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

• ClinicalTrials.gov Identifier: NCT02097056
• Recruitment Status: Completed
• First Posted: March 26, 2014
• Results First Posted: June 27, 2016
• Last Update Posted: June 27, 2016
• Sponsor: Eisai Korea Inc.
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Korea Inc. )

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Alzheimer's Disease
• Intervention: Drug: Donepezil HCL
• Enrollment: 171

Participant Flow

Recruitment Details
Pre-assignment Details	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
Reason Not Completed
Protocol Violation	2
Withdrawal by Subject	15
Lost to Follow-up	2
Adverse Event	37
Other	2

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 Number of Baseline Participants		170
Baseline 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.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	170 participants
		74.82 (7.18)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	170 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.
Overall Number of Participants Analyzed	170
Measure Type: Number; Unit of Measure: Percentage of participants
AEs	67.65
ADRs	47.06
SAEs	7.06
Serious ADRs	0.59

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.
Overall Number of Participants Analyzed	150
Mean (Standard Deviation); Unit of Measure: Scores on a scale
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.
Overall Number of Participants Analyzed	150
Mean (Standard Deviation); Unit of Measure: Scores on a scale
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 (%)
Total	--/--
Serious Adverse Events
	Donepezil Hydrochloride
	Affected / at Risk (%)
Total	12/170 (7.06%)
Gastrointestinal disorders
Diarrhoea † 1	1/170 (0.59%)
General disorders
Gait disturbance † 1	1/170 (0.59%)
Infections and infestations
Pneumonia † 1	1/170 (0.59%)
Injury, poisoning and procedural complications
Femur fracture † 1	2/170 (1.18%)
Rib fracture † 1	2/170 (1.18%)
Ankle fracture † 1	1/170 (0.59%)
Cervical vertebral fracture † 1	1/170 (0.59%)
Ligament injury † 1	1/170 (0.59%)
Lumbar vertebral fracture † 1	1/170 (0.59%)
Metabolism and nutrition disorders
Decreased appetite † 1	1/170 (0.59%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Donepezil Hydrochloride
	Affected / at Risk (%)
Total	109/170 (64.12%)
Cardiac disorders
Atrioventricular block second degree † 1	2/170 (1.18%)
Bradycardia † 1	1/170 (0.59%)
Eye disorders
Eye pain † 1	1/170 (0.59%)
Gastrointestinal disorders
Nausea † 1	21/170 (12.35%)
Vomiting † 1	19/170 (11.18%)
Diarrhoea † 1	11/170 (6.47%)
Dyspepsia † 1	5/170 (2.94%)
Abdominal discomfort † 1	2/170 (1.18%)
Gastrointestinal disorder † 1	2/170 (1.18%)
Abdominal pain † 1	2/170 (1.18%)
Faecal incontinence † 1	2/170 (1.18%)
Constipation † 1	1/170 (0.59%)
Dental caries † 1	1/170 (0.59%)
General disorders
Asthenia † 1	4/170 (2.35%)
Fatigue † 1	3/170 (1.76%)
Gait disturbance † 1	1/170 (0.59%)
Chills † 1	1/170 (0.59%)
Oedema † 1	1/170 (0.59%)
Pain † 1	1/170 (0.59%)
Immune system disorders
Hypersensitivity † 1	1/170 (0.59%)
Infections and infestations
Nasopharyngitis † 1	1/170 (0.59%)
Periodontitis † 1	1/170 (0.59%)
Pharyngitis † 1	1/170 (0.59%)
Urinary tract infection † 1	1/170 (0.59%)
Injury, poisoning and procedural complications
Ankle fracture † 1	1/170 (0.59%)
Contusion † 1	2/170 (1.18%)
Investigations
Electrocardiogram QT prolonged † 1	5/170 (2.94%)
Weight decreased † 1	5/170 (2.94%)
Blood glucose increased † 1	2/170 (1.18%)
Glucose urine present † 1	2/170 (1.18%)
Alanine aminotransferase increased † 1	1/170 (0.59%)
Aspartate aminotransferase increased † 1	1/170 (0.59%)
Blood cholesterol increased † 1	1/170 (0.59%)
Blood creatine phosphokinase increased † 1	1/170 (0.59%)
Blood triglycerides increased † 1	1/170 (0.59%)
Electrocardiogram ST segment elevation † 1	1/170 (0.59%)
Electrocardiogram T wave abnormal † 1	1/170 (0.59%)
Metabolism and nutrition disorders
Decreased appetite † 1	16/170 (9.41%)
Hyperlipidaemia † 1	2/170 (1.18%)
Hypophagia † 1	2/170 (1.18%)
Hyperglycaemia † 1	1/170 (0.59%)
Hypoglycaemia † 1	1/170 (0.59%)
Hyponatraemia † 1	1/170 (0.59%)
Nervous system disorders
Dizziness † 1	13/170 (7.65%)
Lethargy † 1	8/170 (4.71%)
Headache † 1	6/170 (3.53%)
Somnolence † 1	6/170 (3.53%)
Sedation † 1	2/170 (1.18%)
Tremor † 1	2/170 (1.18%)
Dreamy state † 1	1/170 (0.59%)
Drooling † 1	1/170 (0.59%)
Dysarthria † 1	1/170 (0.59%)
Facial spasm † 1	1/170 (0.59%)
Hypersomnia † 1	1/170 (0.59%)
Paraesthesia † 1	1/170 (0.59%)
Psychiatric disorders
Anxiety † 1	6/170 (3.53%)
Insomnia † 1	5/170 (2.94%)
Aggression † 1	4/170 (2.35%)
Behavioural and psychiatric symptoms of dementia † 1	3/170 (1.76%)
Depression † 1	3/170 (1.76%)
Irritability † 1	2/170 (1.18%)
Sleep disorder † 1	2/170 (1.18%)
Compulsions † 1	1/170 (0.59%)
Compulsive hoarding † 1	1/170 (0.59%)
Confusional state † 1	1/170 (0.59%)
Delusion † 1	1/170 (0.59%)
Depressed mood † 1	1/170 (0.59%)
Disinhibition † 1	1/170 (0.59%)
Nightmare † 1	1/170 (0.59%)
Restlessness † 1	1/170 (0.59%)
Renal and urinary disorders
Urinary incontinence † 1	6/170 (3.53%)
Acute kidney injury † 1	1/170 (0.59%)
Enuresis † 1	1/170 (0.59%)
Incontinence † 1	1/170 (0.59%)
Nocturia † 1	1/170 (0.59%)
Pollakiuria † 1	1/170 (0.59%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	1/170 (0.59%)
Hiccups † 1	1/170 (0.59%)
Nasal discomfort † 1	1/170 (0.59%)
Productive cough † 1	1/170 (0.59%)
Rhinitis allergic † 1	1/170 (0.59%)
Skin and subcutaneous tissue disorders
Hyperhidrosis † 1	2/170 (1.18%)
Cold sweat † 1	2/170 (1.18%)
Vascular disorders
Hypertension † 1	2/170 (1.18%)
Pallor † 1	1/170 (0.59%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA 18.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

 

Results Point of Contact

• Name/Title: Youngji Pyo
• Organization: Eisai Korea Inc.
• Phone: +82-2-3451-5533
• EMail: y-pyo@eisaikorea.com

• Responsible Party: Eisai Inc. ( Eisai Korea Inc. )
• ClinicalTrials.gov Identifier: NCT02097056
• Other Study ID Numbers: ART-M082-401
• First Submitted: March 24, 2014
• First Posted: March 26, 2014
• Results First Submitted: March 30, 2016
• Results First Posted: June 27, 2016
• Last Update Posted: June 27, 2016