Synopsis of Study Results
Name of Sponsor /Company

Name of Finished ProductName of Active Ingredient
Title of Study
Investigators
Study Centre(s)Publication (reference)
Studied PeriodDaiichi Sankyo Co., Ltd.
Memantine hydrochloride
Confirmatory randomized, double-blind, placebo-controlled,parallel-group study of SUN Y7017 (memantine hydrochloride) inpatients with mild to moderate dementia of the Alzheimer’s type
Takashi Asada Total 67 investigators
Tsukuba University Hospital Total 63 centers
NoneOctober 11, 2003 to December 5, 2007

(Date of first subject enrolled todate of last subject completed)

Phase of Development
Objectives

Methodology
Number of Patients (plannedand analyzed)

Diagnosis and Main Criteria
for Inclusion

Test Product, Dose and Modeof Administration, Batch
NumberDuration of Treatment
Reference Therapy, Dose andMode of Administration,
Batch Number
Criteria for Evaluation

Phase IIITo examine the dose-response relationship of memantinehydrochloride in mild to moderate dementia of the Alzheimer’s type,determine the recommended dose, and verify the superiority toplacebo, and also evaluate the safety of memantine hydrochloride.
A double-blind, parallel-group study, comparing placebo (Group P),
memantine hydrochloride 10 mg (Group L) and 20 mg (Group H)(Planned) 180 patients per group, total 540 patients(Analyzed)
Safety analysis set:
564 patients (186 in Group P, 190 in Group L, 188 in Group H)
Efficacy analysis set:
557 patients (180 in Group P, 190 in Group L, 187 in Group H)
Target disease：dementia of the Alzheimer’s type
Inclusion criteria：• Patients diagnosed with probable Alzheimer’s Disease according tothe NINCDS-ADRDA criteria• Patients with an MMSE score between 10 and 23• Patients with a CDR (Clinical Dementia Rating) score of “1=milddementia” or “2=moderate dementia”• Patients aged 50 years or over at the time of consent
Exclusion criteria：• Patients with neurodegenerative disorder with dementia of any
other type than Alzheimer’s type• Patients with systemic disease with dementia• Patients with significant psychological disease determinedaccording to DSM-IV diagnostic criteria• Patients who participated in any previous clinical study ofmemantine hydrochloride• Patients with a history of severe drug allergy• Patients with drug dependence or alcoholism
Memantine hydrochloride 10 mg or 20 mg orally once daily
Batch number：3309、3310、4Y19、4Y20
24 weeks
Placebo orally once daily
Batch number：3306、3307、3308、4Y16、4Y18、5220、5221
Efficacy endpoints
Primary endpoints: ADAS-J cog., CIBIC-plus (ADCS-CGIC)
Secondary endpoints: DAD, Caregiver-rated Crichton Scale , MMSE,
CDR

1/3

Statistical Method

Summary - Conclusion

Safety endpoints
Adverse events, adverse drug reactions
Efficacy
The efficacy was analyzed using the Full Analysis Set (FAS), and theprimary analysis was the LOCF analysis using the FAS. The level ofsignificance was 5% two-sided. However, in analysis using themaximum contrast method, a significace level of 2.5% (one-sided)
was adopted.
1) Primary endpoints
ADAS-J cog.: The change in total score from the baseline of the
double-blind period to Week 24 of treatment (change in score) wascalculated for each of Groups P, L, and H, with comparison of the dose
responsiveness across the three groups, as well as investigation of thesuperiority of the memantine hydrochloride group (Groups L and H)
to the placebo group.
CIBIC-plus: The overall assessment (global change) at Week 24 oftreatment was examined using the contrast test, with comparison ofthe dose responsiveness across the three groups, as well as
investigation of the superiority of the memantine hydrochloride groups
to the placebo group.
2) Secondary endpoints
For individual total scores of the DAD, Caregiver-rated Crichton
Scale, MMSE, and CDR, as the same method of ADAS-J cog. thechange from the baseline of the double-blind period to Week 24 oftreatment (change in score) was calculated in each treatment group,with comparison of the dose responsiveness across the three groups
using contrast test, as well as investigation of the superiority of thememantine hydrochloride groups to the placebo group.
SafetyThe incidences of adverse events and adverse reactions werecalculated by treatment group, with comparison of the dose
responsiveness in the incidences across the three groups using
Cochran-Armitage test.
Efficacy
As for the ADAS-J cog., the change in score of Week 24 was1.80±0.34（Least-squares mean±SE） in Group P, 0.55±0.33 in GroupL, and 1.45±0.34 in Group H. The contrast test with contrast
coefficients of (−1, 0, 1) demonstrated p=0.5863 and that with (−2, 1,1) demonstrated p=0.0785, neither of which showed significantdifference. An analysis using the t-test showed statistically significant
difference for Group L compared to Group P (p=0.0088).
As for the CIBIC-plus, the global change at Week 24 of treatment was
4.53±1.04（Mean±SD） in Group P, 4.30±1.08 in Group L, and
4.28±0.99 in Group H. The contrast test with contrast coefficients of(−2, 1, 1) demonstrated statistically significant difference with
p=0.0197, thereby confirming the dose-response relationship. Ananalysis using the t-test showed statistically significant differences forboth Group L (p=0.0417) and Group H (p=0.0222) compared to GroupP.
As for the DAD, the contrast test of the change in score (LOCFanalysis) with contrast coefficients of (−1, 0, 1) demonstrated
p=0.6266 and that with (−2, 1, 1) demonstrated p=0.6219, neither ofwhich showed significant difference.
As for the Caregiver-rated Crichton Scale, the contrast test of thechange in score with contrast coefficients of (−1, 0, 1) demonstrated
p=0.0191 and that with (−2, 1, 1) demonstrated p=0.0140, thereby

2/3confirming the dose-response relationship.
As for the MMSE, the contrast test of the change in score with
contrast coefficients of (−1, 0, 1) demonstrated p=0.0006, and thatwith (−2, 1, 1) demonstrated p=0.0001, thereby confirming thedose-response relationship.
As for the CDR-SB (CDR-Sum of the Boxes: total score for individual
CDR items), the contrast test of the change in score with contrast
coefficients of (−1, 0, 1) demonstrated p=0.1152, and that with (−2, 1,1) demonstrated p=0.0582, neither of which showed significant
difference.

Date of Report

SafetyThe incidences of adverse events and adverse reactions did not differ
across the three treatment groups.
Feb.14, 2011

3/3