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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 75
- 试验地点
- 4
- 主要终点
- Hopkins Verbal Learning Test-Revised (HVLT-R) Total Trials 1-3
研究概览
简要总结
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:
- To evaluate the effects of treatment with donepezil on verbal memory as assessed by the Hopkins Verbal Learning Test-Revised Total Trial 1-3;
- To evaluate the effects of treatment with donepezil on memory-related activities as measured by the Everyday Memory Questionnaire;
- To evaluate the effects of donepezil on attention, processing speed, neuropsychiatric symptoms, community participation, quality of life, and caregiver experiences.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Participants received donepezil 5 mg daily or matching placebo for 2 weeks followed by donepezil 10 mg daily or matching placebo for 8 weeks; after the 10-week treatment period, treatment was discontinued, and patients were observed for an additional 4 weeks. Participants and all study personnel (except the individual responsible for generation of the randomization code) were unaware of treatment allocation throughout the study. Site investigators attested to the integrity of allocation concealment at the conclusion of the study's treatment phase. For additional details on these and related study drug, randomization, blinding, and allocation concealment methods, see section 12 in part A of the online supplement at https://psychiatryonline.org/doi/10.1176/appi.neuropsych.20230055.
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Donepezil
Donepezil 5 mg capsules daily for 14 days. Donepezil 10 mg capsules daily for 56 days.
干预措施: Donepezil (Drug)
Placebo
Placebo capsules once daily for 70 days.
干预措施: Placebo (Drug)
结局指标
主要结局
Hopkins Verbal Learning Test-Revised (HVLT-R) Total Trials 1-3
时间窗: study week 10
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.
次要结局
- Physical Measures(study week 0, 6, and 10)
- Neuropsychiatric Measures(study week 10)
- Functional Measures(study week 10)
- Cognitive Measures(study week 10)
- Caregiver Measures(study week 10)
研究者
David B. Arciniegas, MD
Senior Scientist, Brain Injury Research Center, TIRR Memorial Hermann; Clinical Professor of Psychiatry, Baylor College of Medicine
Baylor College of Medicine