SYNOPSIS
Name of sponsor/company

Daiichi Sankyo Co., Ltd.

Name of finished product

REZALTASⓇ COMBINATION TABLETS LD・COMBINATIONTABLETS HD

Name of active ingredientCS-866AZ (Olmesartan medoxomil/Azelnidipine)

Title of study

Phase III Study of CS-866AZ

Study centre(s)Seventeen sites in Japan

Publication (reference)

J. Clin. Therap. Med. 26: 63-79, 2010

Studied period

August 2007 to February 2008

Phase of development

Phase III

Objectives

The efficacy and safety of 12-week administration of CS-866AZ
were assessed in "patients with essential hypertension that wasinadequately contralled by monotherapy with angiotensin II
receptor blocker (ARB) or calcium channel blocker (CCB)" and in"patients with grade II essential hypertension."

Methodology

An open-label, uncontrolled, optional dose-titration, multicenter
study

Number of patients

Number of patients planned: 175(planned and analysed)

Number of patients analyzed:
Full analysis set; 315
Safety analysis set; 316

Diagnosis and main criteria

Main inclusion criteria:

for inclusion

・ Age ≥20 years
・ Satisfied 1. or 2. below
1.

Baseline BP during the run-in period (on monotherapy withan ARB or a CCB) was stable and fulfilled the criterion:"systolic BP ≥ 140 mmHg and < 180 mmHg, and diastolic BP≥ 90 mmHg and < 110 mmHg."

2.

Baseline BP during the run-in period (not taking any
antihypertensive drug) was stable and fulfilled the criterion:"Systolic BP ≥ 140 mmHg and < 180 mmHg and diastolic BP≥ 90 mmHg and < 110 mmHg" and either or both of "SystolicBP ≥ 160 mmHg" and "Diastolic BP ≥ 100 mmHg."

Main exclusion criteria:
・ Secondary or malignant hypertension
・ Myocardial infarction or cerebrovascular disorder・ Poorly controlled diabetis
Test product, dose and mode

Run-in period:of administration

Monotherapy with a low/high-dose ARB alone or a low/high-dose
CCB alone
No antihypertensive drug was administered in patients with grade
II essential hypertension
Treatment period:
High-dose ARB or high-dose CCB group: CS-866AZ-20/16 (20/16mg below) was administered.
Low-dose ARB or low-dose CCB group, grade II essential
hypertension group: CS-866AZ-10/8 (10/8 mg below) wasadministered. If sitting BP did not reach the target sitting BP, thedose was titrated to 20/16 mg.
Study drugs were administered orally once a day after breakfast.

Duration of treatment

Run-in period, 4 weeks; Treatment period, 12 weeks

Reference therapy

None

Criteria for evaluation

Efficacy (primary endpoint): The difference between sitting BP(systolic BP and diastolic BP) during the run-in period and that at
the end of treatment (ΔBP)
Safety: Adverse events (occurrence or exacerbation of subjective
symptoms/objective findings and abnormal changes in clinicallaboratory values)

Statistical method

Efficacy (primary endpoint): A linear model analysis wasperformed onΔBP between the value during the run-in period andthat at the end of treatment with the treatment group and BP during
the run-in period as factors. Also the adjusted mean of ΔBP and its
95% confidence interval were calculated for each treatment groupto assess the antihypertensive effect of the study drug
administration.
Safety: The number and percentage of patients who developed AEs
with a possible causal relationship to the study drug and all AEs
were determined.

Summary-conclusionsThe adjusted mean change in BP (Systolic BP/Diastolic BP) was asfollows: -15.9/-12.4 mmHg in the group of patients inadequatelycontrolled by high-dose ARB and given combination therapy withCS-866AZ; -16.8/-11.4 mmHg in the group of patients
inadequately controlled by low-dose ARB, given CS-866AZ;

-10.9/-9.0 mmHg in the group of patients inadequately controlled
by high-dose CCB and given CS-866AZ; -17.4/-12.0 mmHg inthe group of patients inadequately controlled by low-dose CCB,given CS-866AZ; and -23.0/-16.0 mmHg in the group of patientswith grade II hypertension given CS-866AZ. The antihypertensive
effect was also increased after dose titration from CS-866AZ 10/8
mg to CS-866AZ 20/16 mg.
In terms of safety, there was no increase in the incidence ofclinically important adverse events during the administration of
10/8 mg or 20/16 mg, or after dose titration from 10/8 mg to 20/16mg.
Based on the above results, the OLM/AZL combination
formulation, which has components with different mechanisms ofantihypertensive effect (ARB and CCB), was found to enable asafe and good antihypertensive effect and to be a useful therapeutic
alternative for patients with essential hypertension that wasinadequately controlled by monotherapy with ARB or CCB, andfor patients with stage II essential hypertension.
Date of report

October 14, 2010