Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil (Remember)

• ClinicalTrials.gov Identifier: NCT02822573
• Recruitment Status: Recruiting
• First Posted: July 4, 2016
• Last Update Posted: August 1, 2019
• Sponsor: Wake Forest University Health Sciences
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Wake Forest University Health Sciences

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Cognitive Dysfunction; Memory Impairment	Drug: Donepezil 5 mg; Drug: Placebo	Phase 3

Detailed 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 276 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized Placebo Controlled Clinical Trial of Donepezil in Chemotherapy Exposed Breast Cancer Survivors With Cognitive Impairment
• Actual Study Start Date: May 30, 2017
• Estimated Primary Completion Date: October 12, 2020
• Estimated Study Completion Date: October 12, 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Donepezil; Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5 mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.	Drug: Donepezil 5 mg; Participants will be asked to take one 5 mg tablet of donepezil daily for 6 weeks followed by two 5mg tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.; Other Name: Aricept
Placebo Comparator: Placebo; Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.	Drug: Placebo; Participants will be asked to take one tablet of matching placebo daily for 6 weeks followed by two tablets daily for 18 weeks. After 24 weeks, participants will begin a 12 week wash-out period.; Other Name: Sugar Pill

Outcome Measures

Primary Outcome Measures :

1. Changes in Hopkins Verbal Learning Test-Revised (HVLT-R) Results [ Time Frame: Baseline and Week 24 ]
   The HVLT-R measures verbal learning and memory. It consists of a 12-item word list which is read to subjects on three successive learning trials. Free recall scores are recorded for each learning trial. Scores for immediate recall (total of three trials), delayed recall (total number of words recalled after 20 minutes), and recognition (total number of words correctly identified) will be the variables derived from the HVLT-R.

Secondary Outcome Measures :

1. Changes in Digit Symbol Coding Results [ Time Frame: Baseline and Week 24 ]
   The DSC test measures processing speed. It requires respondents to transcribe symbols (e.g., >) associated with a number (0-9) into empty boxes beneath a series of randomly ordered numbers. Total score is number of correctly transcribed symbols in 2 minutes. Scores range from 0-133.
2. Changes in PROMIS 7-item Fatigue Scale Results [ Time Frame: Baseline and Week 24 ]
   This self-report scale assesses fatigue. Scale ranges from 7 to 35, with higher scores representing more fatigue.
3. Changes in FACT-Cognition (Version 3) Results [ Time Frame: Baseline and Week 24 ]
   This is a validated self-report questionnaire that assesses patients' perceptions of their cognitive function and the impact of cognitive problems on overall quality of life over the prior 7 days. Higher scores reflect better cognitive functioning and less impairment.
4. Changes in Controlled Oral Word Association Test (COWA) Results [ Time Frame: Baseline and Week 24 ]
   The COWA measures speed of mental processing, verbal fluency, and executive function. Subjects are asked to name as many words as possible all beginning with a specified letter. A total of three trials are administered, each with a different letter (F-A-S). The score on the COWA is the total number of words named across the three trials minus repetitions.
5. Changes in Trail Making Test, Parts A & B (TMT-A, TMT-B) Results [ Time Frame: Baseline and Week 24 ]
   Part A of the TMT measures attention and visual motor skills and processing speed and requires subjects to connect 25 numbered circles in the proper sequence (1-2-3-…) as quickly as possible. TMT-B is similar except subjects are required to connect dots in an alternating numerical and alphabetical sequence (1-A-2-B-…). TMT-B with its added complexity and set shifting requirements is a widely used measure of executive function. The score for TMT-A and TMT-B is the total time in seconds required to complete the task. Scores can also be generated for number of errors and number of circles correctly connected.
6. Digit Span Test-Backwards (DST-B) [ Time Frame: Baseline and Week 24 ]
   The DST-B assesses attention and working memory. It requires respondents to repeat back in reverse order spans of numbers. Seven pairs of spans of increasing lengths are presented and repeated. A total score is the number of correctly repeated spans.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Karen Craver; (336) 716-0891; NCORP@wakehealth.edu

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Sponsors and Collaborators

Wake Forest University Health Sciences

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephen R Rapp, PhD; Wake Forest University Health Sciences

More Information

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT02822573 History of Changes
• Other Study ID Numbers: IRB00041707; 3UG1CA189824-04S1 ( U.S. NIH Grant/Contract ); WF-97116 ( Other Identifier: NCI ); NCI-2016-01050 ( Registry Identifier: NCI CTRP Trial ID ); IRB00041707 ( Other Identifier: Wake Forest IRB ID )
• First Posted: July 4, 2016
• Last Update Posted: August 1, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Wake Forest NCORP Research Base is committed to following the NIH Statement on Sharing Research Data (available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html). As of July 2018, the WF NCORP RB signed an agreement with NCI to contribute de-identified data and data dictionaries from clinical trials conducted through our RB to the NCI NCTN/NCORP data archive within 6 months of primary and non-primary publications of phase II/III and phase III trials to https://nctn-data-archive.nci.nih.gov/. This will become the primary means for sharing raw data, and we will adhere to the guidelines spelled out in the NCTN/NCORP Data Archive Usage Guide.
• Time Frame: See NIH Policy
• Access Criteria: request using URL below
• URL: https://nctn-data-archive.nci.nih.gov/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Wake Forest University Health Sciences:

Donepezil; Cognition; Breast Cancer

Additional relevant MeSH terms:

Cognitive Dysfunction; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Donepezil; Cholinesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Nootropic Agents