<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/NCT01670526</url>
  </required_header>
  <id_info>
    <org_study_id>CLIN-003-10S</org_study_id>
    <secondary_id>CCTA#0001</secondary_id>
    <nct_id>NCT01670526</nct_id>
  </id_info>
  <brief_title>Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI</brief_title>
  <acronym>RIVET</acronym>
  <official_title>Rivastigmine Patch in Veterans With Cognitive Impairment Following TBI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Difficulties with intellectual functioning, particularly memory functions, are common and&#xD;
      source of long-term disability after Traumatic Brain Injury (TBI). However, there is very&#xD;
      little information about pharmacologic (i.e., medication) treatments targeting these&#xD;
      deficits. There are growing data showing brain abnormalities in acetylcholine, the chemical&#xD;
      system that manages memory, in TBI. These findings provide the rationale for the use of&#xD;
      cholinesterase inhibitors, medications that modulate this system, in TBI patients. As the&#xD;
      prevalence of TBI among Veterans of recent military conflicts increases, becoming a&#xD;
      &quot;signature injury&quot; of the Iraq and Afghanistan conflicts, it is of utmost importance to the&#xD;
      Veterans Health Administration to collect scientific data on the efficacy of pharmacological&#xD;
      treatments for intellectual difficulties in TBI patients. This study will evaluate the&#xD;
      effects of the cholinesterase inhibitor rivastigmine transdermal patch in Veterans with TBI&#xD;
      and posttraumatic memory problems. Results will provide much needed data that will help treat&#xD;
      Veterans with TBI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Traumatic brain injury (TBI) represents one of the most significant health risks related to&#xD;
      military duty; rapidly becoming the &quot;signature injury&quot; of the Iraq and Afghanistan conflicts.&#xD;
      TBI patients often experience multiple cognitive problems, with disturbances in memory,&#xD;
      attention, and executive functions among the most common. Disturbances in memory as well as&#xD;
      attention are particularly problematic, as disruption of these relatively basic cognitive&#xD;
      functions may exacerbate or cause additional disturbances in executive function,&#xD;
      communication and other more complex cognitive domains. These cognitive deficits, especially&#xD;
      when memory is affected, significantly impact day-to-day functioning and are the source of&#xD;
      lingering disability and distress to the affected individuals. However, despite advances made&#xD;
      in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to provide&#xD;
      treatment without the guidance of evidence-based scientific data. This proposal aims to begin&#xD;
      the process of providing clinicians with evidence-based guidelines for pharmacological&#xD;
      management of Veterans with TBI suffering from persistent cognitive deficits following their&#xD;
      injuries. This aim will be accomplished by conducting a clinical trial in Veterans suffering&#xD;
      from moderate to severe posttraumatic memory impairment following TBI. Specifically, this&#xD;
      proposal will evaluate the efficacy and safety of rivastigmine transdermal patch, an&#xD;
      intermediate-acting cholinesterase inhibitor, in this population.&#xD;
&#xD;
      The investigators hypothesize that rivastigmine transdermal patch will be more effective&#xD;
      than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic&#xD;
      memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel&#xD;
      design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states&#xD;
      that compared to placebo, rivastigmine patch will be more effective and equally safe in the&#xD;
      treatment of patients who will continue in a randomized, placebo-controlled phase for a total&#xD;
      of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of&#xD;
      rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 138 Veterans who meet or exceed the&#xD;
      criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate to&#xD;
      severe memory impairment. Memory impairment will be defined as a Total Recall index (Trials&#xD;
      1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower than the&#xD;
      intelligence-adjusted expected score, as assessed by the Wechsler Adult Intelligence Scale -&#xD;
      Fourth Edition (WAIS-IV) Information and Vocabulary subtests. The study consists of a&#xD;
      screening period, one-week single-blind, placebo run-in phase, and a 12-week double-blind&#xD;
      acute treatment phase (Phase I). Subjects will be randomized 1:1 to rivastigmine transdermal&#xD;
      patch 9.5mg/24 hours (10cm2) or matching placebo. During Phase I, there will be an initial&#xD;
      4-week titration period followed by an 8-week continuation phase. Following the 12-week acute&#xD;
      treatment phase, randomized patients will continue in the double-blind phase (Phase II) for&#xD;
      additional 14 weeks or until study treatment period ends. Recruitment stage ended 2.25.16.&#xD;
      Efficacy will be determined by comparing the proportion of patients in each treatment group&#xD;
      who are classified as responders at week 12. Secondary measure of functional capacity&#xD;
      assessing the impact of memory improvement on real-world functioning, other measures of&#xD;
      cognitive domains affected in TBI, namely attention, working and episodic memory and&#xD;
      executive functions, as well as measures of mood and quality of life will be examined. Study&#xD;
      findings will contribute to the body of evidence needed to establish standards of care for&#xD;
      Veterans with posttraumatic memory impairment and other cognitive deficits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">September 2017</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Demonstrated Improvement From Baseline on the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall</measure>
    <time_frame>week 12</time_frame>
    <description>The primary efficacy measure was the Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall Index. HVLT-R was administered at screen, baseline, weeks 4, and 12. The HVLT is a measure that assesses verbal learning and memory. Alternate versions of the HVLT-R were administered at each of the different time points. The test consists of 12 words which are read to participants for three consecutive trials, each trial followed by free recall. The Total Recall score is the total number of words recalled over the three trials. The primary endpoint evaluation was to compare the proportion of patients who demonstrated improvement from baseline on the HVLT-R Total Recall of at least 5-word and at week 12 between the treatment and placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Twelve-week Change in University of California San Diego Performance-based Skills Assessment - Brief (UPSA-B)</measure>
    <time_frame>12 weeks</time_frame>
    <description>UPSA-B is a validated performance-based measure to evaluate the impact of rivastigmine-mediated memory improvements on the ability to perform tasks required for day-to-day functioning in two subdomains of financial management and communication. The scale goes from (0-100) and high score indicates better functions. Comparison of difference in mean changes of UPSA-B from baseline to 12-week follow-up between two groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Twelve-week Change in The PTSD Symptom Checklist-Military Version (PCL-M)</measure>
    <time_frame>12 week</time_frame>
    <description>PCL-M is a validated 17-item self-report measure of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) symptoms of PTSD.The PCL-M asks about problems in response to &quot;stressful military experiences.&quot; Items are rated on a 5-point scale ranging from 1 (&quot;not at all&quot;) to 5 (&quot;extremely&quot;). Higher score indicates more stressful.&#xD;
Comparison of difference in mean changes of PCL-M from baseline to 12-week follow-up between two groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Twelve-week Change in Beck Depression Inventory-II (BDI-II)</measure>
    <time_frame>12 week</time_frame>
    <description>Beck Depression Inventory-II (BDI-II) is a validated 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depressive symptoms. Each answer is scored on a scale value of 0 to 3. Higher score indicates more severe depression.&#xD;
To compare the differences in mean changes of BDI-II between two groups using two groups from baseline to week 12.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">94</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <condition>Cognitive Impairment</condition>
  <arm_group>
    <arm_group_label>Rivastigmine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rivastigmine transdermal patch</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rivastigmine Transdermal Patch</intervention_name>
    <description>Cholinesterase Inhibitor</description>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Rivastigmine</arm_group_label>
    <other_name>Cholinesterase Inhibitor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Be a male or a female of any race&#xD;
&#xD;
          -  Be outpatient Veterans residing in the community&#xD;
&#xD;
          -  Be 19-65 years old at the time of inclusion&#xD;
&#xD;
          -  Female patients of childbearing potential must have a negative pregnancy test at&#xD;
             baseline and must practice an acceptable method of birth control during the trial&#xD;
&#xD;
          -  Satisfy the following diagnostic criteria:&#xD;
&#xD;
               -  A history of previous head trauma(s) at least 12 months prior to study enrollment&#xD;
                  as determined by TBI diagnostic assessment&#xD;
&#xD;
               -  Closed head injury (non-penetrating) based on International Classification of&#xD;
                  Disease (ICD) 9 CM (Clinical Modification) 10 diagnosis code 854.0 as determined&#xD;
                  by TBI diagnostic assessment&#xD;
&#xD;
               -  Meet or exceed the modified American Congress of Rehabilitation Medicines (ACRM)&#xD;
                  criteria for Mild TBI as determined by TBI diagnostic assessment&#xD;
&#xD;
          -  Have a deficit in the area of verbal memory&#xD;
&#xD;
          -  Have subjective memory impairment that was reported to be present from the time of&#xD;
             injury or shortly thereafter to be associated with brain injury&#xD;
&#xD;
          -  Satisfy the Diagnostic and Statistical Manual (DSM, 4th edition) for cognitive&#xD;
             disorder not otherwise specified, dementia due to TBI, or amnestic disorder due to TBI&#xD;
&#xD;
          -  Demonstrate willingness to accept randomization&#xD;
&#xD;
          -  Provide written informed consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Have a medical condition that can interfere with the diagnostic process and the&#xD;
             assessment of clinical and mental status, or possibly endanger their health. Such&#xD;
             conditions include, but are not limited to endocrinological, neurological (including&#xD;
             epilepsy), cardiovascular (including clinically significant bradyarrhythmia, resting&#xD;
             heart rate &lt;50 without a pacemaker or treating physician's approval), pulmonary,&#xD;
             hematologic, hepatic, and renal conditions, and significant laboratory abnormalities&#xD;
             as determined by Study Chair.&#xD;
&#xD;
          -  Have a current diagnosis of any primary neurodegenerative disorder, including&#xD;
             Huntington's disease, Parkinson's disease, or DSM-IV-TR (Diagnostic and Statistical&#xD;
             Manual of Mental Disorders, Fourth Edition, Text Revision) dementia (other than&#xD;
             Dementia Due to Head Trauma).&#xD;
&#xD;
          -  Have suicidal ideations or have been judged to be a significant suicide risk per&#xD;
             clinical judgment and the Columbia Suicide Severity Rating Scale (C-SSRS).&#xD;
&#xD;
          -  Have a history of DSM-IV-TR substance (drug and/or alcohol) dependence disorder within&#xD;
             the last 5 years or a history of a substance abuse disorder within the past 6 months.&#xD;
&#xD;
          -  Have a DSM-IV-TR lifetime and current psychotic disorder (except lifetime depression&#xD;
             with psychotic features), bipolar disorder, or pre-TBI onset&#xD;
             attention-deficit/hyperactivity disorder.&#xD;
&#xD;
          -  Have current PTSD symptoms that can bias or interfere with cognitive and clinical&#xD;
             assessments as determined by study site PI.&#xD;
&#xD;
          -  Have demonstrated suboptimal effort on cognitive testing as defined by:&#xD;
&#xD;
               1. Test of Memory Malingering (TOMM) raw score below 45 on either Trial 2 or the&#xD;
                  Retention Trial, or&#xD;
&#xD;
               2. Green's Medical Symptom Validity Test (MSVT) score of 85% on any one of the&#xD;
                  Immediate Recall, Delayed Recall, or Consistency indices.&#xD;
&#xD;
          -  Have demonstrated a lack of tolerability to rivastigmine treatment in the past or&#xD;
             severe reactions to other cholinesterase inhibitors as determined by the site&#xD;
             investigator.&#xD;
&#xD;
          -  Be taking medications that significantly affect cognitive functioning in TBI&#xD;
             population and/or may enhance the beneficial/adverse/toxic effect of rivastigmine or&#xD;
             vice versa. These compounds include, but are not limited to, centrally-acting&#xD;
             anticholinergic drugs (e.g., atropine), other cholinesterase inhibitors (e.g.,&#xD;
             donepezil, galantamine), and agents that augment cerebral catecholaminergic function&#xD;
             (e.g., psychostimulants, amantadine, memantine, selegiline, levodopa, etc). Subjects&#xD;
             receiving modafinil may be considered for inclusion if they have been on a stable dose&#xD;
             for a minimum of 3 months, and if all inclusion criteria are met. Treatment of&#xD;
             non-exclusionary comorbid psychiatric symptoms with compounds that include, but are&#xD;
             not limited to, antidepressants, anxiolytics, sedative-hypnotics, anticonvulsants, and&#xD;
             atypical antipsychotics will be permitted provided that: 1) the site investigator,&#xD;
             based on review of medical history, records, and current medications and in&#xD;
             consultation with the Study Chair, concludes that the agent(s) are neither cause(s) of&#xD;
             nor significant contributor(s) to the potential subject's memory impairment; 2) the&#xD;
             dose of the agent(s) has been stable for the 3 months preceding study participation;&#xD;
             and 3) the dose of the agent(s) remains stable, where clinically feasible, throughout&#xD;
             the study. For medications prescribed for non-exclusionary conditions on as needed&#xD;
             basis, particularly when those medications include benzodiazepines, sympathomimetics,&#xD;
             antitussive agents or potentially sedating analgesics - every use will be documented&#xD;
             by the subject and will not be taken within 24 hours of performing study-related&#xD;
             cognitive testing. (Appendix A: Exclusionary Medications).&#xD;
&#xD;
          -  Have been exposed to other cholinesterase inhibitors in the 30 days prior to&#xD;
             randomization.&#xD;
&#xD;
          -  Have a history of penetrating brain injury, cerebrovascular disease, cerebral&#xD;
             neoplasm, major brain surgery, or multiple sclerosis.&#xD;
&#xD;
          -  Have a significant visual or auditory deficit that may interfere with ability to&#xD;
             complete study assessments.&#xD;
&#xD;
          -  Have a limited ability to speak and read English.&#xD;
&#xD;
          -  Be participating in another clinical trial with active intervention.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Olga Brawman-Mintzer, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ralph H. Johnson VA Medical Center, Charleston, SC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>VA San Diego Healthcare System, San Diego, CA</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92161</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Miami VA Healthcare System, Miami, FL</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33125</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James A. Haley Veterans' Hospital, Tampa, FL</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Edward Hines Jr. VA Hospital, Hines, IL</name>
      <address>
        <city>Hines</city>
        <state>Illinois</state>
        <zip>60141-5000</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lincoln Community-Based Outpatient Clinic, Lincoln, NE</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ralph H. Johnson VA Medical Center, Charleston, SC</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29401-5799</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Michael E. DeBakey VA Medical Center, Houston, TX</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Salt Lake City Health Care System, Salt Lake City, UT</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84148</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.warrelatedillness.va.gov/</url>
    <description>The War Related Illness and Injury Study Center offers services for combat veterans</description>
  </link>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>August 1, 2012</study_first_submitted>
  <study_first_submitted_qc>August 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2012</study_first_posted>
  <results_first_submitted>May 23, 2017</results_first_submitted>
  <results_first_submitted_qc>June 26, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">July 25, 2017</results_first_posted>
  <last_update_submitted>February 2, 2018</last_update_submitted>
  <last_update_submitted_qc>February 2, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Traumatic Brain Injury</keyword>
  <keyword>Cognitive Impairment</keyword>
  <keyword>Rivastigmine</keyword>
  <keyword>Pharmacologic Actions</keyword>
  <keyword>TBI</keyword>
  <keyword>Memory</keyword>
  <keyword>Cholinesterase Inhibitors</keyword>
  <keyword>Cognition</keyword>
  <keyword>Head Trauma</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>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rivastigmine</mesh_term>
    <mesh_term>Cholinesterase Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Rivastigmine</title>
          <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="45"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
                <participants group_id="P2" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Rivastigmine</title>
          <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</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="49"/>
            <count group_id="B2" value="45"/>
            <count group_id="B3" value="94"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                    <measurement group_id="B2" value="45"/>
                    <measurement group_id="B3" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</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>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="47"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="90"/>
                  </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="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</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>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </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="49"/>
                    <measurement group_id="B2" value="45"/>
                    <measurement group_id="B3" value="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Demonstrated Improvement From Baseline on the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall</title>
        <description>The primary efficacy measure was the Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall Index. HVLT-R was administered at screen, baseline, weeks 4, and 12. The HVLT is a measure that assesses verbal learning and memory. Alternate versions of the HVLT-R were administered at each of the different time points. The test consists of 12 words which are read to participants for three consecutive trials, each trial followed by free recall. The Total Recall score is the total number of words recalled over the three trials. The primary endpoint evaluation was to compare the proportion of patients who demonstrated improvement from baseline on the HVLT-R Total Recall of at least 5-word and at week 12 between the treatment and placebo group.</description>
        <time_frame>week 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rivastigmine</title>
            <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Demonstrated Improvement From Baseline on the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall</title>
          <description>The primary efficacy measure was the Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall Index. HVLT-R was administered at screen, baseline, weeks 4, and 12. The HVLT is a measure that assesses verbal learning and memory. Alternate versions of the HVLT-R were administered at each of the different time points. The test consists of 12 words which are read to participants for three consecutive trials, each trial followed by free recall. The Total Recall score is the total number of words recalled over the three trials. The primary endpoint evaluation was to compare the proportion of patients who demonstrated improvement from baseline on the HVLT-R Total Recall of at least 5-word and at week 12 between the treatment and placebo group.</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="49"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Twelve-week Change in University of California San Diego Performance-based Skills Assessment - Brief (UPSA-B)</title>
        <description>UPSA-B is a validated performance-based measure to evaluate the impact of rivastigmine-mediated memory improvements on the ability to perform tasks required for day-to-day functioning in two subdomains of financial management and communication. The scale goes from (0-100) and high score indicates better functions. Comparison of difference in mean changes of UPSA-B from baseline to 12-week follow-up between two groups.</description>
        <time_frame>12 weeks</time_frame>
        <population>Participants complete 12 weeks follow up included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Rivastigmine</title>
            <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
        </group_list>
        <measure>
          <title>Twelve-week Change in University of California San Diego Performance-based Skills Assessment - Brief (UPSA-B)</title>
          <description>UPSA-B is a validated performance-based measure to evaluate the impact of rivastigmine-mediated memory improvements on the ability to perform tasks required for day-to-day functioning in two subdomains of financial management and communication. The scale goes from (0-100) and high score indicates better functions. Comparison of difference in mean changes of UPSA-B from baseline to 12-week follow-up between two groups.</description>
          <population>Participants complete 12 weeks follow up included in this analysis.</population>
          <units>units 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="49"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.9" spread="6.4"/>
                    <measurement group_id="O2" value="3.3" spread="8.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Twelve-week Change in The PTSD Symptom Checklist-Military Version (PCL-M)</title>
        <description>PCL-M is a validated 17-item self-report measure of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) symptoms of PTSD.The PCL-M asks about problems in response to &quot;stressful military experiences.&quot; Items are rated on a 5-point scale ranging from 1 (&quot;not at all&quot;) to 5 (&quot;extremely&quot;). Higher score indicates more stressful.&#xD;
Comparison of difference in mean changes of PCL-M from baseline to 12-week follow-up between two groups.</description>
        <time_frame>12 week</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rivastigmine</title>
            <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
        </group_list>
        <measure>
          <title>Twelve-week Change in The PTSD Symptom Checklist-Military Version (PCL-M)</title>
          <description>PCL-M is a validated 17-item self-report measure of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) symptoms of PTSD.The PCL-M asks about problems in response to &quot;stressful military experiences.&quot; Items are rated on a 5-point scale ranging from 1 (&quot;not at all&quot;) to 5 (&quot;extremely&quot;). Higher score indicates more stressful.&#xD;
Comparison of difference in mean changes of PCL-M from baseline to 12-week follow-up between two groups.</description>
          <units>units 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="49"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="8.9"/>
                    <measurement group_id="O2" value="-4.4" spread="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Twelve-week Change in Beck Depression Inventory-II (BDI-II)</title>
        <description>Beck Depression Inventory-II (BDI-II) is a validated 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depressive symptoms. Each answer is scored on a scale value of 0 to 3. Higher score indicates more severe depression.&#xD;
To compare the differences in mean changes of BDI-II between two groups using two groups from baseline to week 12.</description>
        <time_frame>12 week</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rivastigmine</title>
            <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
          </group>
        </group_list>
        <measure>
          <title>Twelve-week Change in Beck Depression Inventory-II (BDI-II)</title>
          <description>Beck Depression Inventory-II (BDI-II) is a validated 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depressive symptoms. Each answer is scored on a scale value of 0 to 3. Higher score indicates more severe depression.&#xD;
To compare the differences in mean changes of BDI-II between two groups using two groups from baseline to week 12.</description>
          <units>units 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="49"/>
                <count group_id="O2" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.4" spread="8.8"/>
                    <measurement group_id="O2" value="-0.7" spread="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected on study participants starting from when the first participant was enrolled, December 29, 2012 through June 16, 2016 (3 1/2 years).</time_frame>
      <desc>Adverse event (AE) and serious adverse event (SAE) data based on system organ classes and preferred terms which are derived from MedDRA (Medical Dictionary for Regulatory Activities) coding. MedDRA terminology is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).</desc>
      <group_list>
        <group group_id="E1">
          <title>Rivastigmine</title>
          <description>Rivastigmine transdermal patch&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo&#xD;
Rivastigmine Transdermal Patch: Cholinesterase Inhibitor</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastric perforation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pilonidal cyst</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>post traumatic stress disorder</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>self serious ideation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA</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="10" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Visual impairment</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Nauseau</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>accident at work</sub_title>
                <description>work injury, non study related</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Carpel tunnel syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Application site erythema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>application site irritation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Application site pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="49"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Product adhesion issue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
              <event>
                <sub_title>Skin discoloration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Knee operation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="45"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Tom Sindowski</name_or_title>
      <organization>Hines CSPCC</organization>
      <phone>708-202-5858</phone>
      <email>tom.sindowski@va.gov</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/NCT01670526
org study id: CLIN-003-10S
secondary id: CCTA#0001
nct id: NCT01670526
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Difficulties with intellectual functioning, particularly memory functions, are common and
      source of long-term disability after Traumatic Brain Injury (TBI). However, there is very
      little information about pharmacologic (i.e., medication) treatments targeting these
      deficits. There are growing data showing brain abnormalities in acetylcholine, the chemical
      system that manages memory, in TBI. These findings provide the rationale for the use of
      cholinesterase inhibitors, medications that modulate this system, in TBI patients. As the
      prevalence of TBI among Veterans of recent military conflicts increases, becoming a
      "signature injury" of the Iraq and Afghanistan conflicts, it is of utmost importance to the
      Veterans Health Administration to collect scientific data on the efficacy of pharmacological
      treatments for intellectual difficulties in TBI patients. This study will evaluate the
      effects of the cholinesterase inhibitor rivastigmine transdermal patch in Veterans with TBI
      and posttraumatic memory problems. Results will provide much needed data that will help treat
      Veterans with TBI.
Traumatic brain injury (TBI) represents one of the most significant health risks related to
      military duty; rapidly becoming the "signature injury" of the Iraq and Afghanistan conflicts.
      TBI patients often experience multiple cognitive problems, with disturbances in memory,
      attention, and executive functions among the most common. Disturbances in memory as well as
      attention are particularly problematic, as disruption of these relatively basic cognitive
      functions may exacerbate or cause additional disturbances in executive function,
      communication and other more complex cognitive domains. These cognitive deficits, especially
      when memory is affected, significantly impact day-to-day functioning and are the source of
      lingering disability and distress to the affected individuals. However, despite advances made
      in TBI care, treatment of cognitive deficits in TBI lag behind, forcing clinicians to provide
      treatment without the guidance of evidence-based scientific data. This proposal aims to begin
      the process of providing clinicians with evidence-based guidelines for pharmacological
      management of Veterans with TBI suffering from persistent cognitive deficits following their
      injuries. This aim will be accomplished by conducting a clinical trial in Veterans suffering
      from moderate to severe posttraumatic memory impairment following TBI. Specifically, this
      proposal will evaluate the efficacy and safety of rivastigmine transdermal patch, an
      intermediate-acting cholinesterase inhibitor, in this population.

      The investigators hypothesize that rivastigmine transdermal patch will be more effective
      than, and equally safe as, placebo in the treatment of moderate to severe posttraumatic
      memory impairment in Veterans with TBI when tested in a randomized, multi-site, parallel
      design, placebo-controlled trial, at a 12-week endpoint. The exploratory hypothesis states
      that compared to placebo, rivastigmine patch will be more effective and equally safe in the
      treatment of patients who will continue in a randomized, placebo-controlled phase for a total
      of 26 weeks. To test these hypotheses we will evaluate the effect and the safety of
      rivastigmine 9.5 mg/24 hours (10cm2) transdermal patch in 138 Veterans who meet or exceed the
      criteria for closed, non-penetrating, mild TBI and who present at baseline with moderate to
      severe memory impairment. Memory impairment will be defined as a Total Recall index (Trials
      1-3) of the Hopkins Verbal Learning Test-Revised (HVLT-R) that is at least 25% lower than the
      intelligence-adjusted expected score, as assessed by the Wechsler Adult Intelligence Scale -
      Fourth Edition (WAIS-IV) Information and Vocabulary subtests. The study consists of a
      screening period, one-week single-blind, placebo run-in phase, and a 12-week double-blind
      acute treatment phase (Phase I). Subjects will be randomized 1:1 to rivastigmine transdermal
      patch 9.5mg/24 hours (10cm2) or matching placebo. During Phase I, there will be an initial
      4-week titration period followed by an 8-week continuation phase. Following the 12-week acute
      treatment phase, randomized patients will continue in the double-blind phase (Phase II) for
      additional 14 weeks or until study treatment period ends. Recruitment stage ended 2.25.16.
      Efficacy will be determined by comparing the proportion of patients in each treatment group
      who are classified as responders at week 12. Secondary measure of functional capacity
      assessing the impact of memory improvement on real-world functioning, other measures of
      cognitive domains affected in TBI, namely attention, working and episodic memory and
      executive functions, as well as measures of mood and quality of life will be examined. Study
      findings will contribute to the body of evidence needed to establish standards of care for
      Veterans with posttraumatic memory impairment and other cognitive deficits.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants With Demonstrated Improvement From Baseline on the Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall
time frame: week 12
description: The primary efficacy measure was the Hopkins Verbal Learning Test - Revised (HVLT-R) Total Recall Index. HVLT-R was administered at screen, baseline, weeks 4, and 12. The HVLT is a measure that assesses verbal learning and memory. Alternate versions of the HVLT-R were administered at each of the different time points. The test consists of 12 words which are read to participants for three consecutive trials, each trial followed by free recall. The Total Recall score is the total number of words recalled over the three trials. The primary endpoint evaluation was to compare the proportion of patients who demonstrated improvement from baseline on the HVLT-R Total Recall of at least 5-word and at week 12 between the treatment and placebo group.
measure: Twelve-week Change in University of California San Diego Performance-based Skills Assessment - Brief (UPSA-B)
time frame: 12 weeks
description: UPSA-B is a validated performance-based measure to evaluate the impact of rivastigmine-mediated memory improvements on the ability to perform tasks required for day-to-day functioning in two subdomains of financial management and communication. The scale goes from (0-100) and high score indicates better functions. Comparison of difference in mean changes of UPSA-B from baseline to 12-week follow-up between two groups.
measure: Twelve-week Change in The PTSD Symptom Checklist-Military Version (PCL-M)
time frame: 12 week
description: PCL-M is a validated 17-item self-report measure of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) symptoms of PTSD.The PCL-M asks about problems in response to "stressful military experiences." Items are rated on a 5-point scale ranging from 1 ("not at all") to 5 ("extremely"). Higher score indicates more stressful.
Comparison of difference in mean changes of PCL-M from baseline to 12-week follow-up between two groups.
measure: Twelve-week Change in Beck Depression Inventory-II (BDI-II)
time frame: 12 week
description: Beck Depression Inventory-II (BDI-II) is a validated 21-question multiple-choice self-report inventory, one of the most widely used instruments for measuring the severity of depressive symptoms. Each answer is scored on a scale value of 0 to 3. Higher score indicates more severe depression.
To compare the differences in mean changes of BDI-II between two groups using two groups from baseline to week 12.
arm group label: Rivastigmine
arm group type: Experimental
description: Rivastigmine transdermal patch
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo
intervention type: Drug
intervention name: Rivastigmine Transdermal Patch
description: Cholinesterase Inhibitor
arm group label: Placebo
arm group label: Rivastigmine
other name: Cholinesterase Inhibitor
criteria: 
gender: All
minimum age: 19 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Olga Brawman-Mintzer, MD
role: Principal Investigator
affiliation: Ralph H. Johnson VA Medical Center, Charleston, SC
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.warrelatedillness.va.gov/
description: The War Related Illness and Injury Study Center offers services for combat veterans
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Cognitive Dysfunction
mesh term: Rivastigmine
mesh term: Cholinesterase Inhibitors
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 