<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/NCT03792672</url>
  </required_header>
  <id_info>
    <org_study_id>TAK-653-1003</org_study_id>
    <secondary_id>U1111-1224-5430</secondary_id>
    <secondary_id>2018-004206-26</secondary_id>
    <secondary_id>NL68394.056.18</secondary_id>
    <nct_id>NCT03792672</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate Central Nervous System (CNS) Pharmacodynamic Activity of TAK-653 in Healthy Participants Using Transcranial Magnetic Stimulation (TMS)</brief_title>
  <official_title>A Randomized, Double-blind, Placebo-Controlled, 3-Period Crossover Study Followed by 1 Open-label Comparator Period to Evaluate Central Nervous System Pharmacodynamic Activity of TAK-653 in Healthy Volunteers Using Transcranial Magnetic Stimulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Neurocrine Biosciences</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Takeda</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Neurocrine Biosciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary purpose of this study is to determine whether TAK-653, in comparison to placebo,&#xD;
      increases CNS excitability, assessed with TMS-evoked motor-evoked potential (MEP) in healthy&#xD;
      participants.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The drug being tested in this study is called TAK-653. This study is designed to evaluate the&#xD;
      central pharmacodynamic activity of TAK-653 using TMS. The study will enroll approximately 24&#xD;
      participants to yield 22 participants that complete treatment periods 1, 2, and 3.&#xD;
      Participants will be randomly assigned to 1 of the 6 sequences to receive TAK-653 0.5 mg low&#xD;
      dose or TAK-653 6 mg high dose or Placebo in double-blind treatment periods 1, 2, and 3,&#xD;
      followed by Ketamine 0.5 mg/kg in open-label Treatment period 4.&#xD;
&#xD;
      All participants will receive one dose of TAK-653 (0.5 or 6 mg), or Placebo or Ketamine on&#xD;
      Day 1 of each treatment period.&#xD;
&#xD;
      This single center trial will be conducted in the Netherlands. The overall time to&#xD;
      participate in this study is 15 weeks. Participants will make 5 visits to the clinic. A&#xD;
      washout period of minimum 10 days will be maintained between the doses in treatment periods 1&#xD;
      to 3. Follow-up phone call will be made on Day 14.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 11, 2019</start_date>
  <completion_date type="Actual">June 18, 2019</completion_date>
  <primary_completion_date type="Actual">May 15, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The study is double blind in Treatment Periods 1, 2, and 3 and open-label in Treatment Period 4.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Peak-to-Peak Amplitude of Motor-evoked Potential (MEP) Obtained With Single-pulse Transcranial Magnetic Stimulation (TMS) for TAK-653 at 2.5 Hours Post TAK-653 Dose</measure>
    <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
    <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120 percent (%) of baseline resting motor threshold (rMT). rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 versus (vs.) matched oral placebo.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</measure>
    <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
    <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Magnitude of Long Intracortical Inhibition (LICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</measure>
    <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
    <description>LICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in LICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Magnitude of Short Intracortical Inhibition (SICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</measure>
    <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
    <description>SICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse 80% of baseline rMT and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in SICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in rMT Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post-dose of Ketamine</measure>
    <time_frame>Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose</time_frame>
    <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg/kg Ketamine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in in Peak-to-Peak Amplitude of MEP Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post Dose of Ketamine</measure>
    <time_frame>Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose</time_frame>
    <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment 0.5 mg/kg Ketamine.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 6 milligram (mg) high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 milligram per kilogram (mg/kg), intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TAK-653</intervention_name>
    <description>TAK-653 tablets.</description>
    <arm_group_label>Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>TAK-653 placebo-matching tablets.</description>
    <arm_group_label>Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketamine</intervention_name>
    <description>Ketamine intravenous infusion.</description>
    <arm_group_label>Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</arm_group_label>
    <arm_group_label>TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Must be judged to be in good health by the investigator, based on clinical evaluations&#xD;
             including laboratory safety tests, medical history, physical examination, 12-lead&#xD;
             electrocardiogram (ECG), and vital sign measurements performed at the screening visit&#xD;
             and before the first dose of study drug.&#xD;
&#xD;
          2. Must be male or female (of nonchildbearing potential) aged 18 to 55 years, inclusive,&#xD;
             at the screening visit.&#xD;
&#xD;
          3. Must have a body mass index (BMI) greater than or equal to (&gt;=) 18.5 and less than or&#xD;
             equal to (&lt;=) 30.0 kilogram per square meter (kg/m^2) at the screening visit.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Has a positive alcohol or drug screen.&#xD;
&#xD;
          2. Had major surgery or donated or lost 1 unit of blood (approximately 500 milliliter&#xD;
             [mL]) within 4 weeks before the screening visit.&#xD;
&#xD;
          3. Has a history of alcohol consumption exceeding 2 standard drinks per day on average (1&#xD;
             glass is approximately equivalent to the following: beer [354 mL/12 ounce (oz)], wine&#xD;
             [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).&#xD;
&#xD;
          4. Who regularly smoke more than 5 cigarettes daily or equivalent and unable or unwilling&#xD;
             not to smoke during the in-house period.&#xD;
&#xD;
          5. Consumes excessive amounts, defined as greater than 6 servings (1 serving is&#xD;
             approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks,&#xD;
             or other caffeinated beverages per day.&#xD;
&#xD;
          6. Has a previous or current clinically significant psychiatric disorder according to&#xD;
             Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-5)&#xD;
             including substance use disorder.&#xD;
&#xD;
          7. Has a history of intracranial mass lesion, hydrocephalus and/or head injury or trauma.&#xD;
&#xD;
          8. Has metal objects in brain or skull.&#xD;
&#xD;
          9. Has a cochlear implant or deep brain stimulation device.&#xD;
&#xD;
         10. Has a history of epilepsy, seizures, or convulsions.&#xD;
&#xD;
         11. Has a family history of epilepsy, seizures, or convulsions.&#xD;
&#xD;
         12. Has abnormal sleeping patterns (example, working night shifts)&#xD;
&#xD;
         13. Has an rMT of more than 75% of the maximum stimulator output, measured using&#xD;
             TMS-electromyogram (EMG) during screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Millennium Pharmaceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHDR</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>January 2, 2019</study_first_submitted>
  <study_first_submitted_qc>January 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 3, 2019</study_first_posted>
  <results_first_submitted>June 12, 2020</results_first_submitted>
  <results_first_submitted_qc>June 12, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">July 2, 2020</results_first_posted>
  <last_update_submitted>March 17, 2021</last_update_submitted>
  <last_update_submitted_qc>March 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug Therapy</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 4, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03792672/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 29, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03792672/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants took part in the study at 1 investigative site in Netherlands from 11 February 2019 to 18 June 2019.</recruitment_details>
      <pre_assignment_details>Healthy participants were enrolled in 1 of the 6 treatment sequences of this 3-period crossover study to receive TAK 653 0.5 milligram (mg) (Low dose), TAK-653 6 mg (high dose), placebo in Treatment Periods 1 to 3, and ketamine 0.5 milligram per kilogram (mg/kg) in an open label treatment Period 4.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
        <group group_id="P2">
          <title>Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
        <group group_id="P3">
          <title>TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
        <group group_id="P4">
          <title>TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
        <group group_id="P5">
          <title>TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
        <group group_id="P6">
          <title>TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg</title>
          <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment Period 1 (1 Day)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 1 (10 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Treatment Period 2 (1 Day)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 2 (10 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Treatment Period 3 (1 Day)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 3 (10 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </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="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Treatment Period 4 (2 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The safety analysis set included all participants who were randomized and received at least 1 dose of study drug. Baseline characteristics data has been presented for overall participants analyzed.</population>
      <group_list>
        <group group_id="B1">
          <title>All Participants</title>
          <description>TAK-653 placebo-matching tablets or TAK-653 0.5 mg low dose tablets or TAK-653 6 mg high dose tablets, orally, once, on Day 1 of respective Treatment Period 1, 2 or 3 and Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4. A Washout Period of at least 10 days was maintained between each treatment period.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="24"/>
          </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="27.9" spread="9.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kilogram (Kg)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="79.12" spread="10.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>centimeter (cm)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="181.98" spread="9.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (BMI)</title>
          <units>kilogram per square meter (kg/m^2)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23.93" spread="2.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Peak-to-Peak Amplitude of Motor-evoked Potential (MEP) Obtained With Single-pulse Transcranial Magnetic Stimulation (TMS) for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
        <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120 percent (%) of baseline resting motor threshold (rMT). rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 versus (vs.) matched oral placebo.</description>
        <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
        <population>The pharmacodynamics (PD) set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O2">
            <title>TAK-653 0.5 mg</title>
            <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O3">
            <title>TAK-653 6 mg</title>
            <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Peak-to-Peak Amplitude of Motor-evoked Potential (MEP) Obtained With Single-pulse Transcranial Magnetic Stimulation (TMS) for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
          <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120 percent (%) of baseline resting motor threshold (rMT). rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 versus (vs.) matched oral placebo.</description>
          <population>The pharmacodynamics (PD) set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
          <units>microvolt (mcV)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="898.828" spread="693.1535"/>
                    <measurement group_id="O2" value="841.068" spread="591.1367"/>
                    <measurement group_id="O3" value="1004.127" spread="574.5982"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-139.117" spread="829.5901"/>
                    <measurement group_id="O2" value="17.265" spread="466.2556"/>
                    <measurement group_id="O3" value="139.932" spread="813.9705"/>
                  </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>0.4278</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Least square mean (LSM) difference</param_type>
            <param_value>115</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>144</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-128</ci_lower_limit>
            <ci_upper_limit>359</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0269</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>338</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>147</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>90.5</ci_lower_limit>
            <ci_upper_limit>585</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
        <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
        <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
        <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O2">
            <title>TAK-653 0.5 mg</title>
            <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O3">
            <title>TAK-653 6 mg</title>
            <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
          <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
          <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods.</population>
          <units>percentage of maximum stimulator output</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.3" spread="7.46"/>
                    <measurement group_id="O2" value="55.9" spread="8.99"/>
                    <measurement group_id="O3" value="55.3" spread="8.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 hours post TAK-653 Dose</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.1" spread="2.74"/>
                    <measurement group_id="O2" value="-0.5" spread="1.74"/>
                    <measurement group_id="O3" value="-0.3" spread="1.95"/>
                  </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>0.5089</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-0.388</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.582</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.37</ci_lower_limit>
            <ci_upper_limit>0.595</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.7208</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-0.209</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.581</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.19</ci_lower_limit>
            <ci_upper_limit>0.773</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Magnitude of Long Intracortical Inhibition (LICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
        <description>LICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in LICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
        <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
        <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O2">
            <title>TAK-653 0.5 mg</title>
            <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O3">
            <title>TAK-653 6 mg</title>
            <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Magnitude of Long Intracortical Inhibition (LICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
          <description>LICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in LICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
          <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods.</population>
          <units>percent inhibition</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline: LICI 50 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.113" spread="97.2865"/>
                    <measurement group_id="O2" value="96.515" spread="113.2728"/>
                    <measurement group_id="O3" value="96.568" spread="111.1657"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: LICI 50 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.675" spread="54.5725"/>
                    <measurement group_id="O2" value="18.319" spread="81.4378"/>
                    <measurement group_id="O3" value="19.395" spread="110.0870"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline: LICI 100 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.167" spread="27.0976"/>
                    <measurement group_id="O2" value="10.430" spread="14.1289"/>
                    <measurement group_id="O3" value="46.808" spread="149.9806"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: LICI 100 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.147" spread="29.1567"/>
                    <measurement group_id="O2" value="5.905" spread="18.8939"/>
                    <measurement group_id="O3" value="-28.644" spread="142.5618"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline: LICI 200 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.149" spread="33.1815"/>
                    <measurement group_id="O2" value="48.934" spread="48.6073"/>
                    <measurement group_id="O3" value="49.773" spread="37.7173"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: LICI 200 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.882" spread="21.2459"/>
                    <measurement group_id="O2" value="9.902" spread="42.5761"/>
                    <measurement group_id="O3" value="11.540" spread="30.1594"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline: LICI 300 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.463" spread="31.1596"/>
                    <measurement group_id="O2" value="56.115" spread="36.8452"/>
                    <measurement group_id="O3" value="54.572" spread="30.5543"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: LICI 300 ms</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.996" spread="27.7151"/>
                    <measurement group_id="O2" value="8.618" spread="36.0453"/>
                    <measurement group_id="O3" value="1.638" spread="32.6843"/>
                  </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>
            <groups_desc>LICI 50 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4174</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>14.0</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>17.1</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-14.8</ci_lower_limit>
            <ci_upper_limit>42.8</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>LICI 50 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3832</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>15.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>17.1</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-25.3</ci_lower_limit>
            <ci_upper_limit>31.5</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>LICI 100 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.9368</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-0.326</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>4.09</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-7.23</ci_lower_limit>
            <ci_upper_limit>6.58</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>LICI 100 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3790</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>3.71</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>4.16</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.32</ci_lower_limit>
            <ci_upper_limit>10.7</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>LICI 200 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2580</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>7.36</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>6.41</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.44</ci_lower_limit>
            <ci_upper_limit>18.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>LICI 200 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1524</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>9.36</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>6.41</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.45</ci_lower_limit>
            <ci_upper_limit>20.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>LICI 300 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0220</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>17.2</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>7.21</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>5.06</ci_lower_limit>
            <ci_upper_limit>29.4</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>LICI 300 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1927</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>9.58</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>7.23</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.59</ci_lower_limit>
            <ci_upper_limit>21.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Magnitude of Short Intracortical Inhibition (SICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
        <description>SICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse 80% of baseline rMT and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in SICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
        <time_frame>Baseline, 2.5 hours post TAK-653 dose</time_frame>
        <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O2">
            <title>TAK-653 0.5 mg</title>
            <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
          <group group_id="O3">
            <title>TAK-653 6 mg</title>
            <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Magnitude of Short Intracortical Inhibition (SICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose</title>
          <description>SICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse 80% of baseline rMT and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in SICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.</description>
          <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed first 3 treatment periods. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
          <units>percent inhibition</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline: SICI 2 ms</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.095" spread="30.7011"/>
                    <measurement group_id="O2" value="39.159" spread="39.2536"/>
                    <measurement group_id="O3" value="47.951" spread="42.1139"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: SICI 2 ms</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.052" spread="47.5676"/>
                    <measurement group_id="O2" value="1.772" spread="35.9158"/>
                    <measurement group_id="O3" value="-14.580" spread="37.7311"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Baseline: SICI 5 ms</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70.640" spread="49.8699"/>
                    <measurement group_id="O2" value="59.672" spread="37.7419"/>
                    <measurement group_id="O3" value="72.722" spread="62.0484"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 Hours Post TAK-653 Dose: SICI 5 ms</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="24"/>
                    <count group_id="O2" value="24"/>
                    <count group_id="O3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.303" spread="81.6111"/>
                    <measurement group_id="O2" value="4.274" spread="30.8966"/>
                    <measurement group_id="O3" value="-7.247" spread="52.9205"/>
                  </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>
            <groups_desc>SICI 2 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.5590</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-5.65</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>9.59</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-21.8</ci_lower_limit>
            <ci_upper_limit>10.5</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>SICI 2 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1049</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-16.1</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>9.72</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-32.5</ci_lower_limit>
            <ci_upper_limit>0.242</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>SICI 5 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.2238</p_value>
            <p_value_desc>Based on mixed model analysis, with treatment, period, sequence, treatment-by-period interaction as fixed factors, participant within sequence as a random factor, baseline as a covariate.</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-16.7</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>13.5</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-39.4</ci_lower_limit>
            <ci_upper_limit>6.06</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>SICI 5 ms peak-to-peak amplitude</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1847</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>LSM difference</param_type>
            <param_value>-18.3</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>13.6</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-41.3</ci_lower_limit>
            <ci_upper_limit>4.56</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in rMT Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post-dose of Ketamine</title>
        <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg/kg Ketamine.</description>
        <time_frame>Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose</time_frame>
        <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Ketamine 0.5 mg/kg</title>
            <description>Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4 in all 6 treatment sequences.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in rMT Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post-dose of Ketamine</title>
          <description>The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg/kg Ketamine.</description>
          <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
          <units>percentage of maximum stimulator output</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.4" spread="9.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 hours Ketamine Post Dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.7" spread="4.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 24 hours Ketamine Post Dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.8" spread="3.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in in Peak-to-Peak Amplitude of MEP Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post Dose of Ketamine</title>
        <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment 0.5 mg/kg Ketamine.</description>
        <time_frame>Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose</time_frame>
        <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Ketamine 0.5 mg/kg</title>
            <description>Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4 in all 6 treatment sequences.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in in Peak-to-Peak Amplitude of MEP Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post Dose of Ketamine</title>
          <description>TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment 0.5 mg/kg Ketamine.</description>
          <population>The PD set included of all participants who received study drug and had at least one postdose PD measurement. The PD analysis set included all participants who had completed Treatment Period 4. Participants who were evaluable for this measure at given time point were included for the assessment.</population>
          <units>mcV</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1150.618" spread="1047.3920"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 2.5 hours Ketamine Post Dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-193.897" spread="897.0245"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at 24 hours Ketamine Post Dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-295.041" spread="944.4889"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Treatment-emergent adverse events are adverse events that started after the first dose of study drug until 14 days after last dose in Treatment Period 4 (up to Day 48)</time_frame>
      <desc>At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
        </group>
        <group group_id="E2">
          <title>TAK-653 0.5 mg</title>
          <description>TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
        </group>
        <group group_id="E3">
          <title>TAK-653 6 mg</title>
          <description>TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, 2 or 3 as per assigned treatment sequence.</description>
        </group>
        <group group_id="E4">
          <title>Ketamine 0.5 mg/kg</title>
          <description>Ketamine 0.5 mg/kg, infusion, intravenously, once on Day 1 of Treatment Period 4 in all 6 treatment sequences.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (22.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E4" subjects_affected="20" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision Blurred</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="5" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Feeling Cold</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Feeling Drunk</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal Allergy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="8" subjects_affected="8" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E4" events="4" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Dissociation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E4" events="15" subjects_affected="15" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </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>Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Medical Director</name_or_title>
      <organization>Takeda</organization>
      <phone>1-877-825-3327</phone>
      <email>medicalinformation@tpna.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/NCT03792672
org study id: TAK-653-1003
secondary id: U1111-1224-5430
secondary id: 2018-004206-26
secondary id: NL68394.056.18
nct id: NCT03792672
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The primary purpose of this study is to determine whether TAK-653, in comparison to placebo,
      increases CNS excitability, assessed with TMS-evoked motor-evoked potential (MEP) in healthy
      participants.
The drug being tested in this study is called TAK-653. This study is designed to evaluate the
      central pharmacodynamic activity of TAK-653 using TMS. The study will enroll approximately 24
      participants to yield 22 participants that complete treatment periods 1, 2, and 3.
      Participants will be randomly assigned to 1 of the 6 sequences to receive TAK-653 0.5 mg low
      dose or TAK-653 6 mg high dose or Placebo in double-blind treatment periods 1, 2, and 3,
      followed by Ketamine 0.5 mg/kg in open-label Treatment period 4.

      All participants will receive one dose of TAK-653 (0.5 or 6 mg), or Placebo or Ketamine on
      Day 1 of each treatment period.

      This single center trial will be conducted in the Netherlands. The overall time to
      participate in this study is 15 weeks. Participants will make 5 visits to the clinic. A
      washout period of minimum 10 days will be maintained between the doses in treatment periods 1
      to 3. Follow-up phone call will be made on Day 14.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: The study is a randomized, crossover 6 sequence study in Treatment Periods 1, 2, and 3.
primary purpose: Other
masking: Double (Participant, Investigator)
masking description: The study is double blind in Treatment Periods 1, 2, and 3 and open-label in Treatment Period 4.
measure: Change From Baseline in Peak-to-Peak Amplitude of Motor-evoked Potential (MEP) Obtained With Single-pulse Transcranial Magnetic Stimulation (TMS) for TAK-653 at 2.5 Hours Post TAK-653 Dose
time frame: Baseline, 2.5 hours post TAK-653 dose
description: TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120 percent (%) of baseline resting motor threshold (rMT). rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 versus (vs.) matched oral placebo.
measure: Change From Baseline in Resting Motor Threshold (rMT) Obtained With Single-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose
time frame: Baseline, 2.5 hours post TAK-653 dose
description: The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.
measure: Change From Baseline in Magnitude of Long Intracortical Inhibition (LICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose
time frame: Baseline, 2.5 hours post TAK-653 dose
description: LICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in LICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.
measure: Change From Baseline in Magnitude of Short Intracortical Inhibition (SICI) Obtained With Paired-pulse TMS for TAK-653 at 2.5 Hours Post TAK-653 Dose
time frame: Baseline, 2.5 hours post TAK-653 dose
description: SICI was TMS stimulation paradigm that capture modulation of cortical excitation-inhibition balance with pairs of TMS pulses at stimulation intensity conditioning pulse 80% of baseline rMT and test pulse of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in SICI was be assessed by TMS after treatment with 0.5 mg or 6 mg of TAK-653 vs. matched oral placebo.
measure: Change From Baseline in rMT Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post-dose of Ketamine
time frame: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose
description: The rMT was defined as the minimum stimulus intensity to evoke an MEP. Single-pulse TMS was used to determine rMT. A lower rMT value indicated greater neuronal excitability. TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Change in rMT was be assessed by TMS after treatment with 0.5 mg/kg Ketamine.
measure: Change From Baseline in in Peak-to-Peak Amplitude of MEP Obtained With Single-pulse TMS to Assess the Effect of Ketamine at 2.5 Hours and 24 Hours Post Dose of Ketamine
time frame: Baseline, 2.5 hours post ketamine dose, and 24 hours post ketamine dose
description: TMS was a neurophysiologic test for assessing upper motor neuron function. TMS was a noninvasive neuro stimulation method involving the application of brief magnetic pulses to the skull, based on the principles of electromagnetic induction, create an orthogonal electric current that can be sufficient to depolarize neurons and activate neuronal circuits. Single-pulse TMS was used to determine peak-to-peak amplitude of MEP at a stimulation intensity of 120% of baseline rMT. rMT was defined as the minimum stimulus intensity to evoke an MEP. Change in peak-to peak amplitude of MEP was be assessed by TMS after treatment 0.5 mg/kg Ketamine.
arm group label: TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 6 milligram (mg) high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 milligram per kilogram (mg/kg), intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
arm group label: TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
arm group label: TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
arm group label: TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
arm group label: Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
arm group label: Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group type: Experimental
description: TAK-653 placebo-matching tablets, orally, once on Day 1 of Treatment Period 1, followed by TAK-653 6 mg high dose tablets, orally, once on Day 1 of Treatment Period 2, further followed by TAK-653 0.5 mg low dose tablets, orally, once on Day 1 of Treatment Period 3, followed by Ketamine 0.5 mg/kg, intravenous infusion, once on Day 1 of Treatment Period 4. A washout of 10 to 15 days will be maintained between each treatment period.
intervention type: Drug
intervention name: TAK-653
description: TAK-653 tablets.
arm group label: Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
intervention type: Drug
intervention name: Placebo
description: TAK-653 placebo-matching tablets.
arm group label: Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
intervention type: Drug
intervention name: Ketamine
description: Ketamine intravenous infusion.
arm group label: Placebo + TAK-653 0.5 mg + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: Placebo + TAK-653 6 mg + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + Placebo + TAK-653 6 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 0.5 mg + TAK-653 6 mg + Placebo + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + Placebo + TAK-653 0.5 mg + Ketamine 0.5 mg/kg
arm group label: TAK-653 6 mg + TAK-653 0.5 mg + Placebo + Ketamine 0.5 mg/kg
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Medical Director
role: Study Director
affiliation: Millennium Pharmaceuticals, Inc.
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Ketamine
sharing ipd: Yes
ipd description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 