Memantine treatment for Japanese patients with moderate to severe Alzheimer’s disease: a meta-analysis of double-blind, randomized, placebo-controlled trials

Figures & data

Table 1 Characteristics of included double-blind, randomized, placebo-controlled trials

Study name (study design)	Total, n	Study methods 1. Duration of study 2. Analyzed population 3. Sponsorship	Patients 1. Diagnosis 2. Inclusion criteria 3. Study defined disease severity	Age (mean ± SD)	Male (%)	Baseline cognitive function scales (mean ± SD)	Intervention (mean dose, mg/d)	Study results 1. Cognitive functions 2. Behavioral disturbances
Kitamura et al (2011)^Citation13 (DBRPCT)	315	1. 24 weeks 2. FAS 3. Industry	1. AD, DSM-IV, and NINCDS-ADRDA 2. Age ≥50 years, MMSE 5–14, FAST 6a-7a 3. Moderate to severe	73.3±9.4	29.3	SIB: 71.1±17.8, MMSE: 10.1±3.0	MEM (20 or 10, fixed) vs PBO	1. SIB-J: MEM20.PBO 2. NPI: MEM20=PBO
Nakamura et al (2011)^Citation14 (DBRPCT)	432	1. 24 weeks 2. FAS 3. Industry	1. AD, DSM-IV, and NINCDS-ADRDA 2. Age ≥50 years, MMSE 5–14, FAST 6a-7a 3. Moderate to severe	74.6±8.4	35.7	SIB: 71.0±17.9, MMSE: 9.9±3.0	MEM (20, fixed) vs PBO	1. SIB-J: MEM20.PBO 2. Behave-AD: MEM20=PBO
IE2201^Table Footnotea,^Citation11 (unpublished study, DBRPCT)	35	1. 24 weeks 2. FAS 3. Industry	1. AD, NINCDS-ADRDA 2. Age ≥50 years, MMSE 10–20 3. Moderate	73.2±6.7	54.3	ADAS-cog: 25.7, MMSE: 15.6	MEM (20, fixed)+ChEIs (NR, DON=83%) vs MEM 10 (fixed)+ChEIs (NR, DON=91%) vs PBO+DON (NR, DON=100%)	1. NR 2. NR
Nakamura et al (2016)^Citation15 (DBRPCT)	546	1. 24 weeks 2. FAS 3. Industry	1. AD, DSM-IV-TR, and NINCDS-ADRDA 2. Age ≥50 years, MMSE 1–14, SIB 30–85, patients receiving a ChEI for ≥36 weeks 3. Moderate to severe	78.5±7.8	27.2	SIB: 77.0±13.6, MMSE: 10.8±3.7	MEM (20, fixed)+DON (6.9) vs PBO+DON (6.9)	1. SIB-J: MEM20=PBO 2. Behave-AD: MEM20=PBO

Note:

a This study is presented in the Clinical Study Report or approval application (https://www.pmda.go.jp/).¹¹

Abbreviations: AD, Alzheimer disease; ADAS-cog, Alzheimer’s disease assessment scale-cognitive subscale; ChEI, cholinesterase inhibitor; DBRPCT, double-blind randomized, placebo-controlled trial; DON, donepezil; DSM-IV(-TR), diagnostic and statistical manual of mental disorders fourth edition (-text revision); FAS, full analysis set; MEM, memantine; MMSE, mini mental state examination; n, number of patients; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; NR, not report; NPI, neuropsychiatric inventory; PBO, placebo; SIB, severe impairment battery.

Figure 1 Cognitive function and behavioral disturbances.

Figure 2 Behavioral pathology in Alzheimer’s Disease Rating Scale subscale.

Table 2 Safety outcomes

	N	n	I^2	RR (95% CIs)	P-value
All-causes discontinuation	4	1,328	31%	0.98 (0.71, 1.37)	0.93
Discontinuation due to adverse events	4	1,328	45%	0.88 (0.51, 1.53)	0.66
Discontinuation due to death	4	1,328	0%	1.70 (0.51, 5.72)	0.39
Abdominal pain	2	747	0%	1.07 (0.21, 5.36)	0.93
Abnormal behavior	4	1,328	0%	0.66 (0.22, 1.96)	0.45
Abnormal gait	3	782	0%	0.90 (0.29, 2.82)	0.86
Aggression	2	747	0%	0.90 (0.17, 4.62)	0.90
Agitation	2	747	0%	1.06 (0.30, 3.72)	0.93
AD	3	782	0%	0.45 (0.22, 0.91)	0.03 (NNH=33)
Anorexia/appetite decreased	3	1,293	0%	1.40 (0.68, 2.85)	0.36
Anxiety	2	747	0%	0.56 (0.23, 1.36)	0.20
Aphasia	2	747	0%	2.12 (0.22, 20.30)	0.51
At least one adverse event	4	1,328	0%	1.04 (0.98, 1.11)	0.22
At least one serious adverse event	3	1,293	0%	0.92 (0.65, 1.30)	0.63
Back pain	4	1,328	18%	0.92 (0.43, 1.99)	0.84
Cardiac failure	3	1,293	0%	1.57 (0.27, 9.03)	0.61
Cataract	3	782	0%	0.80 (0.28, 2.31)	0.68
Constipation	3	1,293	0%	1.20 (0.83, 1.73)	0.33
Dehydration	3	1,293	0%	1.23 (0.41, 3.70)	0.71
Delirium	2	747	0%	2.04 (0.27, 15.13)	0.49
Delusion/hallucination	3	782	0%	1.17 (0.31, 4.31)	0.82
Diabetes	3	782	0%	3.84 (0.68, 21.63)	0.13
Diarrhea	4	1,328	0%	0.78 (0.46, 1.32)	0.35
Dizziness/vertigo	4	1,328	0%	1.84 (0.92, 3.66)	0.08
Edema	3	782	6%	0.71 (0.33, 1.52)	0.38
Fall	4	1,328	0%	0.88 (0.59, 1.31)	0.53
Fatigue	2	747	0%	0.71 (0.07, 6.77)	0.76
Fever	3	782	0%	1.08 (0.51, 2.27)	0.84
Headache	2	747	0%	1.07 (0.40, 2.84)	0.89
Insomnia	3	1,293	0%	1.29 (0.76, 2.21)	0.35
Irritability	2	747	0%	3.54 (0.42, 30.11)	0.25
Muscle weakness	2	747	0%	1.18 (0.15, 9.56)	0.88
Nasopharyngitis	4	1,328	17%	0.94 (0.69, 1.29)	0.72
Nausea	3	782	26%	0.84 (0.15, 4.77)	0.84
Parkinsonism	2	467	0%	2.83 (0.32, 24.99)	0.35
Rash	2	747	34%	1.16 (0.14, 9.74)	0.89
Renal failure	2	747	0%	1.18 (0.15, 9.56)	0.88
Seizure	3	1,293	0%	1.14 (0.22, 5.91)	0.87
Somnolence	3	1,293	0%	2.87 (1.09, 7.55)	0.03 (NNH=ns)
Vomiting	3	782	7%	0.62 (0.27, 1.43)	0.26
Weight decreased	2	747	0%	1.08 (0.49, 2.39)	0.85
Weight increased	2	747	0%	1.78 (0.46, 6.86)	0.40

Notes: Bold face: memantine was associated with a lower incidence of the outcome than the control. Italic face: memantine was associated with a higher incidence of the outcome than the control.

Abbreviations: AD, Alzheimer’s disease; N, number of studies; n, number of patients; NNH, number needed to harm; ns, not significant; RR, risk ratio.

KitamuraSHommaANakamuraYYoshimuraIPhase II study of memantine hydrochloride, a new NMDA receptor antagonist, in patients with moderate to severe Alzheimer’s disease – Efficacy, safety and recommended doseJapanese Journal of Geriatric Psychiatry2011224453463

 Google Scholar

NakamuraYHommaAKitamuraSYoshimuraIPhase III study of memantine hydrochloride, a new NMDA receptor antagonist, in patients with moderate to severe Alzheimer’s disease – Efficacy and safetyJapanese Journal of Geriatric Psychiatry2011224464473

 Google Scholar

Pharmaceuticals and Medical Devices Agency Available from: http://www.pmda.go.jp/drugs/2011/P201100018/43057400_22300AMX00423_K101_2.pdfAccessed September 5, 2018

 Google Scholar

NakamuraYKitamuraSNagakuboTKobayashiMHommaAStudy of Memantine Hydrochloride in Combination with Donepezil Hydrochloride in Patients with Moderate to Severe Alzheimer’s disease – Efficacy and safetyJapanese Journal of Geriatric Medicine2016541111471158

 Google Scholar