SYNOPSIS
Name of Sponsor/CompanyDaiichi Sankyo Co., Ltd.

Name of Finished ProductMemary®

Name of Active Ingredient

Memantine hydrochloride

Title of Study

Clinical Study of SUN Y7017 (Memantine Hydrochloride) inCombination with Donepezil Hydrochloride in Patients with
Moderate to Severe Alzheimer's disease.

Investigators

Taira Oe, and 175 other investigators

Study Centre(s)Department of Neuropsychiatry, Oe Hospital, and 142 other centers

Publication (reference)

Geriat. Med. 2016; 54(11): 1147-1158

Geriat. Med. 2017; 55(2): 232

Studied Period

Date of informed consent of the first subject: 28 Feb 2012
Date of final observation: 10 Mar 2016

Phase of Development

Phase 4Objectives

To evaluate the efficacy and safety of memantine hydrochloride atan oral dose of 20 mg once daily for 24 weeks in patients withmoderate to severe Alzheimer's disease receiving treatment with
donepezil hydrochloride in a placebo-controlled, double-blind,parallel-group study design.

Methodology

Study design: Multicenter, randomized, double-blind,placebo-controlled, parallel-group comparative study

Number of Patients (plannedPlanned:500and analyzed)

Analyzed:546

Diagnosis and Main CriteriaDiagnosis:Patients with moderate to severe AD who has been

for Inclusion

taking cholinesterase inhibitors.
Inclusion Criteria:
1. Patients diagnosed with dementia of Alzheimer's type on theDSM-IV-TR and probable Alzheimer' disease on
NINCDS-ADRDA diagnostic criteria.
2. Patients diagnosed with Alzheimer's disease on CT or MRI
intracerebral scans.
3. Patients with MMSE score between 1 and 14.
4. Patients receiving cholinesterase inhibitors continuously before
the start of the screening period.
Annotation; donepezil hydrochloride must be taken for at least
4 weeks before the start of the screening period.
Age: 50 years old or more

Sex: BothExclusion Criteria:
1. Patients with a coexisting dementia other than Alzheimer'sdisease.
2. Patients with serious neuropathy complications.
3. Patients with musculoskeletal diseases that will hamper
conduct of tests and observations in the present study.
4. Others, patients deemed not suitable to take part in the present
study by the investigator.
Test Product, Dose and Mode

The starting dose is 5mg once daily. The dose should be increasedof Administration, Batchin 5mg increments per week to 20mgNumber

Batch Number:Memantine hydrochloride 5 mg tablet (S7017F1S10T01,RR-1011, ZJ-2013)Memantine hydrochloride 10 mg tablet (S7017F1S10T02,ZK-0011, ZK-0020)

Duration of Treatment

12-week run-in period (Period 1) and 24-week double-blind period(Period 2)

Reference Therapy, Dose and

The placebo is administered once daily.

Mode

Batch Number:ofAdministration,

Batch Number

Memantinehydrochloride

5mg

tabletplacebo(S7017F1S10T03, Y7017F1H12T01, Y7017F1H13T01)
Memantinehydrochloride(S7017F1S10T04,

10mg

S7017F1S10T05,tablet

placebo

Y7017F1H12T02,Y7017F1H13T02, Y7017F1H13T03)
Criteria for Evaluation

EfficacyPrimary endpoint

Evaluation of cognitive function (Changes in theSIB-J score from baseline score (Week 24 - Week0))

Secondary endpoints


Evaluation

ofbehavioralandpsychologicalsymptoms of dementia and Evaluation by caregiver(Changes in the Behave-AD score or Crichtonscore from baseline score (Week 24 - Week 0))
Statistical Method

The efficacy analysis was performed by imputing missing
data using the last observation carried forward (LOCF)

approach using the FAS. As the analysis of efficacy, theanalysis of covariance (ANCOVA) on the changes in theSIB-J score (Week 24 – Week 0) in the FAS (LOCF) was
performed with the score at Week 0 and daily dose of
donepezil hydrochloride as covariates and treatment group as
an independent factor at a significance level of 0.05(two-sided)

toverify

thesuperiorityof

memantinehydrochloride at an oral dose of 20 mg once daily for 24
weeks over placebo. The adjustedmean and the 95%
confidence

interval(CI)ofdifferences(memantinehydrochloride group – placebo group; the same hereinafter)
were calculated.
For secondary endpoint, the same analyses were performed asin the primary endpoint.

The changes in the SIB-J score at Week 24 – Week 0 in theFAS (LOCF) were also analyzed using the Wilcoxon rank
sum test at a significance level of 0.05 (two-sided).

Additional analyses was performed on the subject withMMSE score between 5 and 14 points (at the start of thedouble-blind period)

The incidence of adverse events was calculated by treatmentgroup. Adverse drug reaction data were similarly analyzed.
Adverse event terms were converted based on the Medical
Dictionary for Drug Regulatory Activities terminology(MedDRA). Adverse event data were classified by systemorgan class (SOC) and by preferred term (PT).

Summary - ConclusionNo statistically significant difference in the changes in theSIB-J score (Week 24 – Week 0) was found at Week 24 in theANCOVA (p=0.2437); however, the point estimate of thechanges in the SIB-J score was higher in the memantinehydrochloride group than in the placebo group at allmeasurement time points. The results of the normality test on
the changes in the SIB-J score (Week 24 – Week 0) revealed
that the changes in the SIB-J score (Week 24 – Week 0) in thisstudy were not normally distributed.

No statistically significant difference in the changes in theSIB-J score (Week 24 – Week 0) was found in the analysis
using the Wilcoxon rank sum test (p=0.0563), which does notrequire the assumption of normal distribution, either;
however, the P value was smaller than that obtained in theANCOVA.
In the analysis of the secondary endpoints, no statisticallysignificant differences were found in the changes in total
score of Behave-AD, which is the BPSD rating scale, and thetotal score of the Crichton Geriatric Behavioural Rating Scale
between the treatment groups.

As a result of the explorative analysis, a statisticallysignificant difference in the changes in the SIB-J score (Week24 – Week 0) was found in the subgroup of MMSE score
between 5 and 14 points, which is the same patient population
as in Japanese and overseas confirmatory studies in thedevelopment stage (Study IE3501 and Study MEM-MD-02,etc.) (p = 0.0165: Wilcoxon rank sum test), which indicatedthat combination therapy inhibited the reduction in cognitive
function as in Study MEM-MD-02.

No clear differences in the incidence or onset trend of adverse
events or serious adverse events reported in this study werefound between the treatment groups. Common adverse drug
reactions reported in the memantine hydrochloride group(combination group) were known adverse reactions tomemantine hydrochloride used as monotherapy, and none of
the results indicated signs etc. suggesting new safety concerns
about memantine hydrochloride used in combination with
donepezil hydrochloride.

Date of Report

15, Dce, 2017