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Clinical Trial Summary

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.

Clinical Trial Description

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.

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.

Two analysis study populations will be considered in this study, a modified intent-to-treat (mITT) population and a clinically evaluable population. The mITT sample will include individuals deemed eligible for study participation based on the Screening Assessment; who are randomized to study treatment; who are assessed using HVLT-R at the Baseline Visit; and who receive at least one dose of study treatment. The analysis on the mITT sample will be considered the primary analysis. 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 eight weeks of double-blind study treatment, data on primary outcomes at the Outcome Assessment, at least 80% treatment adherence as determined by pill counts on returned blister packs, and no major protocol violations. For the primary outcome HVLT-R Total Trails 1-3, the primary analysis will examine the donepezil effect measured at week 10 using a general linear model (GLM). Because the secondary outcomes are all approximately continuous-type, they will be tested using similar GLM procedures as stated above to estimate and test the effects of donepezil. Additionally, general linear mixed models will be performed to compare the data in the drug and placebo groups, accounting for center effect and other covariables. Side effects data in the form of the frequency of events (drug related/by severity/serious) will be evaluated using a Mantel-Haenszel test. Exact binomial confidence intervals for side effect event frequencies also will be generated.

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. ;

Study Design

Related Conditions & MeSH terms

NCT number NCT02255799
Study type Interventional
Source Baylor College of Medicine
Contact David Arciniegas, MD
Phone 970-642-4612
Status Recruiting
Phase Phase 3
Start date September 2014
Completion date September 2018

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