<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/NCT01676311</url>
  </required_header>
  <id_info>
    <org_study_id>2012-p-002490</org_study_id>
    <nct_id>NCT01676311</nct_id>
  </id_info>
  <brief_title>Effects of Huperzine A in Treatment of Moderate to Severe TBI</brief_title>
  <official_title>Huperzine A for the Treatment of Cognitive, Mood, and Functional Deficits After Moderate and Severe TBI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Spaulding Rehabilitation Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Spaulding Rehabilitation Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      We will explore the use of Huperzine A in patients who have sustained a moderate to severe&#xD;
      Traumatic Brain Injury. We aim to determine whether Huperzine A, as compared with placebo,&#xD;
      would have an effect on memory function after TBI. Additionally, we aim to determine whether&#xD;
      use of Huperzine A in these patients can change brain activity (as indexed by EEG and&#xD;
      Transcranial Magnetic Stimulation - TMS), and reduce prevalence/frequency of post-traumatic&#xD;
      seizures. We also aim to evaluate the safety of Huperzine A in this population as compared&#xD;
      with placebo.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Insufficient accrual rate: 14 participants enrolled (target of 30).&#xD;
  </why_stopped>
  <start_date type="Actual">December 2013</start_date>
  <completion_date type="Actual">August 2018</completion_date>
  <primary_completion_date type="Actual">August 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory</measure>
    <time_frame>Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks.</time_frame>
    <description>Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below:&#xD;
California Verbal Learning Test- 2nd Edition- Total Learning [CVLT-II-TL] (Minimum score=0; Maximum score= 80)&#xD;
California Verbal Learning Test- 2nd Edition- Short delay free recall [CVLT-II-SDFR] (Minimum score=0; Maximum score=16)&#xD;
California Verbal Learning Test- 2nd Edition- Long delay free recall [CVLT-II-LDFR] (Minimum score=0; Maximum score=16)&#xD;
High scores are indicative of greater memory and learning for each index (i.e. better outcome).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Amplitude of Event Related Potentials (ERPs) P50 and P300</measure>
    <time_frame>Baseline, 12 Weeks</time_frame>
    <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Latency of Event Related Potentials (ERPs) P50 and P300</measure>
    <time_frame>Baseline, 12 weeks</time_frame>
    <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window</measure>
    <time_frame>Baseline and weekly for 12 weeks.</time_frame>
    <description>To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Self-reported Side Effects During 12-week Treatment Window</measure>
    <time_frame>Baseline and weekly for 12 weeks.</time_frame>
    <description>To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Huperzine A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Huperzine A</intervention_name>
    <description>Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
    <arm_group_label>Huperzine A</arm_group_label>
    <other_name>huperzia serrata</other_name>
    <other_name>chinese club moss</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females aged 18 to 65&#xD;
&#xD;
          -  Moderate or severe TBI, based on admission Emergency Room GCS 3-12&#xD;
&#xD;
          -  All subjects will be greater than 2 weeks, but no more than 1 year, after the&#xD;
             qualifying TBI, and will be symptomatic at enrollment (i.e. all subjects will exhibit&#xD;
             evidence of ongoing posttraumatic amnesia via the Galveston Orientation Amnesia test&#xD;
             (GOAT), or score at least 1.5 SD below the mean for completion time on Part B of the&#xD;
             Trail Making Test.&#xD;
&#xD;
          -  Agreement to undergo no changes in concomitant medications (including dietary&#xD;
             supplements) or therapeutic interventions during the first 12 weeks of the study (that&#xD;
             is, the 12 weeks of dosing with study drug), except where medically indicated. Stable&#xD;
             concomitant drug regimen (greater than two weeks pre-enrollment without changes)&#xD;
&#xD;
          -  Normal swallowing&#xD;
&#xD;
          -  English-speaking (since not all of the outcome metrics are normed outside of the&#xD;
             English language)&#xD;
&#xD;
          -  Patient can be on seizure medication.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients taking acetylcholinesterase inhibitors and other cholinergic and&#xD;
             anticholinergic drugs (e.g., tacrine, physostigmine, velnacrine, donepezil,&#xD;
             rivastigmine, metrifonate) and CYP1A inducing drugs.&#xD;
&#xD;
          -  Evidence of more than 1 seizure in the past 4 weeks prior to enrollment: Patients may&#xD;
             not be enrolled if there is evidence of more than one seizure (clinical or&#xD;
             electrographic, but not including epileptiform or other irritative discharges) during&#xD;
             the 4 weeks prior to enrollment.&#xD;
&#xD;
          -  Premorbid history of epilepsy with seizure frequency &gt;1 per month: Patients with a&#xD;
             history of idiopathic epilepsy may not be enrolled if their seizure frequency was &gt; 1&#xD;
             per month in the 3 months prior to injury. If pre-injury seizure frequency was &lt; 1 per&#xD;
             month but there is documented evidence that post-injury seizure frequency is &gt; 1 per&#xD;
             month or there is documented evidence of an increase in the severity or duration of a&#xD;
             single seizure relative to the premorbid history, the patient must be excluded.&#xD;
&#xD;
          -  Evidence of premorbid major CNS disorder, developmental disorder, psychiatric disorder&#xD;
             or substance abuse: Prior to sustaining TBI, patient was diagnosed and/or treated for&#xD;
             a major neurologic condition, pervasive developmental disorder (e.g., mental&#xD;
             retardation, autism), psychiatric disorder or substance abuse that continued to&#xD;
             produce functional disability up to the time of injury.&#xD;
&#xD;
          -  Individuals with disorders of consciousness, as defined at the time of screening of&#xD;
             having vegetative and/or minimally conscious state, will not be enrolled. However,&#xD;
             these patients may be followed until they:&#xD;
&#xD;
               -  Meet eligibility criteria&#xD;
&#xD;
               -  Are more than 12 weeks post injury&#xD;
&#xD;
               -  Are discharged&#xD;
&#xD;
          -  Pregnancy, as determined by urine hCG testing before randomization&#xD;
&#xD;
          -  Breast feeding females&#xD;
&#xD;
          -  Significant hematologic, renal or hepatic dysfunction [Hepatic/renal dysfunction is&#xD;
             generally identified as lab results &gt; two times the upper limits of normal (ULN), and&#xD;
             hematologic dysfunction is determined by clinically significant abnormal lab results],&#xD;
             on baseline laboratory examination.&#xD;
&#xD;
          -  Slow heart rate (bradycardia) or other heart conditions related to rate&#xD;
&#xD;
          -  History of peptic ulcer disease&#xD;
&#xD;
          -  History of asthma or emphysema&#xD;
&#xD;
          -  History of GI/urinary tract blockages (i.e. ileus, IBS)&#xD;
&#xD;
          -  History of glaucoma&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ross Zafonte, DO</last_name>
    <role>Principal Investigator</role>
    <affiliation>Spaulding Rehabilitation Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Spaulding Rehabilitation Hospital</name>
      <address>
        <city>Charlestown</city>
        <state>Massachusetts</state>
        <zip>02129</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <results_first_submitted>July 24, 2019</results_first_submitted>
  <results_first_submitted_qc>September 15, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">October 7, 2019</results_first_posted>
  <last_update_submitted>October 22, 2019</last_update_submitted>
  <last_update_submitted_qc>October 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 5, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Spaulding Rehabilitation Hospital</investigator_affiliation>
    <investigator_full_name>Ross D. Zafonte, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>cognition</keyword>
  <keyword>seizures</keyword>
  <keyword>electroencephalography</keyword>
  <keyword>transcranial magnetic stimulation</keyword>
  <keyword>huperzine</keyword>
  <keyword>chinese club moss</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Huperzine A</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 11, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/11/NCT01676311/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Huperzine A</title>
          <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Huperzine A</title>
          <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="7"/>
            <count group_id="B2" value="7"/>
            <count group_id="B3" value="14"/>
          </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="37.00" spread="16.21"/>
                    <measurement group_id="B2" value="38.57" spread="16.60"/>
                    <measurement group_id="B3" value="37.79" spread="15.78"/>
                  </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="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Admission status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Inpatient</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Outpatient</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Days post-injury</title>
          <units>days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="155.40" spread="130.27"/>
                    <measurement group_id="B2" value="226.86" spread="120.30"/>
                    <measurement group_id="B3" value="197.08" spread="124.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory</title>
        <description>Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below:&#xD;
California Verbal Learning Test- 2nd Edition- Total Learning [CVLT-II-TL] (Minimum score=0; Maximum score= 80)&#xD;
California Verbal Learning Test- 2nd Edition- Short delay free recall [CVLT-II-SDFR] (Minimum score=0; Maximum score=16)&#xD;
California Verbal Learning Test- 2nd Edition- Long delay free recall [CVLT-II-LDFR] (Minimum score=0; Maximum score=16)&#xD;
High scores are indicative of greater memory and learning for each index (i.e. better outcome).</description>
        <time_frame>Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Huperzine A</title>
            <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
          </group>
        </group_list>
        <measure>
          <title>California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory</title>
          <description>Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below:&#xD;
California Verbal Learning Test- 2nd Edition- Total Learning [CVLT-II-TL] (Minimum score=0; Maximum score= 80)&#xD;
California Verbal Learning Test- 2nd Edition- Short delay free recall [CVLT-II-SDFR] (Minimum score=0; Maximum score=16)&#xD;
California Verbal Learning Test- 2nd Edition- Long delay free recall [CVLT-II-LDFR] (Minimum score=0; Maximum score=16)&#xD;
High scores are indicative of greater memory and learning for each index (i.e. better outcome).</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CVLT-II-TL - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28.57" spread="12.35"/>
                    <measurement group_id="O2" value="34.40" spread="18.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-TL - Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.43" spread="11.37"/>
                    <measurement group_id="O2" value="45.00" spread="17.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-TL - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.29" spread="14.20"/>
                    <measurement group_id="O2" value="49.60" spread="18.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-TL - Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.29" spread="14.29"/>
                    <measurement group_id="O2" value="44.60" spread="14.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-TL - Week 52</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.43" spread="11.30"/>
                    <measurement group_id="O2" value="49.40" spread="15.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-SDFR - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.86" spread="4.38"/>
                    <measurement group_id="O2" value="5.80" spread="4.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-SDFR - Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.14" spread="3.53"/>
                    <measurement group_id="O2" value="7.83" spread="4.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-SDFR - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.29" spread="4.99"/>
                    <measurement group_id="O2" value="10.40" spread="5.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-SDFR - Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.86" spread="4.45"/>
                    <measurement group_id="O2" value="10.00" spread="4.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-SDFR - Week 52</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.43" spread="3.36"/>
                    <measurement group_id="O2" value="9.80" spread="5.50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-LDFR - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.00" spread="4.80"/>
                    <measurement group_id="O2" value="7.00" spread="5.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-LDFR - Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.43" spread="4.39"/>
                    <measurement group_id="O2" value="8.33" spread="4.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-LDFR - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.00" spread="4.76"/>
                    <measurement group_id="O2" value="10.00" spread="5.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-LDFR - Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.29" spread="4.46"/>
                    <measurement group_id="O2" value="8.40" spread="4.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CVLT-II-LDFR - Week 52</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.14" spread="4.67"/>
                    <measurement group_id="O2" value="10.00" spread="4.74"/>
                  </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>Regression analysis was run incorporating group, CVLT-II-total learning score at baseline and week 12, and covariates (Beck Depression Index [BDI], time post-injury, British Columbia Postconcussion Symptom Inventory [BC-PSI]). Regression analyses were repeated, permuting data observations for each outcome. The BDI and BC-PSI are covariates in the regression model and not pre-specified Primary and Secondary Outcome Measures.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.38</p_value>
            <p_value_desc>For each permutation of the data, relevant result was saved and the corresponding p-value represents the proportion of results at least as extreme as observed in the original data.</p_value_desc>
            <method>Regression, Linear</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Regression analysis was run incorporating group (Huperzine A, placebo), baseline CVLT-II-short delay free recall (SDFR) score, outcome (CVLT-II-SDFR at week 12) and covariates (Beck Depression Index, time post-injury, British Columbia Postconcussion Symptom Inventory). Regression analyses were repeated, permuting data observations for each outcome i.e. we permuted the labels (Huperzine A or placebo) among the data observations and re-ran the regression.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.38</p_value>
            <p_value_desc>For each permutation of the data, relevant result was saved and the corresponding p-value represents the proportion of results at least as extreme as observed in the original data.</p_value_desc>
            <method>Regression, Linear</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Regression analysis was run incorporating group (Huperzine A, placebo), baseline CVLT-II-long delay free recall (LDFR) score, outcome (CVLT-II-LDFR at week 12) and covariates (Beck Depression Index, time post-injury, British Columbia Postconcussion Symptom Inventory). Regression analyses were repeated, permuting data observations for each outcome i.e. we permuted the labels (Huperzine A or placebo) among the data observations and re-ran the regression.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.42</p_value>
            <p_value_desc>For each permutation of the data, relevant result was saved and the corresponding p-value represents the proportion of results at least as extreme as observed in the original data.</p_value_desc>
            <method>Regression, Linear</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Amplitude of Event Related Potentials (ERPs) P50 and P300</title>
        <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
        <time_frame>Baseline, 12 Weeks</time_frame>
        <population>Of the 12 participants who completed the 12-week treatment period, P50 and P500 amplitude data could be analyzed for 4 participants. Data for the other 8 participants could not be analyzed as the data were compromised by movement artifact during recording.</population>
        <group_list>
          <group group_id="O1">
            <title>Huperzine A</title>
            <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Amplitude of Event Related Potentials (ERPs) P50 and P300</title>
          <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
          <population>Of the 12 participants who completed the 12-week treatment period, P50 and P500 amplitude data could be analyzed for 4 participants. Data for the other 8 participants could not be analyzed as the data were compromised by movement artifact during recording.</population>
          <units>mV</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>P300 Amplitude - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.57" lower_limit="9.28" upper_limit="17.86"/>
                    <measurement group_id="O2" value="9.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 Amplitude - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.69" lower_limit="4.10" upper_limit="21.28"/>
                    <measurement group_id="O2" value="9.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 Amplitude - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.89" lower_limit="4.59" upper_limit="11.19"/>
                    <measurement group_id="O2" value="NA">The participant did not have P50 data that could be analyzed.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 Amplitude - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.89" lower_limit="-0.36" upper_limit="12.14"/>
                    <measurement group_id="O2" value="NA">The participant did not have P50 data that could be analyzed.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Latency of Event Related Potentials (ERPs) P50 and P300</title>
        <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
        <time_frame>Baseline, 12 weeks</time_frame>
        <population>Of the 12 participants who completed the 12-week treatment period, P50 and P500 latency data could be analyzed for 3 participants. Data for the other 9 participants could not be analyzed as the data were compromised by movement artifact during recording.</population>
        <group_list>
          <group group_id="O1">
            <title>Huperzine A</title>
            <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Latency of Event Related Potentials (ERPs) P50 and P300</title>
          <description>Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.</description>
          <population>Of the 12 participants who completed the 12-week treatment period, P50 and P500 latency data could be analyzed for 3 participants. Data for the other 9 participants could not be analyzed as the data were compromised by movement artifact during recording.</population>
          <units>ms</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>P300 Latency - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="309" lower_limit="306" upper_limit="312"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P300 Latency - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="311" lower_limit="291" upper_limit="331"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 Latency - Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50" lower_limit="48" upper_limit="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>P50 Latency - Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49" lower_limit="49" upper_limit="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window</title>
        <description>To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence).</description>
        <time_frame>Baseline and weekly for 12 weeks.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Huperzine A</title>
            <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window</title>
          <description>To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </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>0.48</p_value>
            <p_value_desc>A chi-square test with factors of group (Huperzine A, placebo) and occurrence of seizure (yes, no) was performed. A permutation test was the used to assess the effect of Huperzine A on the prevalence of seizures.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Self-reported Side Effects During 12-week Treatment Window</title>
        <description>To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological).</description>
        <time_frame>Baseline and weekly for 12 weeks.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Huperzine A</title>
            <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Self-reported Side Effects During 12-week Treatment Window</title>
          <description>To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Behavioral side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cardiac-respiratory side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dematological side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Gastrointestinal side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Genitourinary/neurological side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hematological side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Musculoskeletal side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neurological side effects</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="5"/>
                  </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>Behavioral side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.44</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of behavioral side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of behavioral side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Cardiac-respiratory side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.81</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of cardiac-respiratory side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Dermatological side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.81</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of dermatological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of dermatological side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Gastrointestinal side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.73</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of gastrointestinal side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Genitourinary/neurological side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.54</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of genitourinary/neurological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Hematological side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.27</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of hematological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Musculoskeletal side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.41</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of musculoskeletal side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Neurological side effects statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>1.00</p_value>
            <p_value_desc>A chi-squared test with factors of group (Huperzine A, placebo) and occurrence of neurological side effects (yes, no) were performed. A permutation test was used to assess the effect of Huperzine A on the incidence of these side effects.</p_value_desc>
            <method>Chi-squared test and permutation test</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Telephone: Weekly from baseline to 12 weeks (active treatment phase). In-person follow-up visits: Baseline, 6, 12, 13, 24, and 52 weeks. Subjects were instructed to call the Study Coordinator if a serious adverse event occurred between scheduled telephone or in-person follow-ups.</time_frame>
      <desc>Adverse events were collected and recorded using a standard adverse event form that included 35 possible adverse events. For 'Adverse Events', 'Serious Adverse Events', and 'Other (Not Including Serious) Adverse Events', results are reported for all participants who were 'at risk' i.e. received Huperzine A or placebo and completed at least one telephone or in-person follow-up visit (Huperzine A group: 7 participants; Placebo group: 6 participants).</desc>
      <group_list>
        <group group_id="E1">
          <title>Huperzine A</title>
          <description>Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.&#xD;
Huperzine A: Huperzine A will be administered for 12 weeks as outlined in the Arm Description</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).&#xD;
Placebo: Placebo Arm (blinded randomization) for Huperzine A Intervention</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="7"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Low white blood cell count</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Abnormal vision</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Loss of appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Increased saliva production</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Increased blood pressure</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Decrease in heart rate</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Difficulty sleeping</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle cramps</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Muscle twitching</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Thinking abnormalities</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Slurred speech</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Light sensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Increased uncontrolled movement</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Difficulty breathing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Enrollment - not able to enroll target N, therefore small number of subjects analyzed.&#xD;
Neurophysiologic measures - difficulty collecting data from subjects for several reasons.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Ross Zafonte, DO</name_or_title>
      <organization>Spaulding Rehabilitation Hospital</organization>
      <phone>617-952-5227</phone>
      <email>rzafonte@mgh.harvard.edu</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/NCT01676311
org study id: 2012-p-002490
nct id: NCT01676311
lead sponsor: 
has dmc: Yes
We will explore the use of Huperzine A in patients who have sustained a moderate to severe
      Traumatic Brain Injury. We aim to determine whether Huperzine A, as compared with placebo,
      would have an effect on memory function after TBI. Additionally, we aim to determine whether
      use of Huperzine A in these patients can change brain activity (as indexed by EEG and
      Transcranial Magnetic Stimulation - TMS), and reduce prevalence/frequency of post-traumatic
      seizures. We also aim to evaluate the safety of Huperzine A in this population as compared
      with placebo.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: California Verbal Learning Test- 2nd Edition (CVLT-II): Learning and Memory
time frame: Baseline, 6 weeks, 12 weeks, 24 weeks and at 52 weeks.
description: Measure of learning and memory function. Three indices of the CVLT-II were calculated. The full name, abbreviated name, and the minimum and maximum possible scores of each index are indicated below:
California Verbal Learning Test- 2nd Edition- Total Learning [CVLT-II-TL] (Minimum score=0; Maximum score= 80)
California Verbal Learning Test- 2nd Edition- Short delay free recall [CVLT-II-SDFR] (Minimum score=0; Maximum score=16)
California Verbal Learning Test- 2nd Edition- Long delay free recall [CVLT-II-LDFR] (Minimum score=0; Maximum score=16)
High scores are indicative of greater memory and learning for each index (i.e. better outcome).
measure: Amplitude of Event Related Potentials (ERPs) P50 and P300
time frame: Baseline, 12 Weeks
description: Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit. P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.
measure: Latency of Event Related Potentials (ERPs) P50 and P300
time frame: Baseline, 12 weeks
description: Event Related Potentials (ERPs): P50 and P300 are neurophysiological measurements that index cortical electrical activity associated with a given stimulus. P50 and P300 were measured using auditory stimuli. P50 represents an index of activity in the cholinergic system and has been used to characterize presynaptic cholinergic deficit and P300 is a measure of general cognitive processing elicited during attention, memory, and executive tasks.
measure: Number of Participants Who Experienced Post-traumatic Seizure During 12-week Treatment Window
time frame: Baseline and weekly for 12 weeks.
description: To determine whether Huperzine A changes the prevalence of post-traumatic seizure after moderate and severe TBI as compared to placebo at 12 weeks post-enrollment (immediate seizures prevalence).
measure: Number of Participants With Self-reported Side Effects During 12-week Treatment Window
time frame: Baseline and weekly for 12 weeks.
description: To evaluate the safety and tolerability of Huperzine A in this patient population as compared to placebo the frequency of self-reported side effects during the 12-week treatment window were grouped categorically by system (behavioral, cardiac-respiratory, dermatological,gastrointestinal, genitourinary/neurological, hematological, musculoskeletal, neurological).
arm group label: Huperzine A
arm group type: Experimental
description: Huperzine A will be administered to patients, titrating dose up from 100mcg/day to 600mcg per day over the course of 20 days - and remaining on the dose of 600mcg/day for the remainder of the drug phase (64 days) - for a total of 12 weeks on Huperzine A.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo will be administered to patients at the same frequency/intervals as the experimental arm (Huperzine-A).
intervention type: Drug
intervention name: Huperzine A
description: Huperzine A will be administered for 12 weeks as outlined in the Arm Description
arm group label: Huperzine A
other name: huperzia serrata
other name: chinese club moss
intervention type: Drug
intervention name: Placebo
description: Placebo Arm (blinded randomization) for Huperzine A Intervention
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ross Zafonte, DO
role: Principal Investigator
affiliation: Spaulding Rehabilitation Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Spaulding Rehabilitation Hospital
investigator full name: Ross D. Zafonte, MD
investigator title: Principal Investigator
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Huperzine A
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Enrollment - not able to enroll target N, therefore small number of subjects analyzed.
Neurophysiologic measures - difficulty collecting data from subjects for several reasons.
point of contact: 