Alzheimer's Disease
Conditions
Keywords
Moderate to Severe Alzheimer's Disease
Brief summary
The purpose of this study is to compare 23 mg donepezil sustained release (SR) to the currently marketed formulation of 10 mg donepezil immediate release (IR) in patients with moderate to severe Alzheimer's disease.
Detailed description
This study consists of a double-blind, double-dummy, parallel-group comparison of 23 mg donepezil SR with the currently marketed donepezil formulation (10 mg donepezil IR) in patients with moderate to severe Alzheimer's disease. Patients must have been taking 10 mg IR (or a bioequivalent generic) for at least 3 months prior to Screening. The study will consist of 24 weeks of daily administration of study medication, with clinic visits at Screening, Baseline, 3 weeks (safety only), 6 weeks, 12 weeks, 18 weeks and 24 weeks or early termination. Patients will receive either 10 mg donepezil IR in combination with the placebo corresponding to 23 mg donepezil SR, or 23 mg donepezil SR in combination with the placebo corresponding to 10 mg donepezil IR. A total of approximately 1600 patients will be enrolled to obtain complete data from approximately 1200 completed patients (Revised per Amendment 02). During the Baseline visit, patients will be randomized in a 2:1 ratio (23 mg donepezil SR to 10 mg donepezil IR). The study will be performed at approximately 200 global sites (Asia, Oceania, Europe, India, Israel, North America, South Africa, and South America) (Revised per Amendments 01 and 02). An Independent Data Monitoring Committee (IDMC) will be established to review safety aspects of the study and to evaluate the results of a planned interim analysis. Patients who complete the study may be eligible to undergo evaluation for enrollment into the open-label extension study, E2020-G000-328.
Interventions
DRUGAricept (donepezil SR 23 mg)
Patients will receive study medication orally, once daily, for 24 weeks according to a double-dummy design: 23 mg donepezil SR concurrently with placebo identical in appearance to the 10 mg donepezil IR formulation.
DRUGAricept (donepezil IR 10 mg)
Patients will receive study medication orally, once daily, for 24 weeks according to a double-dummy design: 10 mg donepezil IR concurrently with placebo identical in appearance to the 23 mg donepezil SR formulation.
Sponsors
Eisai Limited
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
for Patients: 1. Written informed consent. 2. Patient Age range: Adult patients, 45 to 90 years of age, inclusive. 3. The caregiver must separately meet the specified inclusion/
Exclusion criteria
for caregivers. 4. Women must be of non-child-bearing potential (\>1 year post-menopausal or surgically sterile). 5. There must be diagnostic evidence of probable Alzheimer's disease (AD). 6. The patient must have been receiving Aricept at a dose of dose of 10 mg IR (or 10 mg dose of generic donepezil bioequivalent to Aricept), for at least 3 months prior to the Screening visit. 7. A cranial image is required, with no evidence of focal brain disease that would account for dementia. 8. The patient must meet certain psychometric test criteria related to the degree of impairment of cognitive functioning. 9. Health: physically healthy and ambulatory or ambulatory-aided (i.e., walker or cane); corrected vision and hearing sufficient for compliance with testing procedures, and able to read prior to disease onset. 10. Clinical laboratory values must be within normal limits or, if abnormal, must be judged not clinically significant by the investigator. 11. Specified doses of selective serotonin reuptake inhibitors (SSRIs) are allowed in the study if dosage is within approved dose range and stable for 3 months prior to Screening. 12. Other medical conditions, such as hypertension and cardiac disease must be well-controlled and the patient maintained on stable doses of medications for 3 months. 13. Patients with diabetes mellitus or risk factors for diabetes mellitus may be enrolled in the study provided that the patient's disease is stable and that there have been no recent hospitalizations for diabetes complications. 14. Patients whose serum B12 levels at Screening are below the normal range may nonetheless be admitted to the study if they subsequently show normal levels prior to Baseline. 15. Patients with hypothyroidism who are on a stable dose of medication for at least 12 weeks prior to Screening, have normal TSH and free T4 at Screening, and are considered euthyroid will be eligible. 16. Concomitant Medications: Under specified circumstances, the following medications may be allowed: chronic daily benzodiazepine use, bronchodilator medications for treatment of chronic obstructive pulmonary disease (COPD), and memantine. Certain other additional prescription treatments for AD, such as other cholinesterase inhibitors, must have been discontinued for at least 3 months prior to screening. 17. The patient must have a relative/caregiver who supervises the regular taking of the drug at the correct dose and is alert for possible side effects, unless the patient's legal guardian takes on this task. Inclusion Criteria for Caregivers: The designated caregiver must be sufficiently familiar with the patient (as determined by the investigator) to provide accurate data. The caregiver must have regular contact with the patient (i.e., an average of 10 or more hours per week), must be able to observe for possible adverse events, and must be able to accompany the patient to all visits.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in SIB Total Score | Baseline and Week 24 | The SIB is an assessment of cognitive dysfunction across nine domains such as memory, language, and orientation. The score ranges from 0 (worst) to 100 (best). This outcome was calculated using the LOCF (last observation carried forward) method. |
| Overall Change From Baseline in Modified CIBIC+ to Week 24 | Baseline and Week 24 | The CIBIC+ is a rating scale derived from an interview with the patient and caregiver with an independent rater designed to measure several domains of patient function, such as mental/cognitive state, behavior, and activities of daily living. The scores range from 1 (marked improvement) to 7 (marked worsening). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in ADCS-ADL Total Score | Baseline and Week 24 | The ADCS-ADL (Alzhemier's Disease Cooperative Study-Activities of Daily Living) is a 19-item assessment scale used to measure a patient's basic functional abilities, such as walking, grooming, and bathing.Scores range from 0 to 54, with a higher score indicating greater functional ability. |
| Change From Baseline to Week 24 in MMSE Total Score | Baseline and Week 24 | The MMSE (Mini-Mental State Examination) is a 30-item test that evaluates 5 domains of cognitive function (orientation to time and place, immediate and delayed recall, attention, calculation, and language). The scores range from 0 (most impaired) to 30 (no impaiment). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Donepezil SR 23 mg Donepezil sustained release (SR) 23 mg in combination with placebo corresponding to donepezil IR 10 mg ; dosing continued for a 24-week treatment period. | 963 |
| Donepezil IR 10 mg Donepezil immediate release (IR) 10 mg in combination with placebo corresponding to donepezil SR 23 mg; dosing continued for a 24-week treatment period. | 471 |
| Total | 1,434 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 182 | 39 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Medication Non-compliance | 9 | 4 |
| Overall Study | Other | 24 | 12 |
| Overall Study | Protocol Violation | 15 | 5 |
| Overall Study | Request of Investigator or Sponsor | 4 | 5 |
| Overall Study | Withdrawal by Subject | 61 | 22 |
Baseline characteristics
| Characteristic | Donepezil IR 10 mg | Total | Donepezil SR 23 mg |
|---|---|---|---|
| Age, Continuous | 73.8 Years STANDARD_DEVIATION 8.56 | 73.8 Years STANDARD_DEVIATION 8.53 | 73.9 Years STANDARD_DEVIATION 8.53 |
| Race/Ethnicity, Customized Asian/Pacific | 87 Participants | 248 Participants | 161 Participants |
| Race/Ethnicity, Customized Black | 9 Participants | 31 Participants | 22 Participants |
| Race/Ethnicity, Customized Hispanic | 26 Participants | 93 Participants | 67 Participants |
| Race/Ethnicity, Customized Native American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 346 Participants | 1054 Participants | 708 Participants |
| Sex: Female, Male Female | 294 Participants 62.4 | 901 Participants 62.8 | 607 Participants 63 |
| Sex: Female, Male Male | 177 Participants 37.6 | 533 Participants 37.2 | 356 Participants 37 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 233 / 963 | 50 / 471 |
| serious Total, serious adverse events | 80 / 963 | 45 / 471 |
Outcome results
Primary
Change From Baseline to Week 24 in SIB Total Score
The SIB is an assessment of cognitive dysfunction across nine domains such as memory, language, and orientation. The score ranges from 0 (worst) to 100 (best). This outcome was calculated using the LOCF (last observation carried forward) method.
Time frame: Baseline and Week 24
Population: Intent-to-treat (ITT) population: All Randomized patients in Safety Population and Severe Impairment Battery (SIB) or Clinician Interview-Based Impression of Severity Plus Caregiver Input (CIBIS+) data available at Baseline and SIB or Clinician Interview-Based Impression of Change Plus caregiver Input (CIBIC+ ) data available post-Baseline; LOCF
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Donepezil SR 23 mg | Change From Baseline to Week 24 in SIB Total Score | 2.6 Scores on a scale | Standard Error 0.58 |
| Donepezil IR 10 mg | Change From Baseline to Week 24 in SIB Total Score | 0.4 Scores on a scale | Standard Error 0.66 |
Primary
Overall Change From Baseline in Modified CIBIC+ to Week 24
The CIBIC+ is a rating scale derived from an interview with the patient and caregiver with an independent rater designed to measure several domains of patient function, such as mental/cognitive state, behavior, and activities of daily living. The scores range from 1 (marked improvement) to 7 (marked worsening).
Time frame: Baseline and Week 24
Population: ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil SR 23 mg | Overall Change From Baseline in Modified CIBIC+ to Week 24 | 4.23 Scores on a scale | Standard Deviation 1.07 |
| Donepezil IR 10 mg | Overall Change From Baseline in Modified CIBIC+ to Week 24 | 4.29 Scores on a scale | Standard Deviation 1.07 |
Secondary
Change From Baseline to Week 24 in ADCS-ADL Total Score
The ADCS-ADL (Alzhemier's Disease Cooperative Study-Activities of Daily Living) is a 19-item assessment scale used to measure a patient's basic functional abilities, such as walking, grooming, and bathing.Scores range from 0 to 54, with a higher score indicating greater functional ability.
Time frame: Baseline and Week 24
Population: ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil SR 23 mg | Change From Baseline to Week 24 in ADCS-ADL Total Score | -1.2 Scores on a scale | Standard Deviation 6.83 |
| Donepezil IR 10 mg | Change From Baseline to Week 24 in ADCS-ADL Total Score | -1.2 Scores on a scale | Standard Deviation 6.78 |
Secondary
Change From Baseline to Week 24 in MMSE Total Score
The MMSE (Mini-Mental State Examination) is a 30-item test that evaluates 5 domains of cognitive function (orientation to time and place, immediate and delayed recall, attention, calculation, and language). The scores range from 0 (most impaired) to 30 (no impaiment).
Time frame: Baseline and Week 24
Population: ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil SR 23 mg | Change From Baseline to Week 24 in MMSE Total Score | 0.6 Scores on a scale | Standard Deviation 2.93 |
| Donepezil IR 10 mg | Change From Baseline to Week 24 in MMSE Total Score | 0.4 Scores on a scale | Standard Deviation 3.2 |