<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/NCT02255799</url>
  </required_header>
  <id_info>
    <org_study_id>H-33646 MEMRI-TBI-D Study</org_study_id>
    <secondary_id>H133A130047</secondary_id>
    <nct_id>NCT02255799</nct_id>
  </id_info>
  <brief_title>Multicenter Evaluation of Memory Remediation After TBI With Donepezil</brief_title>
  <acronym>MEMRI-TBI-D</acronym>
  <official_title>Four-site, Randomized, Parallel Design, Double-blind, Placebo-controlled, 10-week Trial of Donepezil 10 mg Daily for Verbal Memory Problems Among Adults With TBI in the Subacute or Chronic Recovery Period</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Spaulding Rehabilitation Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Albert Einstein Healthcare Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Indiana University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Craig Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>TIRR Memorial Hermann</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a four-site, randomized, parallel design, double-blind, placebo-controlled, 10-week&#xD;
      trial of donepezil 10 mg daily for verbal memory problems among adults with TBI in the&#xD;
      subacute or chronic recovery period. The study will recruit 160 persons with TBI and&#xD;
      functionally important memory problems during a four-year period of open recruitment.&#xD;
&#xD;
      The study aims are:&#xD;
&#xD;
        1. To evaluate the effects of treatment with donepezil on verbal memory as assessed by the&#xD;
           Hopkins Verbal Learning Test-Revised Total Trial 1-3;&#xD;
&#xD;
        2. To evaluate the effects of treatment with donepezil on memory-related activities as&#xD;
           measured by the Everyday Memory Questionnaire;&#xD;
&#xD;
        3. To evaluate the effects of donepezil on attention, processing speed, neuropsychiatric&#xD;
           symptoms, community participation, quality of life, and caregiver experiences.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND: Memory deficits are among the most common chronic and functionally important&#xD;
      consequences of traumatic brain injury (TBI). Basic and clinical research studies suggest&#xD;
      that persistent deficits in verbal memory are associated with chronically reduced levels of&#xD;
      acetylcholine in the brain. Medicines that increase levels of acetylcholine in the brain&#xD;
      appear to improve memory and other cognitive problems experienced by persons with TBI.&#xD;
      However, the studies performed thus far do not provide the level of evidence needed to&#xD;
      establish best practices. This study will definitively establish whether, and to what extent,&#xD;
      donepezil is an effective treatment for functionally important TBI-related memory deficit.&#xD;
&#xD;
      STUDY DESIGN: The study begins with a Screening visit. After consent to participate in&#xD;
      research is obtained from the participant or his or her legally-authorized representative,&#xD;
      screening assessments are performed. Over the two weeks following that visit, study&#xD;
      eligibility is determined. Participants meeting study inclusion/exclusion criteria are&#xD;
      randomly assigned (1:1) to 1 of 2 drug groups: donepezil or placebo.&#xD;
&#xD;
      Participants then are evaluated at the Baseline (pre-treatment) Visit using assessments of&#xD;
      physical health, cognition, neuropsychiatric status, everyday functioning, community&#xD;
      participation, quality of life, and caregiver appraisal. At the conclusion of this visit,&#xD;
      participants begin a ten week treatment period with either donepezil 5 mg daily or matching&#xD;
      placebo.&#xD;
&#xD;
      Telephone contact occurs at the end of study week 1 and 2. Calls will assess and support&#xD;
      participants' adherence to the study protocol, obtain information on treatment-related side&#xD;
      effects, and address any other safety or tolerability concerns.&#xD;
&#xD;
      At the week 2 telephone contact, participants tolerating the starting dose of study&#xD;
      medication are advanced to donepezil 10 mg daily or matching placebo. Telephone contacts&#xD;
      occur every 2 weeks until the Interim Assessment Visit at study week 6, at which time&#xD;
      assessments of physical health, cognition, neuropsychiatric status, everyday functioning,&#xD;
      community participation, quality of life, and caregiver appraisal are performed.&#xD;
&#xD;
      This visit is followed by a telephone contact at study week 8 and the Outcome Assessment&#xD;
      Visit at study week 10. At that visit participants and caregivers complete assessments of&#xD;
      physical health, cognition, neuropsychiatric status, everyday functioning, community&#xD;
      participation, quality of life, and caregiver appraisal. After completion of all week 10&#xD;
      assessments, the extent to which participants and their caregivers remained blinded to study&#xD;
      condition (allocation concealment) will be evaluated by inquiring whether they believe they&#xD;
      received donepezil or placebo. Study staff also will offer a written opinion on the study&#xD;
      condition to which each participant was assigned.&#xD;
&#xD;
      The Discontinuation period (termination of study medication) begins upon conclusion of the&#xD;
      final visit. Study teams at each site will remain available to receive questions and/or&#xD;
      concerns from participants and/or caregivers during the 4-week Discontinuation period.&#xD;
&#xD;
      ANALYTIC PLAN: All analyses will be conducted using SAS v.9.4 assuming a significance level&#xD;
      of 0.05 unless otherwise stated. Descriptive characteristics of the participants in each&#xD;
      group will be summarized using frequency counts/percentages for nominal variables and&#xD;
      means/standard deviations (SDs) or medians/interquartile ranges (IQRs) for continuous&#xD;
      variables. Comparisons of subject characteristics between groups will be performed using&#xD;
      chi-square tests and t-tests to identify significant differences between the treatment&#xD;
      groups.&#xD;
&#xD;
      Analysis of Primary Outcome (Aim 1): For the primary aim, an ANCOVA approach will be used to&#xD;
      test the hypothesis with a General Linear Mixed Effects Model (GLMM); the difference in the&#xD;
      outcome variable (HVLT-R Total Trials 1-3) at week 10 will be modeled as a function of&#xD;
      treatment group assignment (donepezil vs. placebo), controlled for baseline HVLT-R Total&#xD;
      Trials 1-3 score. A random center effect will also be included to account for between center&#xD;
      variations. If the random effect is not significant it will be removed and a general linear&#xD;
      model (GLM) will be fit. Using this model, a test of the treatment effect will be conducted&#xD;
      at a significance level of 5%. A significant treatment effect (p-value &lt; 0.05) indicates that&#xD;
      outcome HVLT-R Total Trials 1-3 at week 10 differ significantly between the treatment groups,&#xD;
      after controlling for baseline HVLT-R Total Trials 1-3 score. The adjusted mean score at week&#xD;
      10 for each group and the mean difference in outcome scores at week 10 will be estimated and&#xD;
      quantified with 95% confidence intervals.&#xD;
&#xD;
      Primary Intent to Treat versus Secondary Per-Protocol Analyses: Two analysis study&#xD;
      populations will be considered in this study: a modified intent-to-treat (mITT) population&#xD;
      and a clinically evaluable population. The analysis on the mITT sample will be considered the&#xD;
      primary analysis and will include every person who was randomized according to the randomized&#xD;
      group assignment and completed HVLT-R Form 1 at the Baseline Visit (Study Week 0), and took&#xD;
      at least one dose of study medication, and will ignore protocol deviations, withdrawal, and&#xD;
      treatment non-adherence. The clinically evaluable population will be a secondary analysis and&#xD;
      called the per-protocol population. Inclusion in the per-protocol population will require at&#xD;
      least 8 weeks of double-blind study treatment, data on primary outcomes at the Outcome Visit,&#xD;
      at least 80% treatment adherence as determined by capsule counts on returned blister packs,&#xD;
      and no major protocol violations.&#xD;
&#xD;
      Analysis of Secondary Outcomes (Aims 2 and 3): The secondary outcomes relevant to study aims&#xD;
      2 and 3 are organized into 5 sets: Physical, Cognitive, Neuropsychiatric, Functional, and&#xD;
      Caregiver. The same ANCOVA modeling strategy used for the primary outcome will be utilized to&#xD;
      test for treatment effects on each secondary outcome at week 10, adjusted for the associated&#xD;
      baseline measure. A multiple hypothesis testing strategy will be utilized to maximize power&#xD;
      while controlling for the Type I error rate. Specifically, within the categories composed of&#xD;
      more than one outcome (Cognitive, Neuropsychiatric, and Functional) hypothesis-wise error&#xD;
      rates will be adjusted using the Tukey, Ciminera, and Heyse (TCH) method of adjustment for&#xD;
      multiple outcomes. If power does not reach 80% using the TCH adjustment, data reduction&#xD;
      methods (e.g., battery reduction) will be employed. If battery reduction does not yield a&#xD;
      desired reduced number of outcomes to reach 80% power, a composite outcome will be developed&#xD;
      using either principle components analysis or the rank-sum-global test.&#xD;
&#xD;
      Secondary Analyses of Primary and Secondary Outcomes Adjusted for Covariates: There are a&#xD;
      number of additional covariates of interest including age, TBI severity, time since injury,&#xD;
      emotional distress, comorbid neuropsychiatric symptoms, substance use disorder history,&#xD;
      current substance use, and current medications. Secondary analyses of all outcomes (primary&#xD;
      and secondary) will be conducted including these covariates in the models to assess the&#xD;
      sensitivity of the treatment effects; &quot;unadjusted&quot; treatment effects estimated from the&#xD;
      primary analyses (i.e., adjusted only for baseline scores of the outcome) will be compared to&#xD;
      the &quot;adjusted&quot; treatment effects from these secondary analyses (adjusted for these additional&#xD;
      covariates of interest).&#xD;
&#xD;
      Secondary Analyses using all Measured Time Points: A secondary repeated measures analysis&#xD;
      using a GLMM will be conducted to further assess and compare how outcome variables change&#xD;
      over time both within and between groups in greater detail over time from baseline to weeks 6&#xD;
      and 10. The outcome variables will be the change from baseline to either week 6 or 10. Fixed&#xD;
      effects will include baseline (Week 0) score, treatment group, time (week 6 and week 10), and&#xD;
      the treatment group by time interaction effect. A random center effect will be included to&#xD;
      account for variability across centers. Subject specific random intercepts and slopes will be&#xD;
      used to account for correlations in repeated measures over time. Post-hoc comparison using a&#xD;
      Bonferroni adjustment will be used to determine if the change in outcome from baseline&#xD;
      differs between the groups at either 6 weeks or 10 weeks.&#xD;
&#xD;
      Response to Treatment Analysis: Responders are defined as individuals demonstrating at least&#xD;
      a 4-unit increase in the primary outcome measure, HVLT-R Total Trials 1-3, between baseline&#xD;
      and week 10. As a secondary analysis, responders will be defined by a 5-unit change if there&#xD;
      are no significant differences between the groups based on a 4-unit change.&#xD;
&#xD;
      Interim Analysis: The investigators will perform an interim analysis for the primary outcome&#xD;
      using the above-described data analytic methods on the data set comprising study participants&#xD;
      randomized as of September 30, 2018. The investigators will compute the conditional power&#xD;
      using: the current study sample; the maximum attainable sample; a significance level of α =&#xD;
      0.05 for testing a one-sided null hypothesis (H0: treatment mean &gt; control mean HLVT-R Total&#xD;
      Trials score at week 10 after controlling for baseline HVLT-R Total Trials scores); and the&#xD;
      observed treatment effect and associated t-statistic (using the data obtained thus far).&#xD;
      Using the data available as of September 30, 2018, the difference in adjusted means, the&#xD;
      means square error, and the t-statistic for the test of the treatment effect will estimated&#xD;
      based on an ANCOVA model fit using PROC GLM in SAS.&#xD;
&#xD;
      PASS v.14 will be used to determine the conditional power of the one-sided test for a&#xD;
      treatment effect using the estimates from the ANCOVA model and a decision to either stop or&#xD;
      continue recruitment the target enrollment (reset from N=160 to N=80 based on recruitment as&#xD;
      of September 30, 2018).&#xD;
&#xD;
        1. If the ANCOVA model using the present sample yields a t-statistic that is significant at&#xD;
           a 5% level of significance using a one-sided hypothesis test, then enrollment will be&#xD;
           halted due to efficacy and the study will enter the analytic phase.&#xD;
&#xD;
        2. If the ANCOVA model using the present sample yields a t-statistics that is not&#xD;
           significant at the 5% level of significance then the conditional power of identifying a&#xD;
           significant treatment effect after completing the enrollment target will be computed&#xD;
           based on the observed t-statistic, the difference in adjusted means, and the mean square&#xD;
           error.&#xD;
&#xD;
             1. If the conditional power is 80% or higher (corresponding to a futility index ≤ 0.2)&#xD;
                given the data that have emerged so far then recruitment will proceed until the&#xD;
                target sample size is reached, or the end of study year 5, whichever comes first.&#xD;
&#xD;
             2. If the conditional power is less than 80% (futility index &gt; 0.2) given the data&#xD;
                that have emerged then enrollment will halt due to failed recruitment at the&#xD;
                conclusion of this interim analysis. The observed treatment effect and associated&#xD;
                t-statistic will be reported as a guide to future investigations of donepezil for&#xD;
                persistent memory problems after TBI.&#xD;
&#xD;
      The conditional power analysis will be conducted using both HVLT-R Total Trials Raw scores&#xD;
      and T-scores. Preference will be given to the conditional power analysis based on the&#xD;
      T-scores if conclusions differ.&#xD;
&#xD;
      IMPLICATIONS, TRANSLATION, AND DISSEMINATION: Findings from this study will influence the&#xD;
      practices of prescribing healthcare providers and contribute information that will improve&#xD;
      lives of persons with TBI and their families. In addition to dissemination of final study&#xD;
      results, the MEMRI-TBI-D Study team will disseminate information on evidence-based treatments&#xD;
      for memory impairment to consumer and professional audiences throughout the funding period.&#xD;
      Through these knowledge translation activities, consumers and health care providers will be&#xD;
      provided with information regarding the effectiveness of this intervention for persistent&#xD;
      posttraumatic memory impairments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 1, 2013</start_date>
  <completion_date type="Anticipated">December 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</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>Hopkins Verbal Learning Test-Revised (HVLT-R) Total Trials 1-3</measure>
    <time_frame>study week 10</time_frame>
    <description>The effects of study treatment (donepezil or placebo) on persistent verbal memory impairments among persons with traumatic brain injury will be assessed by performance on HVLT-R Total Trials 1-3 at study week 10.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cognitive Measures</measure>
    <time_frame>study week 10</time_frame>
    <description>The effects of study treatment (donepezil or placebo) on attention, processing speed, and executive function among persons with persistent verbal memory impairments following TBI will be assessed using the Trail Making Test - Parts A and B; the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Digit Span, Symbol Search, Coding, Letter-Number Sequencing, and Processing Speed Index; and Controlled Oral Word Association Test at study week 10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychiatric Measures</measure>
    <time_frame>study week 10</time_frame>
    <description>The effects of study treatment (donepezil or placebo) on neuropsychiatric symptoms among persons with persistent verbal memory impairments following TBI will be assessed by Brief Symptom Inventory 18 (BSI 18) - Global Severity Index and the Neuropsychiatric Inventory-Clinician version (NPI-C) Total and Domain scores at study week 10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Measures</measure>
    <time_frame>study week 10</time_frame>
    <description>The effects of study treatment (donepezil or placebo) on functional status among persons with persistent verbal memory impairments will be assessed using participant and caregiver responses to the Everyday Memory Questionnaire, Participation Assessment with Recombined Tools-Objective, and Satisfaction with Life Scale scores at study week 10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Caregiver Measures</measure>
    <time_frame>study week 10</time_frame>
    <description>The effects of study treatment (donepezil or placebo) on distress among caregivers of persons with persistent verbal memory impairments will be assessed by the Caregiver Appraisal Scale - Perceived Burden Subscale as well as the NPI-C Caregiver Distress Scale scores at study week 10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Physical Measures</measure>
    <time_frame>study week 0, 6, and 10</time_frame>
    <description>The frequencies of adverse events associated with study treatment (donepezil or placebo) at study week 0, 6, and 10 will be assessed using the Side Effect Checklist.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <condition>Memory Deficits</condition>
  <arm_group>
    <arm_group_label>Donepezil</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Donepezil 5 mg capsules daily for 14 days. Donepezil 10 mg capsules daily for 56 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsules once daily for 70 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Donepezil</intervention_name>
    <description>Donepezil 5 mg capsule daily for 14 days. Donepezil 10 mg capsule daily for 56 days.</description>
    <arm_group_label>Donepezil</arm_group_label>
    <other_name>Donepezil hydrochloride</other_name>
    <other_name>Aricept</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsule once daily for 70 days.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Man or woman of any race, color, ethnicity, or national origin&#xD;
&#xD;
          -  18-60 years old&#xD;
&#xD;
          -  Primary language English&#xD;
&#xD;
          -  Clinical diagnosis of traumatic brain injury using National Institute of Neurological&#xD;
             Disorders and Stroke TBI Common Data Elements definition and merit assignment of&#xD;
             International Classification of Disease (ICD9) codes 850.0-850.9, 851.0, 851.2, 852.0,&#xD;
             852.2, 852.4, 853.0, or 854.0&#xD;
&#xD;
          -  TBI is non-penetrating&#xD;
&#xD;
          -  TBI is of complicated mild or greater severity&#xD;
&#xD;
          -  TBI occurred at least 6 months prior to study participation&#xD;
&#xD;
          -  Persistent posttraumatic memory impairment, as defined by HVLT-R Total Trials 1-3&#xD;
             (Form 3) impairment ≥ 25% for Wechsler Test of Adult Reading-based intelligence&#xD;
             quotient-adjusted performance expectations&#xD;
&#xD;
          -  Memory impairments are functionally significant, as defined by subject and/or&#xD;
             caregiver endorsement of at least 3 memory problems, occurring at least weekly, on the&#xD;
             Everyday Memory Questionnaire&#xD;
&#xD;
          -  Stable doses of allowed centrally-acting medications for at least 3 months prior to&#xD;
             study participation, and participant and caregiver commitment not to alter doses of&#xD;
             allowed medications during study&#xD;
&#xD;
          -  Capable of providing independent informed consent for study participation or provision&#xD;
             of consent for study participation by a legally-authorized representative is supported&#xD;
             by subject assent to study participation&#xD;
&#xD;
          -  A knowledgeable informant is available and willing to attend study visits or to&#xD;
             provide required information by telephone interview on the day of study visits&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pre-injury neurological and/or neurocognitive disorder&#xD;
&#xD;
          -  Primary diagnosis of hypoxic-ischemic brain injury or clinically definite post-TBI&#xD;
             hypoxic-ischemic event (i.e., respiratory arrest and/or cardiac arrest) or&#xD;
             non-TBI-related stroke&#xD;
&#xD;
          -  Pre- or post-injury psychotic and/or bipolar disorders&#xD;
&#xD;
          -  Post-injury substance use disorder (i.e., abuse or dependence diagnoses)&#xD;
&#xD;
          -  Clinically significant abnormalities on screening laboratory studies&#xD;
&#xD;
          -  Beck Depression Inventory-II (BDI-II) score ≥ 20 or BDI-II item 9 &gt; 0&#xD;
&#xD;
          -  Brief Symptom Inventory 18 (BSI 18) Depression Subscale T score or Anxiety Subscale T&#xD;
             score ≥ 63&#xD;
&#xD;
          -  Penetrating brain injury or cerebral lobectomy&#xD;
&#xD;
          -  Hearing, vision, and/or communication impairments that invalidate neuropsychological&#xD;
             or other study assessments&#xD;
&#xD;
          -  Test of Memory Malingering Trial 2 score &lt; 45&#xD;
&#xD;
          -  Use of an excluded medication in the month prior to study participation, known allergy&#xD;
             to donepezil, or documented intolerance to donepezil&#xD;
&#xD;
          -  Posttraumatic epilepsy&#xD;
&#xD;
          -  Symptomatic bradycardia, cardiac conduction abnormality (i.e., first- or Type I&#xD;
             second-degree atrioventricular blockade), atrial fibrillation, or unstable&#xD;
             cardiovascular disease, including myocardial infarction within three months prior to&#xD;
             study participation&#xD;
&#xD;
          -  Active, severe, or unstable pulmonary condition, including severe asthma&#xD;
&#xD;
          -  Signs or symptoms of gastrointestinal bleeding or active peptic ulcer disease within&#xD;
             three months prior to study participation&#xD;
&#xD;
          -  Serum human chorionic gonadotropin (HCG)-confirmed pregnancy&#xD;
&#xD;
          -  For female participants, unable/unwilling to use barrier contraception during study&#xD;
             participation, intrauterine device, or other implantable contraceptive method,&#xD;
             unable/unwilling to forego breastfeeding infants or children during study&#xD;
             participation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Arciniegas, MD</last_name>
    <role>Study Director</role>
    <affiliation>TIRR Memorial Hermann/Baylor College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Angelle Sander, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>TIRR Memorial Hermann/Baylor College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Joseph Giacino, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Spaulding Rehabilitation Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tessa Hart, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Moss Rehabilitation Research Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Flora Hammond, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Indiana University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mark S Sherer, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>TIRR Memorial Hermann</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <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>
    <facility>
      <name>Moss Rehabilitation Research Institute</name>
      <address>
        <city>Elkins Park</city>
        <state>Pennsylvania</state>
        <zip>19027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TIRR Memorial Hermann</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>September 25, 2014</study_first_submitted>
  <study_first_submitted_qc>September 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 3, 2014</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>David B. Arciniegas, MD</investigator_full_name>
    <investigator_title>Senior Scientist, Brain Injury Research Center, TIRR Memorial Hermann; Clinical Professor of Psychiatry, Baylor College of Medicine</investigator_title>
  </responsible_party>
  <keyword>traumatic brain injury</keyword>
  <keyword>TBI</keyword>
  <keyword>brain injury</keyword>
  <keyword>memory</keyword>
  <keyword>verbal memory deficits</keyword>
  <keyword>memory problems</keyword>
  <keyword>cognition</keyword>
  <keyword>cognitive impairment</keyword>
  <keyword>neuropsychiatric symptoms</keyword>
  <keyword>donepezil</keyword>
  <keyword>acetylcholinesterase inhibitor</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>Memory Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Donepezil</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02255799
org study id: H-33646 MEMRI-TBI-D Study
secondary id: H133A130047
nct id: NCT02255799
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
This is a four-site, randomized, parallel design, double-blind, placebo-controlled, 10-week
      trial of donepezil 10 mg daily for verbal memory problems among adults with TBI in the
      subacute or chronic recovery period. The study will recruit 160 persons with TBI and
      functionally important memory problems during a four-year period of open recruitment.

      The study aims are:

        1. To evaluate the effects of treatment with donepezil on verbal memory as assessed by the
           Hopkins Verbal Learning Test-Revised Total Trial 1-3;

        2. To evaluate the effects of treatment with donepezil on memory-related activities as
           measured by the Everyday Memory Questionnaire;

        3. To evaluate the effects of donepezil on attention, processing speed, neuropsychiatric
           symptoms, community participation, quality of life, and caregiver experiences.
BACKGROUND: Memory deficits are among the most common chronic and functionally important
      consequences of traumatic brain injury (TBI). Basic and clinical research studies suggest
      that persistent deficits in verbal memory are associated with chronically reduced levels of
      acetylcholine in the brain. Medicines that increase levels of acetylcholine in the brain
      appear to improve memory and other cognitive problems experienced by persons with TBI.
      However, the studies performed thus far do not provide the level of evidence needed to
      establish best practices. This study will definitively establish whether, and to what extent,
      donepezil is an effective treatment for functionally important TBI-related memory deficit.

      STUDY DESIGN: The study begins with a Screening visit. After consent to participate in
      research is obtained from the participant or his or her legally-authorized representative,
      screening assessments are performed. Over the two weeks following that visit, study
      eligibility is determined. Participants meeting study inclusion/exclusion criteria are
      randomly assigned (1:1) to 1 of 2 drug groups: donepezil or placebo.

      Participants then are evaluated at the Baseline (pre-treatment) Visit using assessments of
      physical health, cognition, neuropsychiatric status, everyday functioning, community
      participation, quality of life, and caregiver appraisal. At the conclusion of this visit,
      participants begin a ten week treatment period with either donepezil 5 mg daily or matching
      placebo.

      Telephone contact occurs at the end of study week 1 and 2. Calls will assess and support
      participants' adherence to the study protocol, obtain information on treatment-related side
      effects, and address any other safety or tolerability concerns.

      At the week 2 telephone contact, participants tolerating the starting dose of study
      medication are advanced to donepezil 10 mg daily or matching placebo. Telephone contacts
      occur every 2 weeks until the Interim Assessment Visit at study week 6, at which time
      assessments of physical health, cognition, neuropsychiatric status, everyday functioning,
      community participation, quality of life, and caregiver appraisal are performed.

      This visit is followed by a telephone contact at study week 8 and the Outcome Assessment
      Visit at study week 10. At that visit participants and caregivers complete assessments of
      physical health, cognition, neuropsychiatric status, everyday functioning, community
      participation, quality of life, and caregiver appraisal. After completion of all week 10
      assessments, the extent to which participants and their caregivers remained blinded to study
      condition (allocation concealment) will be evaluated by inquiring whether they believe they
      received donepezil or placebo. Study staff also will offer a written opinion on the study
      condition to which each participant was assigned.

      The Discontinuation period (termination of study medication) begins upon conclusion of the
      final visit. Study teams at each site will remain available to receive questions and/or
      concerns from participants and/or caregivers during the 4-week Discontinuation period.

      ANALYTIC PLAN: All analyses will be conducted using SAS v.9.4 assuming a significance level
      of 0.05 unless otherwise stated. Descriptive characteristics of the participants in each
      group will be summarized using frequency counts/percentages for nominal variables and
      means/standard deviations (SDs) or medians/interquartile ranges (IQRs) for continuous
      variables. Comparisons of subject characteristics between groups will be performed using
      chi-square tests and t-tests to identify significant differences between the treatment
      groups.

      Analysis of Primary Outcome (Aim 1): For the primary aim, an ANCOVA approach will be used to
      test the hypothesis with a General Linear Mixed Effects Model (GLMM); the difference in the
      outcome variable (HVLT-R Total Trials 1-3) at week 10 will be modeled as a function of
      treatment group assignment (donepezil vs. placebo), controlled for baseline HVLT-R Total
      Trials 1-3 score. A random center effect will also be included to account for between center
      variations. If the random effect is not significant it will be removed and a general linear
      model (GLM) will be fit. Using this model, a test of the treatment effect will be conducted
      at a significance level of 5%. A significant treatment effect (p-value < 0.05) indicates that
      outcome HVLT-R Total Trials 1-3 at week 10 differ significantly between the treatment groups,
      after controlling for baseline HVLT-R Total Trials 1-3 score. The adjusted mean score at week
      10 for each group and the mean difference in outcome scores at week 10 will be estimated and
      quantified with 95% confidence intervals.

      Primary Intent to Treat versus Secondary Per-Protocol Analyses: Two analysis study
      populations will be considered in this study: a modified intent-to-treat (mITT) population
      and a clinically evaluable population. The analysis on the mITT sample will be considered the
      primary analysis and will include every person who was randomized according to the randomized
      group assignment and completed HVLT-R Form 1 at the Baseline Visit (Study Week 0), and took
      at least one dose of study medication, and will ignore protocol deviations, withdrawal, and
      treatment non-adherence. The clinically evaluable population will be a secondary analysis and
      called the per-protocol population. Inclusion in the per-protocol population will require at
      least 8 weeks of double-blind study treatment, data on primary outcomes at the Outcome Visit,
      at least 80% treatment adherence as determined by capsule counts on returned blister packs,
      and no major protocol violations.

      Analysis of Secondary Outcomes (Aims 2 and 3): The secondary outcomes relevant to study aims
      2 and 3 are organized into 5 sets: Physical, Cognitive, Neuropsychiatric, Functional, and
      Caregiver. The same ANCOVA modeling strategy used for the primary outcome will be utilized to
      test for treatment effects on each secondary outcome at week 10, adjusted for the associated
      baseline measure. A multiple hypothesis testing strategy will be utilized to maximize power
      while controlling for the Type I error rate. Specifically, within the categories composed of
      more than one outcome (Cognitive, Neuropsychiatric, and Functional) hypothesis-wise error
      rates will be adjusted using the Tukey, Ciminera, and Heyse (TCH) method of adjustment for
      multiple outcomes. If power does not reach 80% using the TCH adjustment, data reduction
      methods (e.g., battery reduction) will be employed. If battery reduction does not yield a
      desired reduced number of outcomes to reach 80% power, a composite outcome will be developed
      using either principle components analysis or the rank-sum-global test.

      Secondary Analyses of Primary and Secondary Outcomes Adjusted for Covariates: There are a
      number of additional covariates of interest including age, TBI severity, time since injury,
      emotional distress, comorbid neuropsychiatric symptoms, substance use disorder history,
      current substance use, and current medications. Secondary analyses of all outcomes (primary
      and secondary) will be conducted including these covariates in the models to assess the
      sensitivity of the treatment effects; "unadjusted" treatment effects estimated from the
      primary analyses (i.e., adjusted only for baseline scores of the outcome) will be compared to
      the "adjusted" treatment effects from these secondary analyses (adjusted for these additional
      covariates of interest).

      Secondary Analyses using all Measured Time Points: A secondary repeated measures analysis
      using a GLMM will be conducted to further assess and compare how outcome variables change
      over time both within and between groups in greater detail over time from baseline to weeks 6
      and 10. The outcome variables will be the change from baseline to either week 6 or 10. Fixed
      effects will include baseline (Week 0) score, treatment group, time (week 6 and week 10), and
      the treatment group by time interaction effect. A random center effect will be included to
      account for variability across centers. Subject specific random intercepts and slopes will be
      used to account for correlations in repeated measures over time. Post-hoc comparison using a
      Bonferroni adjustment will be used to determine if the change in outcome from baseline
      differs between the groups at either 6 weeks or 10 weeks.

      Response to Treatment Analysis: Responders are defined as individuals demonstrating at least
      a 4-unit increase in the primary outcome measure, HVLT-R Total Trials 1-3, between baseline
      and week 10. As a secondary analysis, responders will be defined by a 5-unit change if there
      are no significant differences between the groups based on a 4-unit change.

      Interim Analysis: The investigators will perform an interim analysis for the primary outcome
      using the above-described data analytic methods on the data set comprising study participants
      randomized as of September 30, 2018. The investigators will compute the conditional power
      using: the current study sample; the maximum attainable sample; a significance level of α =
      0.05 for testing a one-sided null hypothesis (H0: treatment mean > control mean HLVT-R Total
      Trials score at week 10 after controlling for baseline HVLT-R Total Trials scores); and the
      observed treatment effect and associated t-statistic (using the data obtained thus far).
      Using the data available as of September 30, 2018, the difference in adjusted means, the
      means square error, and the t-statistic for the test of the treatment effect will estimated
      based on an ANCOVA model fit using PROC GLM in SAS.

      PASS v.14 will be used to determine the conditional power of the one-sided test for a
      treatment effect using the estimates from the ANCOVA model and a decision to either stop or
      continue recruitment the target enrollment (reset from N=160 to N=80 based on recruitment as
      of September 30, 2018).

        1. If the ANCOVA model using the present sample yields a t-statistic that is significant at
           a 5% level of significance using a one-sided hypothesis test, then enrollment will be
           halted due to efficacy and the study will enter the analytic phase.

        2. If the ANCOVA model using the present sample yields a t-statistics that is not
           significant at the 5% level of significance then the conditional power of identifying a
           significant treatment effect after completing the enrollment target will be computed
           based on the observed t-statistic, the difference in adjusted means, and the mean square
           error.

             1. If the conditional power is 80% or higher (corresponding to a futility index ≤ 0.2)
                given the data that have emerged so far then recruitment will proceed until the
                target sample size is reached, or the end of study year 5, whichever comes first.

             2. If the conditional power is less than 80% (futility index > 0.2) given the data
                that have emerged then enrollment will halt due to failed recruitment at the
                conclusion of this interim analysis. The observed treatment effect and associated
                t-statistic will be reported as a guide to future investigations of donepezil for
                persistent memory problems after TBI.

      The conditional power analysis will be conducted using both HVLT-R Total Trials Raw scores
      and T-scores. Preference will be given to the conditional power analysis based on the
      T-scores if conclusions differ.

      IMPLICATIONS, TRANSLATION, AND DISSEMINATION: Findings from this study will influence the
      practices of prescribing healthcare providers and contribute information that will improve
      lives of persons with TBI and their families. In addition to dissemination of final study
      results, the MEMRI-TBI-D Study team will disseminate information on evidence-based treatments
      for memory impairment to consumer and professional audiences throughout the funding period.
      Through these knowledge translation activities, consumers and health care providers will be
      provided with information regarding the effectiveness of this intervention for persistent
      posttraumatic memory impairments.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Hopkins Verbal Learning Test-Revised (HVLT-R) Total Trials 1-3
time frame: study week 10
description: The effects of study treatment (donepezil or placebo) on persistent verbal memory impairments among persons with traumatic brain injury will be assessed by performance on HVLT-R Total Trials 1-3 at study week 10.
measure: Cognitive Measures
time frame: study week 10
description: The effects of study treatment (donepezil or placebo) on attention, processing speed, and executive function among persons with persistent verbal memory impairments following TBI will be assessed using the Trail Making Test - Parts A and B; the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Digit Span, Symbol Search, Coding, Letter-Number Sequencing, and Processing Speed Index; and Controlled Oral Word Association Test at study week 10.
measure: Neuropsychiatric Measures
time frame: study week 10
description: The effects of study treatment (donepezil or placebo) on neuropsychiatric symptoms among persons with persistent verbal memory impairments following TBI will be assessed by Brief Symptom Inventory 18 (BSI 18) - Global Severity Index and the Neuropsychiatric Inventory-Clinician version (NPI-C) Total and Domain scores at study week 10.
measure: Functional Measures
time frame: study week 10
description: The effects of study treatment (donepezil or placebo) on functional status among persons with persistent verbal memory impairments will be assessed using participant and caregiver responses to the Everyday Memory Questionnaire, Participation Assessment with Recombined Tools-Objective, and Satisfaction with Life Scale scores at study week 10.
measure: Caregiver Measures
time frame: study week 10
description: The effects of study treatment (donepezil or placebo) on distress among caregivers of persons with persistent verbal memory impairments will be assessed by the Caregiver Appraisal Scale - Perceived Burden Subscale as well as the NPI-C Caregiver Distress Scale scores at study week 10.
measure: Physical Measures
time frame: study week 0, 6, and 10
description: The frequencies of adverse events associated with study treatment (donepezil or placebo) at study week 0, 6, and 10 will be assessed using the Side Effect Checklist.
arm group label: Donepezil
arm group type: Active Comparator
description: Donepezil 5 mg capsules daily for 14 days. Donepezil 10 mg capsules daily for 56 days.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo capsules once daily for 70 days.
intervention type: Drug
intervention name: Donepezil
description: Donepezil 5 mg capsule daily for 14 days. Donepezil 10 mg capsule daily for 56 days.
arm group label: Donepezil
other name: Donepezil hydrochloride
other name: Aricept
intervention type: Drug
intervention name: Placebo
description: Placebo capsule once daily for 70 days.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: David Arciniegas, MD
role: Study Director
affiliation: TIRR Memorial Hermann/Baylor College of Medicine
last name: Angelle Sander, PhD
role: Principal Investigator
affiliation: TIRR Memorial Hermann/Baylor College of Medicine
last name: Joseph Giacino, PhD
role: Principal Investigator
affiliation: Spaulding Rehabilitation Hospital
last name: Tessa Hart, PhD
role: Principal Investigator
affiliation: Moss Rehabilitation Research Institute
last name: Flora Hammond, MD
role: Principal Investigator
affiliation: Indiana University
last name: Mark S Sherer, PhD
role: Principal Investigator
affiliation: TIRR Memorial Hermann
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: David B. Arciniegas, MD
investigator title: Senior Scientist, Brain Injury Research Center, TIRR Memorial Hermann; Clinical Professor of Psychiatry, Baylor College of Medicine
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Memory Disorders
mesh term: Donepezil
sharing ipd: No