<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/NCT01703988</url>
  </required_header>
  <id_info>
    <org_study_id>ISIS 396443 - CS2</org_study_id>
    <secondary_id>2017-000327-27</secondary_id>
    <nct_id>NCT01703988</nct_id>
  </id_info>
  <brief_title>An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy</brief_title>
  <official_title>An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will test the safety, tolerability, and pharmacokinetics of escalating doses of&#xD;
      nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over&#xD;
      the duration of the trial, in participants with spinal muscular atrophy (SMA).&#xD;
&#xD;
      Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort&#xD;
      of approximately 8 participants, where all participants will receive active drug.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In&#xD;
      August 2016, sponsorship of the trial was transferred to Biogen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 31, 2012</start_date>
  <completion_date type="Actual">January 31, 2015</completion_date>
  <primary_completion_date type="Actual">January 31, 2015</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs</measure>
    <time_frame>Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days</time_frame>
    <description>An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)</measure>
    <time_frame>Day 1 and Day 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Pharmacokinetics: Time to Reach Cmax in Plasma</measure>
    <time_frame>Day 1 and Day 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)</measure>
    <time_frame>Day 1 and Day 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations</measure>
    <time_frame>Day 1, Day 29, and Day 85</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine Pharmacokinetics: Renal Clearance, Cohort 4</measure>
    <time_frame>Day 1 and Day 85</time_frame>
    <description>Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Spinal Muscular Atrophy</condition>
  <arm_group>
    <arm_group_label>Nusinersen 3 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nusinersen 6 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nusinersen 9 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nusinersen 12 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nusinersen</intervention_name>
    <description>Single IT injection for each dose</description>
    <arm_group_label>Nusinersen 12 mg</arm_group_label>
    <arm_group_label>Nusinersen 3 mg</arm_group_label>
    <arm_group_label>Nusinersen 6 mg</arm_group_label>
    <arm_group_label>Nusinersen 9 mg</arm_group_label>
    <other_name>ISIS-SMNRx</other_name>
    <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;
          -  Genetic documentation of 5q SMA (homozygous gene deletion or mutation)&#xD;
&#xD;
          -  Clinical signs attributable to SMA&#xD;
&#xD;
          -  Able to complete all study procedures, measurements, and visits and parent/patient has&#xD;
             adequately supportive psychosocial circumstances, in the opinion of the Investigator&#xD;
&#xD;
          -  Estimated life expectancy &gt; 2 years from Screening&#xD;
&#xD;
          -  Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is&#xD;
             planned for study procedure&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Respiratory insufficiency defined by the medical necessity for invasive or&#xD;
             non-invasive ventilation during a 24-hour period&#xD;
&#xD;
          -  Medical necessity for a gastric feeding tube, where the majority of feeds are given by&#xD;
             this route, as assessed by the Investigator&#xD;
&#xD;
          -  Previous scoliosis surgery that would interfere with the lumbar puncture injection&#xD;
             procedure&#xD;
&#xD;
          -  Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2&#xD;
             months of screening or planned during the duration of the study&#xD;
&#xD;
          -  Presence of an untreated or inadequately treated active infection requiring systemic&#xD;
             antiviral or antimicrobial therapy at any time during the screening period&#xD;
&#xD;
          -  History of brain or spinal cord disease that would interfere with lumbar puncture&#xD;
             procedures or cerebrospinal fluid (CSF) circulation&#xD;
&#xD;
          -  Presence of an implanted shunt for the drainage of CSF or an implanted central nervous&#xD;
             system catheter&#xD;
&#xD;
          -  History of bacterial meningitis&#xD;
&#xD;
          -  Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4&#xD;
&#xD;
          -  Dosing with ISIS 396443 in clinical study ISIS 396443-CS10&#xD;
&#xD;
          -  Clinically significant abnormalities in hematology or clinical chemistry parameters or&#xD;
             electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator&#xD;
             that would render the subject unsuitable for inclusion&#xD;
&#xD;
          -  Treatment with investigational drug, biological agent, or device within 1-month of&#xD;
             Screening or 5 half-lives of study agent, whichever is longer. Treatment with&#xD;
             valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or&#xD;
             cell transplantation&#xD;
&#xD;
          -  Ongoing medical condition that would interfere with the conduct and assessments of the&#xD;
             study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that&#xD;
             would interfere with the assessment of safety or would compromise the ability of the&#xD;
             patient to undergo study procedures.&#xD;
&#xD;
        NOTE: Other protocol defined inclusion/exclusion criteria may apply.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>15 Years</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>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT Southwestern Medical Center - Children's Medical Center Dallas</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah School of Medicine</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://clinicalresearch.biogen.com/Content/Studies/CS2%20Biogen.com%20Packet.pdf</url>
    <description>Clinical Study Report (CSR) Synopsis - a results summary</description>
  </link>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>October 8, 2012</study_first_submitted>
  <study_first_submitted_qc>October 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 11, 2012</study_first_posted>
  <results_first_submitted>January 20, 2017</results_first_submitted>
  <results_first_submitted_qc>January 20, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">March 13, 2017</results_first_posted>
  <disposition_first_submitted>May 7, 2016</disposition_first_submitted>
  <disposition_first_submitted_qc>May 7, 2016</disposition_first_submitted_qc>
  <disposition_first_posted type="Estimate">June 3, 2016</disposition_first_posted>
  <last_update_submitted>March 22, 2021</last_update_submitted>
  <last_update_submitted_qc>March 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Spinal Muscular Atrophy</keyword>
  <keyword>SMA</keyword>
  <keyword>SMN</keyword>
  <keyword>SMNRx</keyword>
  <keyword>ISIS-SMNRx</keyword>
  <keyword>ISIS 396443</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>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>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nusinersen 3 mg</title>
          <description>3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection</description>
        </group>
        <group group_id="P2">
          <title>Nusinersen 6 mg</title>
          <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="P3">
          <title>Nusinersen 9 mg</title>
          <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
        </group>
        <group group_id="P4">
          <title>Nusinersen 12 mg</title>
          <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Investigator Judgment</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nusinersen 3 mg</title>
          <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="B2">
          <title>Nusinersen 6 mg</title>
          <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="B3">
          <title>Nusinersen 9 mg</title>
          <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
        </group>
        <group group_id="B4">
          <title>Nusinersen 12 mg</title>
          <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="9"/>
            <count group_id="B4" value="9"/>
            <count group_id="B5" value="34"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.6" spread="5.4"/>
                    <measurement group_id="B2" value="8.1" spread="5.2"/>
                    <measurement group_id="B3" value="6.0" spread="4.0"/>
                    <measurement group_id="B4" value="6.9" spread="4.3"/>
                    <measurement group_id="B5" value="7.4" spread="4.6"/>
                  </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="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="6"/>
                    <measurement group_id="B5" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs</title>
        <description>An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.</description>
        <time_frame>Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days</time_frame>
        <population>Safety Population, defined as all enrolled participants who received at least 1 dose of study drug.</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 3 mg</title>
            <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O2">
            <title>Nusinersen 6 mg</title>
            <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O3">
            <title>Nusinersen 9 mg</title>
            <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
          </group>
          <group group_id="O4">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs</title>
          <description>An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.</description>
          <population>Safety Population, defined as all enrolled participants who received at least 1 dose of study drug.</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="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="9"/>
                <count group_id="O4" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any AE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="9"/>
                    <measurement group_id="O4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any drug-related AE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Any SAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Discontinued due to an AE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Highest severity of AE=mild</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="6"/>
                    <measurement group_id="O4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Highest severity of AE=moderate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Highest severity of AE=severe</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)</title>
        <time_frame>Day 1 and Day 85</time_frame>
        <population>Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 3 mg</title>
            <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O2">
            <title>Nusinersen 6 mg</title>
            <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O3">
            <title>Nusinersen 9 mg</title>
            <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
          </group>
          <group group_id="O4">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)</title>
          <population>Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="9"/>
                <count group_id="O4" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.5" spread="72.7"/>
                    <measurement group_id="O2" value="79.8" spread="57.2"/>
                    <measurement group_id="O3" value="141.0" spread="52.8"/>
                    <measurement group_id="O4" value="208.0" spread="110.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.5" spread="32.3"/>
                    <measurement group_id="O2" value="52.8" spread="33.5"/>
                    <measurement group_id="O3" value="127.0" spread="37.7"/>
                    <measurement group_id="O4" value="132.0" spread="85.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Pharmacokinetics: Time to Reach Cmax in Plasma</title>
        <time_frame>Day 1 and Day 85</time_frame>
        <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 3 mg</title>
            <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O2">
            <title>Nusinersen 6 mg</title>
            <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O3">
            <title>Nusinersen 9 mg</title>
            <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
          </group>
          <group group_id="O4">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Pharmacokinetics: Time to Reach Cmax in Plasma</title>
          <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="9"/>
                <count group_id="O4" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.09" lower_limit="2.03" upper_limit="12.0"/>
                    <measurement group_id="O2" value="5.93" lower_limit="2.00" upper_limit="23.0"/>
                    <measurement group_id="O3" value="3.92" lower_limit="2.00" upper_limit="8.03"/>
                    <measurement group_id="O4" value="4.05" lower_limit="1.97" upper_limit="12.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.08" lower_limit="4.12" upper_limit="6.17"/>
                    <measurement group_id="O2" value="6.04" lower_limit="5.97" upper_limit="6.25"/>
                    <measurement group_id="O3" value="4.12" lower_limit="2.00" upper_limit="6.25"/>
                    <measurement group_id="O4" value="5.92" lower_limit="1.95" upper_limit="6.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)</title>
        <time_frame>Day 1 and Day 85</time_frame>
        <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 3 mg</title>
            <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O2">
            <title>Nusinersen 6 mg</title>
            <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O3">
            <title>Nusinersen 9 mg</title>
            <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
          </group>
          <group group_id="O4">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)</title>
          <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point.</population>
          <units>ng*hr/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="9"/>
                <count group_id="O4" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="181" spread="225"/>
                    <measurement group_id="O2" value="306" spread="259"/>
                    <measurement group_id="O3" value="601" spread="249"/>
                    <measurement group_id="O4" value="823" spread="442"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="110" spread="107"/>
                    <measurement group_id="O2" value="179" spread="135"/>
                    <measurement group_id="O3" value="524" spread="185"/>
                    <measurement group_id="O4" value="555" spread="398"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations</title>
        <time_frame>Day 1, Day 29, and Day 85</time_frame>
        <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point. (This study includes participants previously enrolled in Study ISIS 396443 - CS1 (NCT01494701).</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 3 mg</title>
            <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O2">
            <title>Nusinersen 6 mg</title>
            <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
          <group group_id="O3">
            <title>Nusinersen 9 mg</title>
            <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
          </group>
          <group group_id="O4">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations</title>
          <population>PK Population, defined as all enrolled participants who have evaluable PK data; number analyzed=participants with an assessment at given time point. (This study includes participants previously enrolled in Study ISIS 396443 - CS1 (NCT01494701).</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="9"/>
                <count group_id="O4" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="6"/>
                    <count group_id="O4" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0651" spread="0.117"/>
                    <measurement group_id="O2" value="0.0560" spread="0.104"/>
                    <measurement group_id="O3" value="NA" spread="NA">below the limit of quantification (50 pg/mL)</measurement>
                    <measurement group_id="O4" value="NA" spread="NA">below the limit of quantification (50 pg/mL)</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 29</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.41" spread="0.456"/>
                    <measurement group_id="O2" value="2.65" spread="1.44"/>
                    <measurement group_id="O4" value="2.22" spread="0.924"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                    <count group_id="O2" value="8"/>
                    <count group_id="O3" value="9"/>
                    <count group_id="O4" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.12" spread="0.573"/>
                    <measurement group_id="O2" value="3.76" spread="2.05"/>
                    <measurement group_id="O3" value="1.50" spread="0.447"/>
                    <measurement group_id="O4" value="3.36" spread="1.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Urine Pharmacokinetics: Renal Clearance, Cohort 4</title>
        <description>Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.</description>
        <time_frame>Day 1 and Day 85</time_frame>
        <population>Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data</population>
        <group_list>
          <group group_id="O1">
            <title>Nusinersen 12 mg</title>
            <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
          </group>
        </group_list>
        <measure>
          <title>Urine Pharmacokinetics: Renal Clearance, Cohort 4</title>
          <description>Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.</description>
          <population>Pharmacokinetic (PK) Population, defined as all enrolled participants who have evaluable PK data</population>
          <units>mL/hr</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.674" spread="0.602"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 85</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.5" spread="92.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days.</time_frame>
      <desc>Treatment emergent AEs are presented regardless of seriousness or relationship to investigational product.</desc>
      <group_list>
        <group group_id="E1">
          <title>Nusinersen 3 mg</title>
          <description>3 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="E2">
          <title>Nusinersen 6 mg</title>
          <description>6 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
        <group group_id="E3">
          <title>Nusinersen 9 mg</title>
          <description>9 mg nusinersen on Days 1 and 85, IT injection</description>
        </group>
        <group group_id="E4">
          <title>Nusinersen 12 mg</title>
          <description>12 mg nusinersen on Days 1, 29, 85, IT injection</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 14.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Drug hypersensitivity</sub_title>
                <description>Event assessed as unlikely to be related to study drug.</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Post lumbar puncture syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 14.1</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="8" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Strabismus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Food poisoning</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia oral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Lip pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Puncture site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Catheter site haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Catheter site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Catheter site related reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Feeling cold</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gravitational oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Vessel puncture site haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pharyngitis streptococcal</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Viral upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Localised infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Ear infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Eye infection staphylococcal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gastrointestinal viral infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Impetigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Respiratory syncytial virus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Skin bacterial infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Post lumbar puncture syndrome</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Laceration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Sunburn</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Torus fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Agitation postoperative</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Limb injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Postoperative ileus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Thermal burn</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Tibia fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bicarbonate decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Joint contracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Scoliosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pelvic deformity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Skin papilloma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dyslexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Attention deficit/hyperactivity disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dysphoria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Parasomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Atelectasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Restrictive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Night sweats</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="9"/>
              </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>Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Biogen Study Medical Director</name_or_title>
      <organization>Biogen</organization>
      <email>clinicaltrials@biogen.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/NCT01703988
org study id: ISIS 396443 - CS2
secondary id: 2017-000327-27
nct id: NCT01703988
lead sponsor: 
has dmc: Yes
This study will test the safety, tolerability, and pharmacokinetics of escalating doses of
      nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over
      the duration of the trial, in participants with spinal muscular atrophy (SMA).

      Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort
      of approximately 8 participants, where all participants will receive active drug.
This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In
      August 2016, sponsorship of the trial was transferred to Biogen.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs
time frame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
description: An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.
measure: Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
time frame: Day 1 and Day 85
measure: Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
time frame: Day 1 and Day 85
measure: Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)
time frame: Day 1 and Day 85
measure: Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
time frame: Day 1, Day 29, and Day 85
measure: Urine Pharmacokinetics: Renal Clearance, Cohort 4
time frame: Day 1 and Day 85
description: Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.
arm group label: Nusinersen 3 mg
arm group type: Experimental
description: 3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection
arm group label: Nusinersen 6 mg
arm group type: Experimental
description: 6 mg nusinersen on Days 1, 29, 85, IT injection
arm group label: Nusinersen 9 mg
arm group type: Experimental
description: 9 mg nusinersen on Days 1 and 85, IT injection
arm group label: Nusinersen 12 mg
arm group type: Experimental
description: 12 mg nusinersen on Days 1, 29, 85, IT injection
intervention type: Drug
intervention name: Nusinersen
description: Single IT injection for each dose
arm group label: Nusinersen 12 mg
arm group label: Nusinersen 3 mg
arm group label: Nusinersen 6 mg
arm group label: Nusinersen 9 mg
other name: ISIS-SMNRx
other name: ISIS 396443
other name: BIIB058
other name: Spinraza
criteria: 
gender: All
minimum age: 2 Years
maximum age: 15 Years
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Biogen
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://clinicalresearch.biogen.com/Content/Studies/CS2%20Biogen.com%20Packet.pdf
description: Clinical Study Report (CSR) Synopsis - a results summary
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/
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 