&#xD;
          -  Prior exposure to Nusinersen&#xD;
&#xD;
          -  Ongoing severe or serious AEs related to onasemnogene abeparvovec&#xD;
&#xD;
          -  Treatment with an investigational drug, biological agent, or device within 30 days or&#xD;
             5 half-lives of the agent, whichever is longer, prior to study; any prior or current&#xD;
             treatment with any survival motor neuron 2 (SMN2)-directed splicing modifier; prior&#xD;
             antisense oligonucleotide treatment or cell transplantation; gene therapy for the&#xD;
             treatment of SMA other than onasemnogene abeparvovec. Note: treatment with&#xD;
             onasemnogene abeparvovec as part of an investigational study is allowed&#xD;
&#xD;
        Additional Criteria for Subgroups A and B:&#xD;
&#xD;
          -  Weight-for-age is below the third percentile, based on WHO Child Growth Standards at&#xD;
             the time of receiving onasemnogene abeparvovec. Adjustments for the gestational weight&#xD;
             of premature babies enrolled in Subgroups A and B are allowed provided IV onasemnogene&#xD;
             abeparvovec was dosed per the approved label or per local/regional regulations.&#xD;
&#xD;
        Note: Other protocol defined Inclusion/Exclusion criteria may apply.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Months</minimum_age>
    <maximum_age>36 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Biogen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Arkansas Children's Hospital Research Institute</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford Neuromuscular Research</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemours Children's Hospital</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32827</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rare Disease Research, LLC</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30318</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ann &amp; Robert H. Lurie Children's Hospital of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gillette Children's Specialty Healthcare</name>
      <address>
        <city>Saint Paul</city>
        <state>Minnesota</state>
        <zip>55101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University (OHSU)</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Philadelphia - Neurology</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of The King's Daughters</name>
      <address>
        <city>Norfolk</city>
        <state>Virginia</state>
        <zip>23510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charité - Campus Virchow-Klinikum</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitaetsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Schneider Children's Medical Center</name>
      <address>
        <city>Petah Tikva</city>
        <zip>4920235</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Neurologico Carlo Besta</name>
      <address>
        <city>Milano</city>
        <state>Milan</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione Policlinico Universitario Agostino Gemelli IRCCS</name>
      <address>
        <city>Roma</city>
        <zip>00168</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kurume University Hospital</name>
      <address>
        <city>Kurume-Shi</city>
        <state>Fukuoka-Ken</state>
        <zip>830-0011</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hyogo Medical University Hospital</name>
      <address>
        <city>Nishinomiya</city>
        <state>Hyogo</state>
        <zip>663-8501</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Joan de Déu</name>
      <address>
        <city>Esplugues Del Llobregat</city>
        <state>Barcelona</state>
        <zip>08950</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La paz</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.sma-europe.eu/</url>
    <description>SMA Europe</description>
  </link>
  <link>
    <url>https://www.curesma.org/</url>
    <description>CureSMA</description>
  </link>
  <link>
    <url>https://www.mda.org/disease/spinal-muscular-atrophy</url>
    <description>Muscular Dystrophy Association</description>
  </link>
  <link>
    <url>https://www.childneurologyfoundation.org/</url>
    <description>Child Neurology Foundation</description>
  </link>
  <link>
    <url>https://www.biogentriallink.com/en-us/home.html</url>
    <description>Biogen Trial Link</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>September 15, 2023</last_update_submitted>
  <last_update_submitted_qc>September 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>Atrophy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/</ipd_description>
    <ipd_url>https://vivli.org/</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04488133
org study id: 232SM404
secondary id: 2020-003492-18
nct id: NCT04488133
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary objective of this study is to evaluate the clinical outcomes following treatment
      with Nusinersen in participants with spinal muscular atrophy (SMA) who previously received
      onasemnogene abeparvovec.

      The secondary objectives of this study are to evaluate the safety and tolerability; and
      clinical outcomes following treatment with Nusinersen in participants with SMA who previously
      received onasemnogene abeparvovec.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score
time frame: Up to Day 778
description: Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp (0 to 3), ability to kick in supine position (0 to 4), head control (0 to 2), rolling (0 to 3), sitting (0 to 4), crawling (0 to 4), standing (0 to 3), and walking (0 to 3). Total HINE score is the sum of points from each item and can range from 0 to 26, with higher scores depicting better level of ability.
measure: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
time frame: Up to Day 778
description: An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect or is a medically important event.
measure: Number of Participants with Change from Baseline in Clinical Laboratory Parameters
time frame: Up to Day 778
measure: Number of Participants with Change from Baseline in Electrocardiograms (ECGs)
time frame: Up to Day 778
measure: Number of Participants with Change from Baseline in Vital Signs
time frame: Up to Day 778
measure: Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria
time frame: Up to Day 778
description: The motor milestones as defined by WHO criteria includes the following six test items: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone.
measure: Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score
time frame: Up to Day 778
description: The CHOP INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. The total score ranges from 0-64, with higher scores depicting better response.
measure: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score
time frame: Up to Day 778
description: The HFMSE is a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale (HFMS) was expanded to include 13 additional items to improve sensitivity for the higher functioning ambulant population. Participants will be asked to complete a specific movement and are then graded on the quality and execution of that movement. Higher scores indicate higher levels of motor ability. The overall score is the sum of the scores for all activities, with a maximum score of 66 with higher scores depicting better ability to perform activities.
measure: Change from Baseline in Revised Upper Limb Module (RULM) Score
time frame: Up to Day 778
description: The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living. The RULM is scored from 0 to 37 points, with higher scores indicating better function.
measure: Time to Death or Permanent Ventilation
time frame: Up to Day 778
description: Permanent ventilation is defined as tracheostomy or ≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event.
arm group label: Nusinersen 12 mg
arm group type: Experimental
description: Participants will receive Nusinersen 12 milligrams (mg) via intrathecal (IT) injection as loading doses on Days 1, 15, 29, and 64 followed by maintenance doses, every 4 months, on Days 183, 302, 421, 540 and 659.
intervention type: Drug
intervention name: Nusinersen
description: Administered as specified in the treatment arm.
arm group label: Nusinersen 12 mg
other name: ISIS 396443
other name: BIIB058
other name: Spinraza
criteria: 
gender: All
minimum age: 2 Months
maximum age: 36 Months
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Biogen
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
country: Israel
country: Italy
country: Japan
country: Spain
country: United States
url: https://www.sma-europe.eu/
description: SMA Europe
url: https://www.curesma.org/
description: CureSMA
url: https://www.mda.org/disease/spinal-muscular-atrophy
description: Muscular Dystrophy Association
url: https://www.childneurologyfoundation.org/
description: Child Neurology Foundation
url: https://www.biogentriallink.com/en-us/home.html
description: Biogen Trial Link
responsible party type: Sponsor
mesh term: Muscular Atrophy
mesh term: Muscular Atrophy, Spinal
mesh term: Atrophy
sharing ipd: Yes
ipd description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
ipd url: https://vivli.org/