SAVE: Safety and Efficacy of Donepezil HCl 23 mg in Patients With Moderate to Severe Alzheimer's Disease

• Sponsor: Eisai Korea Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02097056
• Collaborator: (none)
• Enrollment: 171
• Locations: 13
• Arm: 1
• Duration (Months): 14.9
• Patients Per Site: 13.2
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a multi-center, open-label, single-arm, prospective, phase IV trial, evaluating safety and efficacy of donepezil hydrochloride in patients with moderate to severe Alzheimer's disease.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Donepezil HCL	Phase 4

Detailed Description

This study consisted of pre-treatment and treatment phase. Pre-treatment phase was approximately 4 weeks including the screening and baseline process. In treatment phase, about 190 subjects received Donepezil HCl 23 mg once daily for 24 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 171 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Donepezil HCl 23 mg in Patients With Moderate to Severe Alzheimer's Disease
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: May 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: donepezil HCl 23 mg Donepezil HCl 23 mg once daily, just before bed, for 24 weeks	Drug: Donepezil HCL; Donepezil HCl 23 mg once daily, just before bed, for 24 weeks

Outcome Measures

Primary Outcome Measures

1. Overall Summary of Adverse Events (AEs) [Baseline (Day 1) up to Week 24]

   Safety of study drug was assessed by clinical laboratory assessments, vital signs, weight, 12-lead electrocardiogram (ECG), physical and neurological examination. Treatment-Emergent Adverse Events (TEAEs) were defined as any event not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Serious adverse events were defined as AEs that led to or were life-threatening, resulted in or prolonged hospitalization, caused important or long-lasting disability, caused congenital abnormality or malformation, or resulted in death. Adverse drug reactions were defined as any harmful or unintended reaction to study treatment and were considered possibly related or probably related to study drug. Specific AEs and SAEs due to changes in clinical laboratory assessments, vital signs, weight, ECG, and physical and neurological exam are listed in the safety section.

Secondary Outcome Measures

1. Change From Baseline in the Mini-Mental State Examination (MMSE) Score [Baseline, Week 12, and Week 24 (Final visit)]

   The MMSE was used to measure cognitive impairment. The MMSE can evaluate overall cognitive function, and is widely used for the assessment of cognitive impairment in dementia patients. The questionnaire consists of 11 items, and each item aims to evaluate different cognitive domains such as orientation, memory, attention, and construction. The score ranged from 0 to 30, with a higher score indicating better function. A positive change score indicated improvement from baseline. The mean change was analyzed by Wilcoxon's signed rank test.

2. Change From Baseline in the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Distress Total Scores [Baseline, Week 12, and Week 24 (Follow up visit)]

   The NPI-Q assessed twelve behavioral domains common in dementia including; hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep/night-time behavior change, and appetite/eating change. The questionnaire is given by the clinician to the patient's caregiver who was asked if the behavior described is present in the patient. If "Yes", the informant then rates both the Severity of the symptoms present within the last month on a 3-point scale (1 = mild, 2= moderate, and 3= severe) and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale (0 = not distressing at all, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe, and 5 = extreme or very severe). The total severity score represents the sum of individual scores and ranges from 0 to 36. The total distress score represents the sum of individual symptom scores and ranges from 0 to 60.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Male or female aged 45 to 90 years

2. Patients have eligible conditions of dementia diagnosis listed in DSM-IV

3. Diagnosed as a probable Alzheimer's Disease patient according to NINCDS-ADRDA criteria

4. At the timing of screening, MMSE less than or equal to 20 AND CDR greater than or equal to 2 OR GDS greater than or equal to 4

5. Patients, who have been taking stable donepezil 10 mg for 3 months or longer before the start of the study (screening visit), are evaluated as eligible to take donepezil 23 mg by investigator

6. Patients who have not received any other medications for AD such as AChE inhibitors at least for 3 months prior to the screening visit excluding donepezil hydrochloride (However, concomitant use of memantine is allowed if taken at stable dose that are less than or equal to the approved dose range for at least 3 months prior to screening)

7. Medicines for cerebral activation such as Gingko Biloba is allowed to be taken if the patient has received it as stable dose for 3 months prior to the screening visit

Exclusion Criteria

1. Patients who have been participated in any other clinical trial 3 months prior to the screening visit

2. Patients who are having any severe psychiatric disorder or schizophrenia

3. Patients who are having a neurological disorder other than AD which affect the subject's cognition or ability to assess the cognition

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Chungju	Chungcheongbuk-do	Korea, Republic of
2		Ansan	Gyeonggi-do	Korea, Republic of
3		Buchoen	Gyeonggi-do	Korea, Republic of
4		Seongnam	Gyeonggi-do	Korea, Republic of
5		Jinju	Gyeongsangnam-do	Korea, Republic of
6		Iksan	Jeollabuk-do	Korea, Republic of
7		Hwasun	Jeollanam-do	Korea, Republic of
8		Busan		Korea, Republic of
9		Daegu		Korea, Republic of
10		Daejeon		Korea, Republic of
11		Incheon		Korea, Republic of
12		Jeju		Korea, Republic of
13		Seoul		Korea, Republic of

Sponsors and Collaborators

• Eisai Korea Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Korea Inc.
• ClinicalTrials.gov Identifier: NCT02097056
• Other Study ID Numbers: ART-M082-401
• First Posted: Mar 26, 2014
• Last Update Posted: Jun 27, 2016
• Last Verified: May 1, 2016

• Keywords provided by Eisai Korea Inc.: Alzheimer's disease
• Additional relevant MeSH terms: Alzheimer Disease; Donepezil

Study Results

Participant Flow

Pre-assignment Detail	Out of the 171 participants enrolled into the study, 1 was not treated resulting in 170 participants in the safety population.

Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
Period Title: Overall Study
STARTED	171
ParticipantsTreated	170
COMPLETED	113
NOT COMPLETED	58

Baseline Characteristics

Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
Overall Participants	170
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	74.82 (7.18)
Sex: Female, Male (Count of Participants)
Female	123 72.4%
Male	47 27.6%

Outcome Measures

1. Primary Outcome

Title	Overall Summary of Adverse Events (AEs)
Description	Safety of study drug was assessed by clinical laboratory assessments, vital signs, weight, 12-lead electrocardiogram (ECG), physical and neurological examination. Treatment-Emergent Adverse Events (TEAEs) were defined as any event not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. Serious adverse events were defined as AEs that led to or were life-threatening, resulted in or prolonged hospitalization, caused important or long-lasting disability, caused congenital abnormality or malformation, or resulted in death. Adverse drug reactions were defined as any harmful or unintended reaction to study treatment and were considered possibly related or probably related to study drug. Specific AEs and SAEs due to changes in clinical laboratory assessments, vital signs, weight, ECG, and physical and neurological exam are listed in the safety section.
Time Frame	Baseline (Day 1) up to Week 24

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of study treatment and had at least one postbaseline safety assessment.

Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
Measure Participants	170
AEs	67.65 39.8%
ADRs	47.06 27.7%
SAEs	7.06 4.2%
Serious ADRs	0.59 0.3%

2. Secondary Outcome

Title	Change From Baseline in the Mini-Mental State Examination (MMSE) Score
Description	The MMSE was used to measure cognitive impairment. The MMSE can evaluate overall cognitive function, and is widely used for the assessment of cognitive impairment in dementia patients. The questionnaire consists of 11 items, and each item aims to evaluate different cognitive domains such as orientation, memory, attention, and construction. The score ranged from 0 to 30, with a higher score indicating better function. A positive change score indicated improvement from baseline. The mean change was analyzed by Wilcoxon's signed rank test.
Time Frame	Baseline, Week 12, and Week 24 (Final visit)

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all participants who took at least one dose of study drug and had at least one baseline and at least one post-baseline assessment of the efficacy parameter. Twenty participants had no efficacy variables collected.

Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
Measure Participants	150
Change W12	-0.31 (2.76)
Change W24	-0.40 (2.75)

3. Secondary Outcome

Title	Change From Baseline in the Neuropsychiatric Inventory Questionnaire (NPI-Q) Severity and Distress Total Scores
Description	The NPI-Q assessed twelve behavioral domains common in dementia including; hallucinations, delusions, agitation/aggression, dysphoria/depression, anxiety, irritability, disinhibition, euphoria, apathy, aberrant motor behavior, sleep/night-time behavior change, and appetite/eating change. The questionnaire is given by the clinician to the patient's caregiver who was asked if the behavior described is present in the patient. If "Yes", the informant then rates both the Severity of the symptoms present within the last month on a 3-point scale (1 = mild, 2= moderate, and 3= severe) and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale (0 = not distressing at all, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe, and 5 = extreme or very severe). The total severity score represents the sum of individual scores and ranges from 0 to 36. The total distress score represents the sum of individual symptom scores and ranges from 0 to 60.
Time Frame	Baseline, Week 12, and Week 24 (Follow up visit)

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all participants who took at least one dose of study drug and had at least one baseline and at least one post-baseline assessment of the efficacy parameter. Twenty participants had no efficacy variables collected.

Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
Measure Participants	150
Change Week 12 (Severity)	0.33 (4.74)
Change Week 24 (Severity)	0.09 (5.67)
Change Week 12 (Distress)	0.19 (6.83)
Change Week 24 (Distress)	0.29 (7.60)

Adverse Events

Time Frame	AEs were collected from Day 1 through Week 24 of study.
Adverse Event Reporting Description	Safety population included all participants who received at least one dose of study treatment and had at least one postbaseline safety assessment. Summary and analysis of adverse events were analyzed using TEAEs.
Arm/Group Title	Donepezil Hydrochloride
Arm/Group Description	Donepezil hydrochloride (HCl) at 23 mg was administered once daily, just before bed, for 24 weeks.
All Cause Mortality
	Donepezil Hydrochloride
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Donepezil Hydrochloride
	Affected / at Risk (%)	# Events
Total	12/170 (7.1%)
Gastrointestinal disorders
Diarrhoea	1/170 (0.6%)
General disorders
Gait disturbance	1/170 (0.6%)
Infections and infestations
Pneumonia	1/170 (0.6%)
Injury, poisoning and procedural complications
Femur fracture	2/170 (1.2%)
Rib fracture	2/170 (1.2%)
Ankle fracture	1/170 (0.6%)
Cervical vertebral fracture	1/170 (0.6%)
Ligament injury	1/170 (0.6%)
Lumbar vertebral fracture	1/170 (0.6%)
Metabolism and nutrition disorders
Decreased appetite	1/170 (0.6%)
Other (Not Including Serious) Adverse Events
	Donepezil Hydrochloride
	Affected / at Risk (%)	# Events
Total	109/170 (64.1%)
Cardiac disorders
Atrioventricular block second degree	2/170 (1.2%)
Bradycardia	1/170 (0.6%)
Eye disorders
Eye pain	1/170 (0.6%)
Gastrointestinal disorders
Nausea	21/170 (12.4%)
Vomiting	19/170 (11.2%)
Diarrhoea	11/170 (6.5%)
Dyspepsia	5/170 (2.9%)
Abdominal discomfort	2/170 (1.2%)
Gastrointestinal disorder	2/170 (1.2%)
Abdominal pain	2/170 (1.2%)
Faecal incontinence	2/170 (1.2%)
Constipation	1/170 (0.6%)
Dental caries	1/170 (0.6%)
General disorders
Asthenia	4/170 (2.4%)
Fatigue	3/170 (1.8%)
Gait disturbance	1/170 (0.6%)
Chills	1/170 (0.6%)
Oedema	1/170 (0.6%)
Pain	1/170 (0.6%)
Immune system disorders
Hypersensitivity	1/170 (0.6%)
Infections and infestations
Nasopharyngitis	1/170 (0.6%)
Periodontitis	1/170 (0.6%)
Pharyngitis	1/170 (0.6%)
Urinary tract infection	1/170 (0.6%)
Injury, poisoning and procedural complications
Ankle fracture	1/170 (0.6%)
Contusion	2/170 (1.2%)
Investigations
Electrocardiogram QT prolonged	5/170 (2.9%)
Weight decreased	5/170 (2.9%)
Blood glucose increased	2/170 (1.2%)
Glucose urine present	2/170 (1.2%)
Alanine aminotransferase increased	1/170 (0.6%)
Aspartate aminotransferase increased	1/170 (0.6%)
Blood cholesterol increased	1/170 (0.6%)
Blood creatine phosphokinase increased	1/170 (0.6%)
Blood triglycerides increased	1/170 (0.6%)
Electrocardiogram ST segment elevation	1/170 (0.6%)
Electrocardiogram T wave abnormal	1/170 (0.6%)
Metabolism and nutrition disorders
Decreased appetite	16/170 (9.4%)
Hyperlipidaemia	2/170 (1.2%)
Hypophagia	2/170 (1.2%)
Hyperglycaemia	1/170 (0.6%)
Hypoglycaemia	1/170 (0.6%)
Hyponatraemia	1/170 (0.6%)
Nervous system disorders
Dizziness	13/170 (7.6%)
Lethargy	8/170 (4.7%)
Headache	6/170 (3.5%)
Somnolence	6/170 (3.5%)
Sedation	2/170 (1.2%)
Tremor	2/170 (1.2%)
Dreamy state	1/170 (0.6%)
Drooling	1/170 (0.6%)
Dysarthria	1/170 (0.6%)
Facial spasm	1/170 (0.6%)
Hypersomnia	1/170 (0.6%)
Paraesthesia	1/170 (0.6%)
Psychiatric disorders
Anxiety	6/170 (3.5%)
Insomnia	5/170 (2.9%)
Aggression	4/170 (2.4%)
Behavioural and psychiatric symptoms of dementia	3/170 (1.8%)
Depression	3/170 (1.8%)
Irritability	2/170 (1.2%)
Sleep disorder	2/170 (1.2%)
Compulsions	1/170 (0.6%)
Compulsive hoarding	1/170 (0.6%)
Confusional state	1/170 (0.6%)
Delusion	1/170 (0.6%)
Depressed mood	1/170 (0.6%)
Disinhibition	1/170 (0.6%)
Nightmare	1/170 (0.6%)
Restlessness	1/170 (0.6%)
Renal and urinary disorders
Urinary incontinence	6/170 (3.5%)
Acute kidney injury	1/170 (0.6%)
Enuresis	1/170 (0.6%)
Incontinence	1/170 (0.6%)
Nocturia	1/170 (0.6%)
Pollakiuria	1/170 (0.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/170 (0.6%)
Hiccups	1/170 (0.6%)
Nasal discomfort	1/170 (0.6%)
Productive cough	1/170 (0.6%)
Rhinitis allergic	1/170 (0.6%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	2/170 (1.2%)
Cold sweat	2/170 (1.2%)
Vascular disorders
Hypertension	2/170 (1.2%)
Pallor	1/170 (0.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.