<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/NCT01709149</url>
  </required_header>
  <id_info>
    <org_study_id>CY 4026</org_study_id>
    <nct_id>NCT01709149</nct_id>
  </id_info>
  <brief_title>Study of Safety, Tolerability &amp; Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS)</brief_title>
  <official_title>A Phase IIb, Multi-National, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Efficacy of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS) (BENEFIT-ALS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cytokinetics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cytokinetics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to evaluate the safety and effectiveness of CK-2017357&#xD;
      when taken with or without riluzole (also called Rilutek®) in patients with Amyotrophic&#xD;
      Lateral Sclerosis (ALS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The length of the study, including screening, dosing, and follow-up, is approximately 20&#xD;
      weeks. After a one-week open-label phase during which all patients will receive CK-2017357&#xD;
      125 milligrams (mg) twice daily, patients who tolerate the open-label 125 mg of CK-2017357&#xD;
      will be randomized one to one (fifty-fifty) to receive double-blind CK-2017357 or matching&#xD;
      placebo. The CK-2017357/placebo dose will be increased no faster than weekly to each&#xD;
      patient's highest tolerated daily dose, with a maximum of 250 mg twice daily. The dose may be&#xD;
      decreased based on tolerability. Patients will continue treatment at the highest tolerated&#xD;
      dose to complete a total of 12 weeks of double-blind treatment. Patients may be on riluzole&#xD;
      or not on riluzole at study entry. Patients not on riluzole must stay off riluzole. Patients&#xD;
      on riluzole who are getting double-blind CK-2017357 will be given riluzole at half the&#xD;
      labeled dosage (50 mg once a day instead of 50 mg twice a day). Blood tests for safety will&#xD;
      be performed. Information about any side effects that may occur will also be collected.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">March 2014</completion_date>
  <primary_completion_date type="Actual">March 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment</measure>
    <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
    <description>A hand-held dynamometer (HHD), with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">711</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>CK-2017357</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>125 mg tablets</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo tablets</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CK-2017357</intervention_name>
    <description>CK-2017357 125 mg tablets twice daily</description>
    <arm_group_label>CK-2017357</arm_group_label>
    <other_name>tirasemtiv</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo tablets</intervention_name>
    <description>Tablets</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riluzole</intervention_name>
    <description>Tablets</description>
    <arm_group_label>CK-2017357</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Rilutek</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able to comprehend and willing to sign an Informed Consent Form (ICF)&#xD;
&#xD;
          2. Male or female 18 years of age or older&#xD;
&#xD;
          3. A diagnosis of familial or sporadic ALS (defined as meeting the possible,&#xD;
             laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS&#xD;
             according to the World Federation of Neurology El Escorial criteria)&#xD;
&#xD;
          4. Upright Slow Vital Capacity (SVC) &gt;50 % of predicted for age, height and sex&#xD;
&#xD;
          5. At least 4 of the 12 ALSFRS-R questions must be scored 2 or 3&#xD;
&#xD;
          6. Diminished but measurable maximum voluntary grip strength in at least one hand; i.e.,&#xD;
             between 10 and 50 pounds (females) and 10 and 70 pounds (males)&#xD;
&#xD;
          7. Able to swallow tablets without crushing&#xD;
&#xD;
          8. A caregiver (if one is needed) who can and will observe and report the patient's&#xD;
             status&#xD;
&#xD;
          9. Pre-study clinical laboratory findings within normal range or, if outside of the&#xD;
             normal range, deemed not clinically significant by the Investigator&#xD;
&#xD;
         10. Male patients must agree for the duration of the study and 10 weeks after the end of&#xD;
             the study to use a condom during sexual intercourse with female partners who are of&#xD;
             reproductive potential and to have female partners use an additional effective means&#xD;
             of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) or the male&#xD;
             patient must agree to abstain from sexual intercourse during and for 10 weeks after&#xD;
             the end of the study&#xD;
&#xD;
         11. Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of&#xD;
             childbearing potential, not be breastfeeding, have a negative pregnancy test, have no&#xD;
             intention to become pregnant during the course of the study, and use contraceptive&#xD;
             drugs or devices as detailed in item 10 for the duration of the study and for 10 weeks&#xD;
             after the end of the study&#xD;
&#xD;
         12. Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30&#xD;
             days prior to screening or have not taken riluzole for at least 30 days prior to&#xD;
             screening and are willing not to begin riluzole use during the conduct of this study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive&#xD;
             airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) for any portion of&#xD;
             the day, or mechanical ventilation via tracheostomy, or on any form of oxygen&#xD;
             supplementation&#xD;
&#xD;
          2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS&#xD;
             placement during the course of the study&#xD;
&#xD;
          3. Body Mass Index (BMI) of 19.0 kg/m2 or lower&#xD;
&#xD;
          4. Unwilling to discontinue tizanidine and theophylline-containing medications during&#xD;
             study participation&#xD;
&#xD;
          5. Serum chloride &lt; 100 mmol/L&#xD;
&#xD;
          6. Neurological impairment due to a condition other than ALS, including history of&#xD;
             transient ischemic attack (TIA) within the past year&#xD;
&#xD;
          7. Presence at screening of any medically significant cardiac, pulmonary,&#xD;
             gastrointestinal (GI), musculoskeletal, or psychiatric illness that might interfere&#xD;
             with the patient's ability to comply with study procedures or that might confound the&#xD;
             interpretation of clinical safety or efficacy data&#xD;
&#xD;
          8. Has taken any investigational study drug within 30 days or 5 half-lives of the prior&#xD;
             agent, whichever is greater, prior to dosing&#xD;
&#xD;
          9. Previously received CK-2017357 in any previous clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jinsy Andrews, MD</last_name>
    <role>Study Director</role>
    <affiliation>Cytokinetics, Inc.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeremy Shefner, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>State University of New York - Upstate Medical University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeremy Shefner, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>State University of New York - Upstate Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Barrow Neurology</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California, San Diego</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UC Irvine ALS &amp; Neuromuscular Center</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Coordinated Clinical Research</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>California Pacific Medical Center Forbes Norris MDA/ALS Research Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital for Special Care</name>
      <address>
        <city>New Britain</city>
        <state>Connecticut</state>
        <zip>06053</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The George Washington University</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic Florida Department of Neurology</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University, School of Medicine</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Georgia Health Sciences University</name>
      <address>
        <city>Augusta</city>
        <state>Georgia</state>
        <zip>30912</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University Department of Neurology</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospitals and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Massachusetts Medical School</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01655</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Henry Ford Hospital</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Mary's Healthcare</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hennepin County Medical Center - Berman Center for Research</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55415</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Louis University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology Associates</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital for Special Surgery</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Rochester</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SUNY Upstate Medical University</name>
      <address>
        <city>Syracuse</city>
        <state>New York</state>
        <zip>13120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carolinas Medical Center Department of Neurology</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>27406</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke University</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wake Forest University, School of Medicine</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Department of Neurology</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43221</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence ALS Center</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Hershey Neuroscience Clinics</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Drexel Neurology</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Neurology</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75214</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UTHSCSA Department of Neurology</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Virginia University Department of Neurology</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Heritage Medical Research</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 4Z6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Alberta Hospital</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>B3H 3A7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of British Columbia</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 2G9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stan Cassidy Centre for Rehabilitation</name>
      <address>
        <city>Fredericton</city>
        <state>New Brunswick</state>
        <zip>E3B 0C7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>QE II Health Sciences Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <zip>B3H 3A7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McMaster University Medical Centre</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8S 4K1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen's University : Kingston General</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <zip>K7L 2V7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>London Health Sciences</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5A5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Univ. of Toronto - Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Notre Dame (CHUM) Centre Hospitalier de l'Universite de Montreal</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H2L4M1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Montreal Neurological Institute</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3A 2B4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Quebec: Hopital l'Enfant-Jesus</name>
      <address>
        <city>Quebec</city>
        <zip>G1J 1Z4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Lille - Hôpital Roger Salengro</name>
      <address>
        <city>Lille</city>
        <zip>F-59037 LILLE cedex</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges - Hôpital Dupuytren</name>
      <address>
        <city>Limoges</city>
        <zip>87042 LIMOGES CEDEX</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital La Timone Adulte</name>
      <address>
        <city>Marseille</city>
        <zip>13005</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Montepellier</name>
      <address>
        <city>Montpellier</city>
        <zip>34295 Montpellier Cedex 5</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Archet 1</name>
      <address>
        <city>Nice</city>
        <zip>06602</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital de la Salpêtrière</name>
      <address>
        <city>Paris</city>
        <zip>Cedex 13</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Bretonneau</name>
      <address>
        <city>Tours</city>
        <zip>37000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charite Universitätsmedizin</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hannover Medical School</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Ulm</name>
      <address>
        <city>Ulm</city>
        <zip>89081</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Trinity College, Beaumont Hospital</name>
      <address>
        <city>Dublin</city>
        <zip>9</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitair Medisch Centrum Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Carlos III</name>
      <address>
        <city>Madrid</city>
        <zip>28029</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Barts and the London MND &amp; the Centre Royal London Hospital</name>
      <address>
        <city>Whitechapel</city>
        <state>London</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Walton Centre for Neurology and Neurosurgery</name>
      <address>
        <city>Liverpool</city>
        <zip>L9 7LJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kings College Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SE5 8AF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>John Radcliffe Hospital</name>
      <address>
        <city>Oxford</city>
        <zip>OX3 9DU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plymouth Hospitals NHS Trust</name>
      <address>
        <city>Plymouth</city>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheffield Institute for Translational Neuroscience</name>
      <address>
        <city>Sheffield</city>
        <zip>S10 2HQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>France</country>
    <country>Germany</country>
    <country>Ireland</country>
    <country>Netherlands</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>October 16, 2012</study_first_submitted>
  <study_first_submitted_qc>October 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 18, 2012</study_first_posted>
  <results_first_submitted>January 30, 2020</results_first_submitted>
  <results_first_submitted_qc>March 30, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">March 31, 2020</results_first_posted>
  <disposition_first_submitted>March 26, 2015</disposition_first_submitted>
  <disposition_first_submitted_qc>October 6, 2015</disposition_first_submitted_qc>
  <disposition_first_posted type="Estimate">November 1, 2015</disposition_first_posted>
  <last_update_submitted>March 30, 2020</last_update_submitted>
  <last_update_submitted_qc>March 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Motor Neuron Disease</mesh_term>
    <mesh_term>Amyotrophic Lateral Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Riluzole</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients with familial or sporadic amyotrophic lateral sclerosis were enrolled at 73 sites in Canada, France, Germany, Ireland, Netherlands, Spain, the United Kingdom, and the United States. The first patient was screened on 23 October 2012 and the last subject completed follow-up on 21 March 2014.</recruitment_details>
      <pre_assignment_details>A total of 711 patients were enrolled in the study and began treatment with open-label tirasemtiv during the 7-day lead-in phase of the study. Patients who completed this phase were randomized (1:1) to receive either placebo (N=295) or tirasemtiv (N=301) in the double-blind treatment period.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Open-label lead-in Treatment: Tirasemtiv</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.</description>
        </group>
        <group group_id="P2">
          <title>Double-blind Treatment: Placebo</title>
          <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
        </group>
        <group group_id="P3">
          <title>Double-blind Treatment: Tirasemtiv</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily. Minimum dose was 125 mg bid and patients were up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Open-label Lead-in Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="711"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="596"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="115"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="109"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Double-blind, Placebo-controlled Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="295"/>
                <participants group_id="P3" count="301"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="269"/>
                <participants group_id="P3" count="204"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="26"/>
                <participants group_id="P3" count="97"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="78"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>not defined</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety Analysis Set (all patients who received any study drug)</population>
      <group_list>
        <group group_id="B1">
          <title>Did Not Complete Open-label Lead-in Treatment</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily for 7 days. This group started open-label treatment but discontinued early and did not receive double-blind treatment.</description>
        </group>
        <group group_id="B2">
          <title>Double-blind Treatment: Placebo</title>
          <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
        </group>
        <group group_id="B3">
          <title>Double-blind Treatment: Tirasemtiv</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
        </group>
        <group group_id="B4">
          <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="115"/>
            <count group_id="B2" value="295"/>
            <count group_id="B3" value="301"/>
            <count group_id="B4" value="711"/>
          </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="60.0" spread="9.83"/>
                    <measurement group_id="B2" value="56.9" spread="11.10"/>
                    <measurement group_id="B3" value="57.0" spread="11.17"/>
                    <measurement group_id="B4" value="57.5" spread="10.98"/>
                  </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="52"/>
                    <measurement group_id="B2" value="88"/>
                    <measurement group_id="B3" value="86"/>
                    <measurement group_id="B4" value="226"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="63"/>
                    <measurement group_id="B2" value="207"/>
                    <measurement group_id="B3" value="215"/>
                    <measurement group_id="B4" value="485"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="102"/>
                    <measurement group_id="B2" value="250"/>
                    <measurement group_id="B3" value="259"/>
                    <measurement group_id="B4" value="611"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="26"/>
                    <measurement group_id="B4" value="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Time since ALS symptom onset</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.0" lower_limit="4" upper_limit="278"/>
                    <measurement group_id="B2" value="21.0" lower_limit="4" upper_limit="224"/>
                    <measurement group_id="B3" value="23.0" lower_limit="5" upper_limit="272"/>
                    <measurement group_id="B4" value="22.0" lower_limit="4" upper_limit="278"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Site of symptom onset</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Lower limb</title>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                    <measurement group_id="B2" value="110"/>
                    <measurement group_id="B3" value="116"/>
                    <measurement group_id="B4" value="269"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Upper limb</title>
                  <measurement_list>
                    <measurement group_id="B1" value="51"/>
                    <measurement group_id="B2" value="145"/>
                    <measurement group_id="B3" value="149"/>
                    <measurement group_id="B4" value="345"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Bulbar</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="35"/>
                    <measurement group_id="B4" value="95"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Respiratory</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>El Escorial Diagnostic Criteria for ALS</title>
          <description>Per El Escorial criteria, ALS was diagnosed as: Possible (upper motor neuron [UMN] and lower motor neuron [LMN] signs in 1 region, or UMN signs in at least 2 regions, or UMN and LMN signs in 2 regions with no UMN signs rostral to LMN signs); Probable, Laboratory Supported (UMN signs in 1 or more regions and LMN signs defined by electromyography in at least 2 regions); Probable (UMN and LMN signs in 2 regions with some UMN signs rostral to the LMN signs); and Definite (UMN and LMN signs in 3 regions).&#xD;
The El Escorial criteria do not relate to grading of ALS nor to outcome.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Possible</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="31"/>
                    <measurement group_id="B4" value="68"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Probable, laboratory supported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="63"/>
                    <measurement group_id="B4" value="135"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Probable</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="119"/>
                    <measurement group_id="B3" value="103"/>
                    <measurement group_id="B4" value="268"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Definite</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="91"/>
                    <measurement group_id="B3" value="104"/>
                    <measurement group_id="B4" value="240"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function.</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <population>Modified Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function.</description>
          <population>Modified Full Analysis Set</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.40" spread="0.246"/>
                    <measurement group_id="O2" value="-2.98" spread="0.277"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1140</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>-0.58</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.366</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.30</ci_lower_limit>
            <ci_upper_limit>0.14</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <population>Modified Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).</description>
          <population>Modified Full Analysis Set</population>
          <units>L/min</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.27" spread="1.332"/>
                    <measurement group_id="O2" value="-3.79" spread="1.497"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.8083</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>0.48</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.963</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.38</ci_lower_limit>
            <ci_upper_limit>4.34</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <population>Modified Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.</description>
          <population>Modified Full Analysis Set</population>
          <units>cm H2O</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.89" spread="1.103"/>
                    <measurement group_id="O2" value="-4.29" spread="1.243"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0372</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>-3.40</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.627</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-6.60</ci_lower_limit>
            <ci_upper_limit>-0.20</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]).</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <population>Modified Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]).</description>
          <population>Modified Full Analysis Set</population>
          <units>% predicted</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.24" spread="0.691"/>
                    <measurement group_id="O2" value="-2.98" spread="0.780"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>4.25</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.030</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.23</ci_lower_limit>
            <ci_upper_limit>6.28</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force.</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force.</description>
          <units>pounds</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.54" spread="0.640"/>
                    <measurement group_id="O2" value="-2.78" spread="0.714"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4328</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>0.75</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.956</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.13</ci_lower_limit>
            <ci_upper_limit>2.63</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first.</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <population>Modified Full Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first.</description>
          <population>Modified Full Analysis Set</population>
          <units>seconds</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.76" spread="2.863"/>
                    <measurement group_id="O2" value="2.01" spread="3.331"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.9546</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>0.25</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>4.399</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-8.40</ci_lower_limit>
            <ci_upper_limit>8.90</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment</title>
        <description>A hand-held dynamometer (HHD), with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.</description>
        <time_frame>Baseline, 8 weeks, 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
          </group>
          <group group_id="O2">
            <title>Tirasemtiv</title>
            <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment</title>
          <description>A hand-held dynamometer (HHD), with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.</description>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="210"/>
                <count group_id="O2" value="178"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-10.71" spread="2.108"/>
                    <measurement group_id="O2" value="-9.10" spread="2.425"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6166</p_value>
            <method>Repeated-measures mixed model</method>
            <param_type>Least squares mean difference</param_type>
            <param_value>1.61</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>3.207</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-4.70</ci_lower_limit>
            <ci_upper_limit>7.91</ci_upper_limit>
            <estimate_desc>Least squares mean difference: tirasemtiv minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs were collected from the first dose of open-label study drug through 30 days after the last dose of study drug or Week 16, whichever was earlier.</time_frame>
      <desc>An AE was treatment-emergent if it started or worsened in severity after the first dose of study drug (in either the open-label or double-blind periods). For the double-blind period, if the AE started in the open-label period and continued into the double-blind period for more than 96 hours, it was assigned an onset of 96 hours after the first dose of double-blind study drug.</desc>
      <group_list>
        <group group_id="E1">
          <title>Open-label lead-in Treatment: Tirasemtiv</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily for 7 days prior to randomization to the Double-blind treatment period.</description>
        </group>
        <group group_id="E2">
          <title>Double-blind Treatment: Placebo</title>
          <description>Placebo oral capsules administered twice daily for a total of 12 weeks of double-blind dosing.</description>
        </group>
        <group group_id="E3">
          <title>Double-blind Treatment: Tirasemtiv</title>
          <description>Tirasemtiv 125 mg oral capsules administered twice daily, which was up- or down-titrated over 3 to 4 weeks to the patient's maximum tolerated dose (MTD) to a maximum of 250 mg twice daily. Patients then remained at their MTD for an additional 9 weeks, for a total of 12 weeks of double-blind dosing.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (15.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="27" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Coagulopathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Tachycardia paroxysmal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Acute coronary syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Faeces discoloured</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </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="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Kidney infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Parainfluenzae virus infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Post procedural infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Humerus fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Joint dislocation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Face injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Spinal column stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Lung neoplasm malignant</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Prostate cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>cerebral haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Paresis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Spinal haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Hypercapnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (15.1)</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="525" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="258" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="291" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="77" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="66" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="111" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="100" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="40" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="37" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="48" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="25" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Laceration</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Excoriation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="30" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="45" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="34" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="291" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="58" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="153" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="54" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="50" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="39" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Muscle contractions involuntary</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Balance disorder</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="31" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="301"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="301"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="711"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="295"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="301"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>MD Cytokinetics</name_or_title>
      <organization>Cytokinetics, Inc.</organization>
      <phone>650-624-2929</phone>
      <email>medicalaffairs@cytokinetics.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/NCT01709149
org study id: CY 4026
nct id: NCT01709149
lead sponsor: 
has dmc: Yes
The purpose of this research study is to evaluate the safety and effectiveness of CK-2017357
      when taken with or without riluzole (also called Rilutek®) in patients with Amyotrophic
      Lateral Sclerosis (ALS).
The length of the study, including screening, dosing, and follow-up, is approximately 20
      weeks. After a one-week open-label phase during which all patients will receive CK-2017357
      125 milligrams (mg) twice daily, patients who tolerate the open-label 125 mg of CK-2017357
      will be randomized one to one (fifty-fifty) to receive double-blind CK-2017357 or matching
      placebo. The CK-2017357/placebo dose will be increased no faster than weekly to each
      patient's highest tolerated daily dose, with a maximum of 250 mg twice daily. The dose may be
      decreased based on tolerability. Patients will continue treatment at the highest tolerated
      dose to complete a total of 12 weeks of double-blind treatment. Patients may be on riluzole
      or not on riluzole at study entry. Patients not on riluzole must stay off riluzole. Patients
      on riluzole who are getting double-blind CK-2017357 will be given riluzole at half the
      labeled dosage (50 mg once a day instead of 50 mg twice a day). Blood tests for safety will
      be performed. Information about any side effects that may occur will also be collected.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function.
measure: Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min).
measure: Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP.
measure: Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]).
measure: Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force.
measure: Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first.
measure: Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment
time frame: Baseline, 8 weeks, 12 weeks
description: A hand-held dynamometer (HHD), with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.
arm group label: CK-2017357
arm group type: Experimental
description: 125 mg tablets
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo tablets
intervention type: Drug
intervention name: CK-2017357
description: CK-2017357 125 mg tablets twice daily
arm group label: CK-2017357
other name: tirasemtiv
intervention type: Other
intervention name: Placebo tablets
description: Tablets
arm group label: Placebo
intervention type: Drug
intervention name: Riluzole
description: Tablets
arm group label: CK-2017357
arm group label: Placebo
other name: Rilutek
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jinsy Andrews, MD
role: Study Director
affiliation: Cytokinetics, Inc.
last name: Jeremy Shefner, MD, PhD
role: Study Chair
affiliation: State University of New York - Upstate Medical University
last name: Jeremy Shefner, MD, PhD
role: Principal Investigator
affiliation: State University of New York - Upstate Medical University
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country: Canada
country: France
country: Germany
country: Ireland
country: Netherlands
country: Spain
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
mesh term: Riluzole
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certain agreements: 
point of contact: 