Multicenter Evaluation of Memory Remediation After TBI With Donepezil

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.

Inclusion Criteria:

- Man or woman of any race, color, ethnicity, or national origin

- 18-60 years old

- Primary language English

- Clinical diagnosis of traumatic brain injury using National Institute of Neurological
Disorders and Stroke TBI Common Data Elements definition and merit assignment of
International Classification of Disease (ICD9) codes 850.0-850.9, 851.0, 851.2, 852.0,
852.2, 852.4, 853.0, or 854.0

- TBI is non-penetrating

- TBI is of complicated mild or greater severity

- TBI occurred at least 6 months prior to study participation

- Persistent posttraumatic memory impairment, as defined by HVLT-R Total Trials 1-3
(Form 3) impairment ≥ 25% for Wechsler Test of Adult Reading-based intelligence
quotient-adjusted performance expectations

- Memory impairments are functionally significant, as defined by subject and/or
caregiver endorsement of at least 3 memory problems, occurring at least weekly, on the
Everyday Memory Questionnaire

- Stable doses of allowed centrally-acting medications for at least 3 months prior to
study participation, and participant and caregiver commitment not to alter doses of
allowed medications during study

- Capable of providing independent informed consent for study participation or provision
of consent for study participation by a legally-authorized representative is supported
by subject assent to study participation

- A knowledgeable informant is available and willing to attend study visits or to
provide required information by telephone interview on the day of study visits

Exclusion Criteria:

- Pre-injury neurological and/or neurocognitive disorder

- Primary diagnosis of hypoxic-ischemic brain injury or clinically definite post-TBI
hypoxic-ischemic event (i.e., respiratory arrest and/or cardiac arrest) or
non-TBI-related stroke

- Pre- or post-injury psychotic and/or bipolar disorders

- Post-injury substance use disorder (i.e., abuse or dependence diagnoses)

- Clinically significant abnormalities on screening laboratory studies

- Beck Depression Inventory-II (BDI-II) score ≥ 20 or BDI-II item 9 > 0

- Brief Symptom Inventory 18 (BSI 18) Depression Subscale T score or Anxiety Subscale T
score ≥ 63

- Penetrating brain injury or cerebral lobectomy

- Hearing, vision, and/or communication impairments that invalidate neuropsychological
or other study assessments

- Test of Memory Malingering Trial 2 score < 45

- Use of an excluded medication in the month prior to study participation, known allergy
to donepezil, or documented intolerance to donepezil

- Posttraumatic epilepsy

- Symptomatic bradycardia, cardiac conduction abnormality (i.e., first- or Type I
second-degree atrioventricular blockade), atrial fibrillation, or unstable
cardiovascular disease, including myocardial infarction within three months prior to
study participation

- Active, severe, or unstable pulmonary condition, including severe asthma

- Signs or symptoms of gastrointestinal bleeding or active peptic ulcer disease within
three months prior to study participation

- Serum human chorionic gonadotropin (HCG)-confirmed pregnancy

- For female participants, unable/unwilling to use barrier contraception during study
participation, intrauterine device, or other implantable contraceptive method,
unable/unwilling to forego breastfeeding infants or children during study
participation