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

Add-on, open-label, phase III study of CS-866AZ

Study centre(s)Sixteen sites in Japan

Publication (reference)

J. Clin. Therap. Med. 26: 47-62, 2010

Studied period

July 2006 to March 2008

Phase of development

Phase III

Objectives

1) and 2) were assessed in patients with essential hypertension thatwas inadequately controlled by monotherapy with olmesartan
medoxomil (OLM) or azelnidipine (AZL):
1) Efficacy and safety of 12-week co-administration of OLM andAZL
2) Safety of 1-year co-administration of OLM and AZL

Methodology

A multicenter, open-label study

Number of patients

Number of patients planned: 180(planned and analysed)

Number of patients analyzed:
Full analysis set; 208
Safety analysis set; 210

Diagnosis and main criteria

Main inclusion criteria:

for inclusion

・ Age ≥20 years
・ Baseline BP during the monotherapy period was stable andfulfilled the criterion: "systolic BP ≥ 140 mmHg and < 180mmHg, and diastolic BP ≥ 90 mmHg and < 110 mmHg."
・ The 24-hour BP determined by ambulatory blood pressure
monitoring (ABPM) during the monotherapy period met thecriterion: "systolic BP ≥ 135 mmHg and diastolic BP ≥ 80 mmHg."
Main exclusion criteria:
・ Secondary or malignant hypertension
・ Myocardial infarction or cerebrovascular disorder・ Night-shift workers

Test product, dose and mode

Monotherapy period : AZL 8 mg tablet, OLM 10 mg tablet, AZLof administration

16 mg tablet, OLM 20 mg tablet

Co-administration period: Co-administration of OLM 20 mg tablet
and AZL 16 mg tablet (OLM 20 mg/AZL 16 mg below),
Co-administration of OLM 10 mg tablet and AZL 8 mg tablet(OLM 10 mg/AZL 8 mg below). If sitting BP did not reach thetarget sitting BP, the dose was increased to OLM 20 mg/AZL 16mg.
Study drugs were administered orally once a day after breakfast.
Duration of treatment

Monotherapy period, 6 weeks; Co-administration period, 52 weeks

Reference therapy

NoneCriteria for evaluation

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

Statistical method

Efficacy (primary and main secondary endpoint): A linear model
analysis was performed on ΔBP at the co-administration periodwith the dose during the monotherapy period and BP during thesame period as factors. Also the adjusted mean of ΔBP and its 95%
confidence interval were calculated for each of the dose during themonotherapy period to assess the effect of the co-administrationcompared to that of monotherapy.
Safety: The number and percentage of patients who developed
adverse events (AEs) with a possible causal relationship to thestudy drug and all AEs were determined.

Summary-conclusions

The changes from baseline to weeks 12 and 52 in seated bloodpressure[systolicbloodpressure/diastolicbloodpressure(SBP/DBP)] were -15.7/-11.8 mmHg and -17.6/-13.0 mmHg,
respectively, in the group of patients with hypertension
inadequately controlled by OLM 20 mg and given OLM/AZL.
Similarly, the changes in the group of patients inadequately
controlled by OLM 10 mg and given OLM/AZL, were -15.7/-9.1mmHg and -19.6/-12.7 mmHg, respectively. The changes were-16.6/-10.9 mmHg and -18.4/-12.5 mmHg, respectively, in thegroup who were inadequately controlled by AZL 16 mg and given
co-administration therapy with OLM/AZL; and -19.3/-11.5 mmHg
and -21.5/-13.4 mmHg, respectively, in the group who wereinadequately controlled by AZL 8 mg and given OLM/AZL. Theabove results demonstrated the good antihypertensive effect of the12-week and 52-week (long-term) combination therapy with OLMand AZL in the groups of patients with hypertension that wasinadequately controlled by monotherapy with either OLM or AZL.
In terms of safety, there was no increase in either the type or theincidence of clinically important adverse events during thelong-term combination therapy with OLM and AZL. The dose
titration from OLM 10 mg/AZL 8 mg to OLM 20 mg/AZL 16 mg
did not cause any safety problems.
Based on these results, combination therapy with OLM and AZL
was well tolerated, showed a good antihypertensive effect, andmaintained the antihypertensive effect during long-term use inpatients with essential hypertension that was inadequately
controlled by monotherapy with OLM or AZL. In conclusion,
combination therapy with OLM and AZL might be a useful option
in patients whose hypertension is inadequately controlled bymonotherapy.
Date of report

October 14, 2010