The Effect of Donepezil in Radiotherapy-related Cognitive Impairment.

Study Overview
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Brief Summary
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Purpose: This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the therapeutic effects of donepezil in radiotherapy-related cognitive impairment. Further study details as provided by Sun Yat-sen Memorial Hospital, Sun Yat-sen University / Yameitang. Primary outcome measure: cognitive improvement, which is determined by the difference value of ADAS-cog score before and after the treatment of donepezil.

Detailed Description
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Application of radiotherapy to patients with head and neck cancer is a mainstay treatment in contemporary oncology practice. However, patients who received radiation are vulnerable to development of cognitive impairment. There is no acknowledged and effective standard treatment for radiotherapy-related cognitive impairment. The investigators supposed that donepezil, as a cholinesterase inhibitor, would relieve radiotherapy-related cognitive impairment after head and neck cancer, and would improve the life quality for these patients and their families. Primary objectives: This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the efficacy of donepezil on cognition in radiotherapy-related cognitive impairment. Secondary objectives: To evaluate the effect of donepezil on sleep disorder, mood disorder, activities of daily living, and safety in patients with radiotherapy-related cognitive impairment. OUTLINE: This is randomized, double-blind, placebo-controlled clinical trial. Patients will be enrolled and administrated with donepezil or placebo. Donepezil will be supplied as 10 mg per pill to be taken by mouth. Placebo will be supplied as substitute of 10 mg donepezil per pill to be taken by mouth. Patients will be screened, consented, enrolled and have a washout period for 6 weeks. Then these patients will be randomized to two arms. Arm І: Patients receive donepezil with a dosage of 5 milligram at 8 am for one week (Week 1), then 10 milligram at 8 am for 23 weeks (Week 2-24), in the absence of unacceptable toxicity or severe deterioration. Arm ІI: Patients receive placebo with a dosage of one half pill at 8 am for one week (Week 1), then one pill at 8 am for 23 weeks (Week 2-24), in the absence of unacceptable toxicity or severe deterioration.

Official Title
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The Effect of Donepezil in Radiotherapy-related Cognitive Impairment: a Randomized, Double-blind, Placebo-controlled Clinical Trial

Conditions
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Radiation Injuries, Cognitive Impairment

Intervention / Treatment
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* Drug: Donepezil Hydrochloride
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (1) Received radiation therapy due to head and neck cancer. (2) Prior irradiation ≥ 1.5 years and ≤ 6 years. (3) Age>/= 35 years and age</=60. (4) Estimated life expectancy ≥ 12 months. (5) Cognitive impairment ≥ 4 weeks, with MMSE total score ≤26, or MoCA total score ≤ 25. (6) Routine laboratory studies: normal bilirubin, normal aspartate aminotransferase (AST or SGOT), normal alanine aminotransferase (ALT), normal creatinine, normal white-cell count; normal neutrophils count, normal platelets count; Hb >/=110 gram per millilitres; PT, APTT, INR in a normal range. (7) Constant caregivers who well understand and have willingness to sign a written informed consent document. Exclusion Criteria: (1) evidence of tumor metastasis, recurrence, or invasion; (2) evidence of very high intracranial pressure that suggests brain hernia and need surgery; (3) previous treatment with donepezil or other medications for cognitive impairment; (4) history of mental disorders, epilepsy, cognitive impairment before radiotherapy; (5) history of stroke, or high risk of vascular dementia; (6) family history of Alzheimer's disease, Pick's disease, etc.; (7) history of severe head trauma; (8) clinically significant active disease, e.g. New York Heart Association Grade II or greater congestive heart failure, serious and inadequately controlled cardiac arrhythmia, bradycardia, significant vascular disease, severe infection; (9) history of allergy to relevant drugs; (10) pregnancy, lactation, or fertility program in the following 12 months; (11) participation in other experimental studies.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donepezil<br>Patients receive donepezil with a dosage of 5 milligram at 8 am for one week (Week 1), then 10 milligram at 8 am for 23 weeks (Week 2-24), in the absence of unacceptable toxicity or severe deterioration. | Drug: Donepezil Hydrochloride<br>* Donepezil will be used with a dosage of 5 milligram at 8 am for one week (Week 1), then 10 milligram at 8 am for 23 weeks (Week 2-24).<br>|
| Placebo Comparator: Control<br>Patients receive placebo with a dosage of one half pill at 8 am for one week (Week 1), then one pill at 8 am for 23 weeks (Week 2-24), in the absence of unacceptable toxicity or severe deterioration. | Other: Placebo<br>* Placebo will be used with a dosage of one half pill at 8 am for one week (Week 1), then one pill at 8 am for 23 weeks (Week 2-24).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cognitive change | Cognitive change, which is determined by the difference value of ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) before and after the treatment of donepezil. The rating of ADAS-cog is made on 6-point scale rating from 0 to 5 in 12 domains. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| global condition change | Efficacy of donepezil on global condition using CIBIC-plus (Clinician's Interview-Based Impression of Change plus). The rating is made on a 7-point scale ranging from 1 = marked improvement to 7 = marked worsening. A score of 4 indicates no change. | Baseline to Week 24 | 
| changes of activities of daily living | Efficacy of donepezil on activities of daily living using ADL (Activities of Daily Living). Total score is from 0 to 54. The higher score, the lower impairment. | Baseline to Week 24 | 
| cognition change | Efficacy of donepezil on mental statement using MMSE (Mini Mental Status Examination). The total score of MMSE is 30. | Baseline to Week 24 | 
| psychological statement change | Efficacy of donepezil on psychological statement, including sleep disorder, mood disorder etc. using Neuropsychiatric Inventory (NPI) total score. | Baseline to Week 24 |