Anxiety Disorder, Breast Cancer, Cognition Disorders, Depression, Fatigue, Sleep Disorders
Conditions
Keywords
fatigue, sleep disorders, depression, anxiety disorder, cognitive/functional effects, breast cancer, cancer survivor
Brief summary
RATIONALE: Donepezil hydrochloride may help lessen cognitive dysfunction caused by chemotherapy. PURPOSE: This phase II trial is studying donepezil hydrochloride in treating cognitive dysfunction after chemotherapy in female breast cancer survivors.
Detailed description
OBJECTIVES: Primary * Determine the feasibility of conducting a randomized placebo-controlled clinical trial for cognitive symptoms in female breast cancer survivors. Secondary * Estimate the variability of the clinical outcomes (FACT-Cognition Perceived Cognitive Impairment subscale, neurocognitive battery, FACIT-Fatigue, FACT Cog Total Score, PROMIS Fatigue, Epworth Sleepiness Scale, Beck Depression Inventory, Beck Anxiety Inventory, and RAND Short Form-36). * Estimate the within patient correlation over time of the clinical outcomes. * Obtain preliminary estimates of the effect of donepezil on the primary and secondary outcome variables. * Correlate the reports of fatigue, sleep disturbance, and mood with measures of cognitive symptoms and neurocognitive test performance. * Document the severity of cognitive symptoms and functional impairment in female breast cancer survivors who enroll on this pilot study. * Correlate cognitive symptoms with cognitive test performance. * Document the toxicities associated with donepezil hydrochloride use. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to menopausal status (pre- vs peri-/post-menopausal) and time since end of chemotherapy (12-36 months vs 36.01-60 months). Arm I: Patients receive donepezil hydrochloride orally (PO) once daily (QD). Arm II: Patients receive placebo PO QD. In both arms treatment continues for 24 weeks. Patients complete the entire battery of neurocognitive tests and questionnaires (FACT-Cognition Perceived Cognitive Impairment subscale, neurocognitive battery, FACIT-Fatigue, FACT Cog Total Score, PROMIS Fatigue, Epworth Sleepiness Scale, Beck Depression Inventory, Beck Anxiety Inventory, and RAND Short Form-36) at baseline (pre-treatment), 24 weeks (end of medication), and 36 weeks (end of wash-out). After completion of therapy, patients are followed at 12 weeks.
Interventions
DRUGdonepezil hydrochloride
Given PO
DRUGPlacebo
Given PO
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults \>18 years old. * Female with history of invasive breast cancer * Must have completed adjuvant chemotherapy between 1 and 5 years prior to registration * Received at least 4 cycles of cytotoxic chemotherapy * Documentation of prior chemotherapy * Patients receiving ongoing hormonal therapy for breast cancer must be on the same hormonal agent for at least 3 months prior to study registration and continue for the duration of the study (9 months) * Karnofsky Performance Status must be \> 60 or ECOG 0-2. * Use of psychotropic medications (anti-depressants, anxiolytics, sleeping aids, narcotics) is permitted. Patient will be asked to list any that have been taken within the last 3 days on the recent medication sheet. * Patients must be able to give informed consent to participate in the study, including signing the consent form. * Self-reported cognitive disruption (FACT-Cog Version 3 Perceived Cognitive Impairments sub-score of \< 63) * Negative serum pregnancy test within 10 days prior to registration for women of child-bearing potential.
Exclusion criteria
* Evidence or suspected recurrent or metastatic disease * History of dementia, Alzheimer's disease, multi-infarct dementia or CVA (history of transient ischemic attack (TIA is allowed) * Current use of donepezil, galantamine, rivastigmine, tacrine, memantine, methylphenidate, dextroamphetamine, or any other specific cognition enhancing drugs.are not allowed. For patients who have used these medications they must not have used them within 4 weeks prior to registration. Patients may not currently be taking Ketoconazole or Quinidine * Hypersensitivity to donepezil. * Use of investigational medications within the last 30 days. * Prior brain metastasis * Traumatic brain injury, multiple sclerosis or recent myocardial infarction * History of schizophrenia, psychosis or substance abuse * Untreated current severe depression. (Currently treated depression is permitted if treatment is stable.) * Acute severe fatigue, chronic fatigue syndrome or fibromyalgia. * History of hepatic or renal dysfunction or disease * Pregnant women are excluded from this study. The effects of donepezil on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because donepezil is known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. * It is unknown whether donepezil is excreted in breast milk, for this reason women who are currently breast-feeding are not eligible for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Retention | 24 Weeks | Retention is the percentage of participants who stay in the study for 24 weeks. |
| Compliance | 24 weeks | Compliance is the percentage of pills taken while on study (based on returned diaries) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HVLT-IR | 24 weeks | Hopkins verbal learning test - immediate recall is the number of words (of 12) than can be remembers during three tries. The total score ranges from 0 to 36. Higher is better. |
| Fatigue | 24 weeks | Fatigue is quantified by the FACIT-Fatigue scale. It consists of 13 questions answered on a 0 to 4 point scale. The fatigue score is the sum of the responses (some reverse scored) so that higher values represent less fatigue. |
Participant flow
Recruitment details
Patients were accrued between 7/12 and 1/13 from CCOP sites across the nation.
Pre-assignment details
No wash-out or run-in period. All enrolled patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Arm I - Donepezil Patients receive donepezil hydrochloride PO QD. | 31 |
| Arm II - Placebo Patients receive placebo PO QD. | 31 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Multiple | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Progression | 1 | 0 |
| Overall Study | Toxicity | 4 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Arm I - Donepezil | Arm II - Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 4 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 27 Participants | 51 Participants |
| Age, Continuous | 56 years | 56 years | 56 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 31 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 29 Participants | 56 Participants |
| Region of Enrollment United States | 31 participants | 31 participants | 62 participants |
| Sex: Female, Male Female | 31 Participants | 31 Participants | 62 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 28 | 30 / 30 |
| serious Total, serious adverse events | 2 / 28 | 1 / 30 |
Outcome results
Primary
Compliance
Compliance is the percentage of pills taken while on study (based on returned diaries)
Time frame: 24 weeks
Population: Participants who returned pill diaries. Note that some participants did not return diaries so the numbers of participants for this analysis may not agree with the numbers for other analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I | Compliance | 98.0 percentage of pills |
| Arm II | Compliance | 98.0 percentage of pills |
Primary
Retention
Retention is the percentage of participants who stay in the study for 24 weeks.
Time frame: 24 Weeks
Population: All randomized patients
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I | Retention | 71.0 percentage of participants | Standard Error 8.3 |
| Arm II | Retention | 80.7 percentage of participants | Standard Error 7.2 |
Secondary
Fatigue
Fatigue is quantified by the FACIT-Fatigue scale. It consists of 13 questions answered on a 0 to 4 point scale. The fatigue score is the sum of the responses (some reverse scored) so that higher values represent less fatigue.
Time frame: 24 weeks
Population: All randomized participants except two who did not provide any data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I | Fatigue | 35.89 units on a scale | Standard Error 2.2 |
| Arm II | Fatigue | 35.51 units on a scale | Standard Error 2.02 |
Secondary
HVLT-IR
Hopkins verbal learning test - immediate recall is the number of words (of 12) than can be remembers during three tries. The total score ranges from 0 to 36. Higher is better.
Time frame: 24 weeks
Population: All randomized participants except two who did not provide any data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Arm I | HVLT-IR | 25.58 number of words recalled | Standard Error 1.36 |
| Arm II | HVLT-IR | 22.94 number of words recalled | Standard Error 1.24 |