Breast Cancer Clinical Trial
Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil
Summary
This study is to compare the safety and effects of donepezil (Aricept) for patients reporting cognitive or memory issues after receiving chemotherapy for breast cancer. Patients will receive either donepezil or placebo for 24 weeks. The primary objective is to see if memory improves with the use of donepezil during the study.
Full Description
Randomized, double-blind, placebo-controlled study with 24 weeks of exposure to drug or placebo followed by a 12 week wash-out period. Patients who meet the eligibility criteria will be stratified by age (<50, 50-59, 60-69, ≥70) and randomized to donepezil or placebo with equal probability. A total of 276 patients will be enrolled (138 per arm). We expect an accrual rate of 7-10 participants per month based on our prior feasibility study. We expect the study to be complete within 40 months.
Participants will be asked to take one 5mg tablet of donepezil or one tablet of matching placebo orally once a day for 6 weeks followed by two 5mg tablets (10mg total) of donepezil or two placebo tablets orally once a day for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.
Time points for performing study assessments. Participants will be administered the cognitive battery of tests and questionnaires at baseline, week 12, week 24 and week 36. In addition, a single vial of blood will be drawn at baseline for APOE genotyping and subsequent bioassays (pending supplemental funding).
Eligibility Criteria
Inclusion Criteria:
Women ≥18 years old with history of invasive breast cancer
Must have completed at least 4 cycles of adjuvant/neo-adjuvant cytotoxic chemotherapy between 1 and 5 years prior to registration (Ongoing herceptin or other chronic HER 2 directed therapies are allowed).
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 plan to continue for the duration of the study (9 months)
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) if dose is stable over previous 12 weeks. Patients who were previously on one of these psychotropic medications and have subsequently discontinued the drug must have been off the medication for at least 4 weeks prior to enrollment. Patients who have been on a psychotropic medication for at least 12 weeks but have recently switched to a medicine in the same class (for example, switching from one SSRI antidepressant to a different SSRI antidepressant) need to be on a stable dose of the new medication for at least 4 weeks prior to enrollment to be eligible.
Self-reported cognitive problem plus a measured memory deficit (score <7 on single trial of Eligibility Pre-screen HVLT-R Form 3).
ECOG performance status 0-2
Ability to understand and the willingness to sign a written informed consent document.
Must be able to speak English.
Patients currently taking a moderate risk QTc prolongation medication (see Appendix A) are allowed if one of the following criteria are met: 1) The moderate risk QTc prolongation medication is stopped. The patient should be off the moderate risk QTc prolongation medication for at least 5 half-lives before starting study drug. 2) Patients that continue using a moderate risk QTc prolongation medication must have a normal QTc interval (≤ 460 milliseconds) on a screening ECG following informed consent and prior to study enrollment. These patients will also be monitored at designated study follow-up visits per Section 7.5 (monitored 3-7 days after initiating study drug, at week 3, and 3-7 days after the study drug dose increase with ECG's to assess the QTc interval; the QTc level must be ≤ 500 milliseconds at these time points in order to continue on the study drug). 3) Moderate risk QTc prolongation medications that are only taken occasionally may be stopped at the discretion of the treating site physician. Patients must be off medication for at least 5 half-lives prior to starting study drug to be eligible.
Patients currently taking a moderate risk bradycardia-causing agent (see Appendix B) are allowed if one of the following criteria are met: 1) The moderate risk bradycardia-causing agent is stopped. The patient should be off the moderate risk bradycardia-causing agent for at least 5 half-lives before starting study drug. 2) Patients that continue using a moderate risk bradycardia-causing agent must have a resting heart rate ≥ 55 beats per minute at screening following informed consent. These patients' resting heart rate will be monitored 3-7 days after initiating study drug, at week 3, and 3-7 days after the study drug dose increase per Section 7.5. 3) Moderate risk bradycardia-causing agents that are only taken occasionally may be stopped at the discretion of the treating site physician. Patients must be off medication for at least 5 half-lives prior to starting study drug to be eligible.
Exclusion Criteria:
Evidence or suspected recurrent or metastatic disease.
Prior brain irradiation is not allowed.
Planned therapy (surgery, radiation, chemotherapy, or immunotherapy) while on the study for brain and/or extracranial primary/metastatic disease.
Hypersensitivity to donepezil or piperidine derivatives
Current use of ceritinib
Current use of Succinylcholine/Acetylcholinesterase Inhibitors(as listed in Appendix C). For patients who have used these medications, they must not have used them within 4 weeks prior to enrollment.
Current use of high-risk QTc prolonging medication(s). See Appendix D
Current use of quinidine or systemic ketoconazole (topical ketoconazole is acceptable to use while on study).
History of dementia, Alzheimer's disease, multi-infarct dementia or clinically significant Cerebrovascular Accident (history of transient ischemic attack (TIA) is allowed).
Current use of donepezil, galantamine, rivastigmine, tacrine, memantine, methylphenidate, dextroamphetamine, or any other specific cognition enhancing drug(s). For patients who have used these medications, they must not have used them within 4 weeks prior to pre-screening. Patients who plan to start taking a cognition enhancing drug while on this study are also excluded.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to donepezil. Hypersensitivity to donepezil.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, recent myocardial infarction, cardiac arrhythmia.
Major medical conditions that affect cognition, traumatic brain injury, multiple sclerosis, acute severe fatigue, chronic fatigue syndrome or fibromyalgia.
Psychiatric illness/social situations that would limit compliance with study requirements including but not limited to a history of schizophrenia, psychosis or substance abuse.
Untreated current severe depression. Currently treated depression is permitted if treatment is stable.
Patients with a resting heart rate less than 55 beats per minute, seizure disorder or peptic ulcer disease (PUD).
History of congenital long QT syndrome or torsades de pointes.
Screening QTc of > 460 milliseconds will make the patient ineligible.
Pregnant women are excluded from this study. Following informed consent, women of child-bearing potential will be screened with a serum or urine pregnancy test within 10 days of enrollment. 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.
On another intervention study involving medication at the time of enrollment or during participation in this study. (Exception: Patients will remain eligible for this study if they are also enrolled on the Alliance for Clinical Trials in Oncology study (NCT02927249): Aspirin in Preventing Recurrence of Cancer in Patients with HER2 Negative Stage II-III Breast Cancer After Chemotherapy, Surgery, and/or Radiation Therapy. Studies that involve only blood draws or questionnaires are also permitted.)
Use of investigational drugs likely to affect cognition within 30 days prior to pre-screening visit.
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There are 241 Locations for this study
Anaheim California, 92806, United States
Antioch California, 94531, United States
Baldwin Park California, 91706, United States
Bellflower California, 90706, United States
Fontana California, 92335, United States
Fremont California, 94538, United States
Fresno California, 93720, United States
Fresno California, 93720, United States
Harbor City California, 90710, United States
Irvine California, 92618, United States
Los Angeles California, 90027, United States
Los Angeles California, 90034, United States
Modesto California, 95356, United States
Oakland California, 94611, United States
Ontario California, 91761, United States
Panorama City California, 91402, United States
Rancho Cordova California, 95670, United States
Richmond California, 94801, United States
Riverside California, 92505, United States
Roseville California, 95661, United States
Roseville California, 95678, United States
Sacramento California, 95814, United States
Sacramento California, 95823, United States
Sacramento California, 95823, United States
Sacramento California, 95825, United States
San Diego California, 92120, United States
San Francisco California, 94115, United States
San Jose California, 95119, United States
San Leandro California, 94577, United States
San Marcos California, 92078, United States
San Rafael California, 94903, United States
San Rafael California, 94903, United States
Santa Clara California, 95051, United States
Santa Rosa California, 95403, United States
South San Francisco California, 94080, United States
Stockton California, 95210, United States
Vacaville California, 95688, United States
Vallejo California, 94589, United States
Walnut Creek California, 94596, United States
Woodland Hills California, 91367, United States
Colorado Springs Colorado, 80907, United States
Colorado Springs Colorado, 80907, United States
Denver Colorado, 80205, United States
Denver Colorado, 80210, United States
Lafayette Colorado, 80026, United States
Littleton Colorado, 80122, United States
Lone Tree Colorado, 80124, United States
Longmont Colorado, 80501, United States
Parker Colorado, 80138, United States
Newark Delaware, 19713, United States
Newark Delaware, 19713, United States
Newark Delaware, 19718, United States
Rehoboth Beach Delaware, 19971, United States
Seaford Delaware, 19973, United States
Fort Lauderdale Florida, 33308, United States
'Aiea Hawaii, 96701, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96813, United States
Honolulu Hawaii, 96817, United States
Honolulu Hawaii, 96817, United States
Honolulu Hawaii, 96819, United States
Honolulu Hawaii, 96826, United States
Boise Idaho, 83712, United States
Fruitland Idaho, 83619, United States
Meridian Idaho, 83642, United States
Nampa Idaho, 83686, United States
Twin Falls Idaho, 83301, United States
Bloomington Illinois, 61704, United States
Canton Illinois, 61520, United States
Centralia Illinois, 62801, United States
Danville Illinois, 61832, United States
Decatur Illinois, 62526, United States
Decatur Illinois, 62526, United States
Effingham Illinois, 62401, United States
Effingham Illinois, 62401, United States
Galesburg Illinois, 61401, United States
Kewanee Illinois, 61443, United States
Mattoon Illinois, 61938, United States
Ottawa Illinois, 61350, United States
Pekin Illinois, 61554, United States
Peoria Illinois, 61615, United States
Peru Illinois, 61354, United States
Urbana Illinois, 61801, United States
Urbana Illinois, 61801, United States
Cedar Rapids Iowa, 52402, United States
Des Moines Iowa, 50309, United States
Des Moines Iowa, 50309, United States
Des Moines Iowa, 50314, United States
Des Moines Iowa, 50314, United States
Des Moines Iowa, 50316, United States
West Des Moines Iowa, 50266, United States
Chanute Kansas, 66720, United States
El Dorado Kansas, 67042, United States
Fort Scott Kansas, 66701, United States
Independence Kansas, 67301, United States
Kingman Kansas, 67068, United States
Manhattan Kansas, 66502, United States
McPherson Kansas, 67460, United States
Newton Kansas, 67114, United States
Parsons Kansas, 67357, United States
Salina Kansas, 67401, United States
Wellington Kansas, 67152, United States
Wichita Kansas, 67208, United States
Wichita Kansas, 67208, United States
Wichita Kansas, 67214, United States
Wichita Kansas, 67214, United States
Winfield Kansas, 67156, United States
Bardstown Kentucky, 40004, United States
Lexington Kentucky, 40504, United States
Lexington Kentucky, 40509, United States
London Kentucky, 40741, United States
Alexandria Louisiana, 71301, United States
Baton Rouge Louisiana, 70805, United States
Baton Rouge Louisiana, 70809, United States
Baton Rouge Louisiana, 70809, United States
Baton Rouge Louisiana, 70809, United States
New Orleans Louisiana, 70112, United States
New Orleans Louisiana, 70112, United States
New Orleans Louisiana, 70121, United States
Shreveport Louisiana, 71105, United States
Ann Arbor Michigan, 48106, United States
Brighton Michigan, 48114, United States
Brighton Michigan, 48114, United States
Canton Michigan, 48188, United States
Canton Michigan, 48188, United States
Caro Michigan, 48723, United States
Chelsea Michigan, 48118, United States
Chelsea Michigan, 48118, United States
Clarkston Michigan, 48346, United States
Clarkston Michigan, 48346, United States
Dearborn Michigan, 48124, United States
Escanaba Michigan, 49829, United States
Farmington Hills Michigan, 48336, United States
Flint Michigan, 48503, United States
Flint Michigan, 48503, United States
Flint Michigan, 48503, United States
Flint Michigan, 48503, United States
Grand Rapids Michigan, 49503, United States
Grand Rapids Michigan, 49503, United States
Grosse Pointe Michigan, 48230, United States
Livonia Michigan, 48154, United States
Muskegon Michigan, 49444, United States
Pontiac Michigan, 48341, United States
Pontiac Michigan, 48341, United States
Reed City Michigan, 49677, United States
Royal Oak Michigan, 48073, United States
Saginaw Michigan, 48601, United States
Saginaw Michigan, 48604, United States
Tawas City Michigan, 48764, United States
Traverse City Michigan, 49684, United States
Troy Michigan, 48085, United States
West Branch Michigan, 48661, United States
Wyoming Michigan, 49519, United States
Ypsilanti Michigan, 48197, United States
Burnsville Minnesota, 55337, United States
Coon Rapids Minnesota, 55433, United States
Edina Minnesota, 55435, United States
Fridley Minnesota, 55432, United States
Maple Grove Minnesota, 55369, United States
Maplewood Minnesota, 55109, United States
Maplewood Minnesota, 55109, United States
Minneapolis Minnesota, 55407, United States
Minneapolis Minnesota, 55415, United States
Minneapolis Minnesota, 55454, United States
New Ulm Minnesota, 56073, United States
Robbinsdale Minnesota, 55422, United States
Saint Louis Park Minnesota, 55416, United States
Saint Paul Minnesota, 55101, United States
Saint Paul Minnesota, 55102, United States
Shakopee Minnesota, 55379, United States
Stillwater Minnesota, 55082, United States
Waconia Minnesota, 55387, United States
Willmar Minnesota, 56201, United States
Woodbury Minnesota, 55125, United States
Wyoming Minnesota, 55092, United States
Columbus Mississippi, 39705, United States
New Albany Mississippi, 38652, United States
Oxford Mississippi, 38655, United States
Southhaven Mississippi, 38671, United States
Jefferson City Missouri, 65109, United States
Saint Louis Missouri, 63131, United States
Springfield Missouri, 65804, United States
Kearney Nebraska, 68847, United States
Asheboro North Carolina, 27203, United States
Asheville North Carolina, 28801, United States
Asheville North Carolina, 28803, United States
Asheville North Carolina, 28816, United States
Belmont North Carolina, 28012, United States
Chapel Hill North Carolina, 27599, United States
Clemmons North Carolina, 27012, United States
Clinton North Carolina, 28328, United States
Gastonia North Carolina, 28054, United States
Gastonia North Carolina, 28054, United States
Goldsboro North Carolina, 27534, United States
Greensboro North Carolina, 27403, United States
Hendersonville North Carolina, 28791, United States
Hendersonville North Carolina, 28792, United States
Jacksonville North Carolina, 28546, United States
Winston-Salem North Carolina, 27157, United States
Bismarck North Dakota, 58501, United States
Fargo North Dakota, 58122, United States
Fargo North Dakota, 58122, United States
Belpre Ohio, 45714, United States
Cincinnati Ohio, 45220, United States
Cincinnati Ohio, 45242, United States
Cincinnati Ohio, 45247, United States
Cincinnati Ohio, 45255, United States
Columbus Ohio, 43214, United States
Columbus Ohio, 43214, United States
Findlay Ohio, 45840, United States
Marietta Ohio, 45750, United States
Newark Ohio, 43055, United States
Portland Oregon, 97227, United States
Danville Pennsylvania, 17822, United States
Hazleton Pennsylvania, 18201, United States
Lewisburg Pennsylvania, 17837, United States
Pottsville Pennsylvania, 17901, United States
Scranton Pennsylvania, 18510, United States
Selinsgrove Pennsylvania, 17870, United States
Wilkes-Barre Pennsylvania, 18711, United States
Anderson South Carolina, 29621, United States
Boiling Springs South Carolina, 29316, United States
Easley South Carolina, 29640, United States
Gaffney South Carolina, 29341, United States
Georgetown South Carolina, 29440, United States
Greenville South Carolina, 29605, United States
Greenville South Carolina, 29605, United States
Greenville South Carolina, 29615, United States
Greenwood South Carolina, 29646, United States
Greer South Carolina, 29650, United States
Greer South Carolina, 29651, United States
Seneca South Carolina, 29672, United States
Spartanburg South Carolina, 29303, United States
Union South Carolina, 29379, United States
Sioux Falls South Dakota, 57104, United States
Sioux Falls South Dakota, 57117, United States
Memphis Tennessee, 38120, United States
Memphis Tennessee, 38120, United States
Memphis Tennessee, 38120, United States
Nashville Tennessee, 37208, United States
Burlington Wisconsin, 53105, United States
Chippewa Falls Wisconsin, 54729, United States
Eau Claire Wisconsin, 54701, United States
Fond Du Lac Wisconsin, 54937, United States
Germantown Wisconsin, 53022, United States
Grafton Wisconsin, 53024, United States
Green Bay Wisconsin, 54301, United States
Green Bay Wisconsin, 54303, United States
Green Bay Wisconsin, 54311, United States
Kenosha Wisconsin, 53142, United States
La Crosse Wisconsin, 54601, United States
Ladysmith Wisconsin, 54848, United States
Manitowoc Wisconsin, 54221, United States
Marinette Wisconsin, 54143, United States
Marinette Wisconsin, 54143, United States
Marshfield Wisconsin, 54449, United States
Milwaukee Wisconsin, 53209, United States
Milwaukee Wisconsin, 53215, United States
Milwaukee Wisconsin, 53233, United States
Minocqua Wisconsin, 54548, United States
New Richmond Wisconsin, 54017, United States
Oconto Falls Wisconsin, 54154, United States
Oshkosh Wisconsin, 54904, United States
Racine Wisconsin, 53406, United States
Rice Lake Wisconsin, 54868, United States
Sheboygan Wisconsin, 53081, United States
Stevens Point Wisconsin, 54482, United States
Sturgeon Bay Wisconsin, 54235, United States
Summit Wisconsin, 53066, United States
Two Rivers Wisconsin, 54241, United States
Wausau Wisconsin, 54401, United States
Wauwatosa Wisconsin, 53226, United States
West Allis Wisconsin, 53227, United States
Weston Wisconsin, 54476, United States
Wisconsin Rapids Wisconsin, 54494, United States
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