Efficacy and Safety Study of Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide Combination Therapy in Patients With Hypertension Not Controlled With Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy

A Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Triple Fixed Dose Combination Therapy With Olmesartan Medoxomil 20mg, Amlodipine 5mg and Hydrochlorothiazide 12.5mg in Patients With Hypertension Not Controlled With Dual Fixed Dose Combination Therapy With Olmesartan Medoxomil 20mg and Hydrochlorothiazide 12.5mg

CS-8635 combines three widely prescribed antihypertensive medications, olmesartan medoxomil(OM), amlodipine (AML), and hydrochlorothiazide (HCTZ), to lower blood pressure. The purpose of the study is to evaluate the efficacy and safety of triple therapy with CS-8635 compared with dual therapy in Korean patients with hypertension not controlled with dual fixed dose combination therapy (Olmetec® Plus). The treatments that will be used in this study are as follows: Run-in period -OM/HCTZ 20/12.5 mg (Olmetec® Plus 20/12.5 mg) ; Double blind treatment period - OM/AML/HCTZ 20/5/12.5mg (CS8635 20/5/12.5mg) + its matching placebo vs.OM/HCTZ 20/12.5mg (Olmetec® Plus 20/12.5 mg) + its matching placebo; Open label extension period - OM/AML/HCTZ 40/5/12.5mg (CS8635 40/5/12.5mg) or OM/AML/HCTZ 20/5/12.5mg (CS8635 20/5/12.5mg).

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: CS8635 20/5/12.5mg and placebo; Drug: Olmetec® Plus 20/12.5mg and placebo

Detailed Description

Please refer to arms, outcome measures and eligibility criteria for details.

• Study Type: Interventional
• Enrollment (Actual): 344
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Ansan, Korea, Republic of, 425-707
    • Korea University Ansan Hospital
  • Anyang, Korea, Republic of, 431-796
    • Hallym University Medical Center
  • Bucheon, Korea, Republic of, 420-767
    • Soonchunhyang University Hospital
  • Busan, Korea, Republic of, 602-739
    • Pusan National University Hospital
  • Busan, Korea, Republic of, 614-735
    • Inje University Busan Paik Hospital
  • Busan, Korea, Republic of, 602-715
    • Dong-A University Hospital
  • Busan, Korea, Republic of, 612-896
    • Inje University Haeundae Paik Hospital
  • Busan, Korea, Republic of, 607-711
    • Daedong hospital
  • Cheongju, Korea, Republic of, 361-711,
    • Chungbuk National University Hospital
  • Cheonju, Korea, Republic of, 560-750
    • Presbyterian Medical Center
  • Cheonju, Korea, Republic of, 561-712
    • Chonbuk National University Hospital
  • Daegu, Korea, Republic of, 700-712
    • Keimyung University Dongsan Medical Center
  • Daegu, Korea, Republic of, 705-718
    • Daegu Catholic University Medical Center
  • Daejeon, Korea, Republic of, 302-718
    • Konyang University Hospital
  • Daejeon, Korea, Republic of, 301-721
    • Chungnam National University Hospital
  • Goyang, Korea, Republic of, 410-719
    • Health Insurance Service Ilsan Hospital
  • Guri, Korea, Republic of, 471-701
    • Hanyang University Guri Hospital
  • Gwangju, Korea, Republic of, 501-757
    • Chonnam National University Hospital
  • Incheon, Korea, Republic of, 405-835
    • Gachon University Gil Medical Center
  • Seongnam, Korea, Republic of, 463-707
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 138-736
    • Asan Medical Center
  • Seoul, Korea, Republic of, 110-744
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 156-755
    • Chung-Ang University Hospital
  • Seoul, Korea, Republic of, 135-720
    • Gangnam Severance Hospital
  • Seoul, Korea, Republic of, 143-729
    • Konkuk University Medical Center
  • Seoul, Korea, Republic of, 120-752
    • Severance Hospital
  • Seoul, Korea, Republic of, 136-705
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 137-701
    • Seoul St. Mary's Hospital of the Catholic University of Korea
  • Seoul, Korea, Republic of, 130-702
    • Kyung Hee University Medical Center
  • Seoul, Korea, Republic of, 139-711
    • Eulji General Hospital
  • Seoul, Korea, Republic of, 134-727
    • Kyunghee University Hospital at Gandong
  • Seoul, Korea, Republic of, 134-791
    • Seoul Veterans Hospital
  • Seoul, Korea, Republic of, 135-710
    • Sanmsung Medical Center
  • Seoul, Korea, Republic of, 150-713
    • Yeouido St. Mary's Hospital of the Catholic University of Korea
  • Seoul, Korea, Republic of, 152-840
    • Korea University Guro Hospital
  • Suncheon, Korea, Republic of, 540-719
    • St. Carollo Hospital
  • Suwon, Korea, Republic of, 443-380
    • Ajou University Hospital
  • Ulsan, Korea, Republic of, 682-714
    • Ulsan University Hospital
  • Wonju, Korea, Republic of, 220-701
    • Wonju Severance Christian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Screening

• Male or female at the age of 20 to 75 years
• Voluntary written informed consent to participation in this study
• Patients with hypertension either newly diagnosed or without treatment of antihypertensive drugs within 4 weeks of screening, who have mean seated diastolic blood pressure (msDBP) ≥ 100 mmHg at screening, or
• Patients who have been on a stable dose of antihypertensive drugs for at least 4 weeks before run-in period and meet the following blood pressure criteria at screening: Monotherapy: msDBP ≥ 95 mmHg, or Dual combination therapy: msDBP ≥ 90 mmHg, or Triple combination therapy: 70 mmHg ≤ msDBP < 90 mmHg

Inclusion criteria for randomization

• msSBP/DBP at randomization: msSBP ≥ 140 mmHg (msSBP ≥ 130 mmHg in subjects with diabetes or chronic renal disease), and msDBP ≥ 90 mmHg (msDBP ≥ 80 mmHg in subjects with diabetes or chronic renal disease)

Exclusion Criteria:

• msDBP ≥ 115mmHg or msSBP ≥ 200 mmHg measured at screening and randomization
• Patients with mini-max blood pressure difference of SeSBP ≥ 20 mmHg or SeDBP ≥ 10 mmHg in the chosen arm at screening
• Patients with blood pressure difference of SeSBP ≥ 20 mmHg and SeDBP ≥ 10 mmHg in both arms at screening
• Patients with hypersensitivity to the investigational product or any of its components
• Patients with medical history or hypersensitivity to sulfonamide, dihydropyridine, or thiazide diuretics
• History of secondary hypertension or history of any of the diseases suspected of secondary hypertension
• Symptomatic orthostatic hypotension
• Uncontrolled diabetes mellitus
• Severe heart disease, or ischemic heart disease, peripheral vascular disease
• Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter, or other arrhythmia considered clinically significant
• Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, or hemodynamically significant stenosis on aortic valve or mitral valve.
• Severe cerebrovascular disorder
• Known moderate or malignant retinopathy
• Consumption disease , autoimmune disease, or connective tissue disease
• Patients requiring chronic anti-inflammatory treatment
• Anuria or severe renal failure
• Severe hepatic failure, AST or ALT > 3 times the upper limit of normal, biliary obstruction, biliary cirrhosis, or cholestasis
• Patients who have been treated for hyponatremia, hypokalemia, hyperkalemia, hypercalcemia, or symptomatic hyperuricemia
• Addison's disease
• Glucose-galactose malabsorption, galactose intolerance, or Lapp lactase deficiency
• Gastrointestinal tract disease or surgical operation that may affect absorption, distribution, metabolism, and excretion of drugs, presence of active gastritis or gastrointestinal/rectal bleeding considered clinical significant by the investigator, active inflammatory bowel syndrome within the last 12 months, etc
• Patients with history of or suspected of drug or alcohol abuse
• Pregnant or lactating women, or women of childbearing potential who do not agree to use appropriate contraceptive methods such as progestin hormone therapy (Oral, implant), intrauterine device, barrier methods of contraception (condom or occlusive cap (diaphragm or cervical/vault caps) with spermicide), male sterilisation or true abstinence
• Patients who participated in other clinical study within 1 month prior to screening
• Patients considered to be incapable of complying with the protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CS8635 20/5/12.5mg and placebo; Participants receiving Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5 mg) for the 4-week, Run-in Period but who do not meet their blood pressure goals(Non-responders) could start receiving this triple fixed dose combination therapy (CS8635 20/5/12.5mg (OM/AML/HCTZ 20/5/12.5mg) + placebo) in randomized, 8-week, double-blind Period. The non-responders finishing double-blind treatment could continue the 8-week Open-label Period with CS8635 40/5/12.5mg (OM/AML/HCTZ 40/5/12.5 mg).	Drug: CS8635 20/5/12.5mg and placebo; Run-in period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, given once a day. Double-blind period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine (AML)-Hydrochlorothiazide(HCTZ) 20-5-12.5mg, oral placebo tablet. All tablets are given once a day. Open-label period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine(AML)-Hydrochlorothiazide(HCTZ) 40-5-12.5mg, given once a day.
Active Comparator: Olmetec® Plus 20/12.5mg and placebo; Participants receiving Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5 mg) for the 4-week, Run-in Period but who do not meet their blood pressure goals(Non-responders) could start receiving this dual fixed dose combination therapy (Olmetec® Plus 20/12.5mg (OM/HCTZ 20/12.5mg) + Placebo) in randomized, 8-week, double-blind Period. The non-responders finishing double-blind treatment could continue the 8-week Open-label Period with CS8635 20/5/12.5mg (OM/AML/HCTZ 20/5/12.5 mg).	Drug: Olmetec® Plus 20/12.5mg and placebo; Run-in period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, given once a day. Double-blind period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Hydrochlorothiazide(HCTZ) 20-12.5mg, oral placebo tablet. All tablets are given once a day. Open-label period: Coated, Oral tablet containing Olmesartan medoxomil(OM)-Amlodipine(AML)-Hydrochlorothiazide(HCTZ) 20-5-12.5mg, given once a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The changes of seated diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg	from baseline to week 8

Secondary Outcome Measures

Outcome Measure	Time Frame
The changes of mean seated systolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg	from baseline to Week 8
The changes of mean seated systolic and diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg	from baseline to week 4
Percentage of subjects achieving blood pressure goal of the Triple Combinations OM/AML/HCTZ 20/5/12.5mg vs.OM/HCTZ 20/12.5mg	at Week 4, and Week 8
Percentage of subjects achieving blood pressure goal of the Triple Combinations OM/AML/HCTZ 40/5/12.5mg vs.OM/AML/HCTZ 20/5/12.5mg	At week 16
The changes of mean seated systolic and diastolic blood pressure of the Triple Combinations OM/AML/HCTZ 40/5/12.5mg vs.OM/AML/HCTZ 20/5/12.5mg	from Week 8 to Week 16

Other Outcome Measures

Outcome Measure	Time Frame
Collection of safety data from Adverse event, Laboratory test, Physical examination, Vital signs with pulse and ECG	from screening to Week 16

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Korea Co., Ltd., a Daiichi Sankyo Company
• Investigators: Principal Investigator: Chang-Wook Nam, Keimyung University Dongsan Medical Center; Principal Investigator: Cheol-Ho Kim, Seoul National University Bundang Hospital; Principal Investigator: Sang-Hong Baek, Seoul St. Mary's Hospital of the Catholic University of Korea; Principal Investigator: Woo-Baek Chung, Yeouido St. Mary's Hospital of the Catholic University of Korea; Principal Investigator: Woo-Shik Kim, Kyunghee University Medical Center; Principal Investigator: Tae-Hoon Ahn, Gachon University Gil Medical Center; Principal Investigator: Jang-Hyun Cho, St. Carollo Hospital; Study Chair: Byung-Hee Oh, Seoul National Univerisity Hospital; Principal Investigator: Hweung-Kon Hwang, Konkuk University Medical Center; Principal Investigator: Chang-Gyu Park, Korea University Guro Hospital; Principal Investigator: Eun-Seok Shin, Ulsan University Hospital; Principal Investigator: Joon-Han Shin, Ajou University School of Medicine; Principal Investigator: Myung-Ho Jeong, Chonnam National University Hospital; Principal Investigator: Jin-Ok Jeong, Chungnam National University Hospital; Principal Investigator: Chong-Jin Kim, Kyunghee University Hospital at Gandong; Principal Investigator: Jang-Ho Bae, Konyang University Hospital; Principal Investigator: Seung-Hwan Lee, Wonju Severance Christian Hospital; Principal Investigator: Se-Joong Rim, Gangnam Severance Hospital; Principal Investigator: Jay-Young Rhew, Presbyterian Medical Center; Principal Investigator: Doo-Il Kim, Inje University; Principal Investigator: Dae-Kyeong Kim, Inje University; Principal Investigator: Soon-Kil Kim, Hanyang University; Principal Investigator: Hye-Sun Seo, Soonchunhyang University Hospital; Principal Investigator: Duk-Hyun Kang, Asan Medical Center; Principal Investigator: Young-Dae Kim, Dong-A University Hospital; Principal Investigator: Dong-Woon Kim, Chungbuk National University Hospital; Principal Investigator: Taek-Jong Hong, Pusan National University Hospital; Principal Investigator: Woo-Jung Park, Hallym University Medical Center; Principal Investigator: Tae Ho Kim, Chung-Ang University Hosptial, Chung-Ang University College of Medicine; Principal Investigator: Kee-Sik Kim, Daegu Catholic University Medical Center; Principal Investigator: Seung-Woo Park, Sanmsung Medical Center; Principal Investigator: Wan-Joo Shim, Korea University Anam Hospital; Principal Investigator: Joo-Young Yang, Health Insurance Service Ilsan Hospital; Principal Investigator: Jae-Woong Choi, Eulji General Hospital; Principal Investigator: Sun-Hwa Lee, Chonbuk National University Hospital; Principal Investigator: Jeong-Cheon Ahn, Korea University; Principal Investigator: Keun Lee, Seoul Veterans Hospital; Principal Investigator: Byung-Soo Kim, Daedong hospital

Publications and helpful links

General Publications

• Sohn IS, Kim CJ, Oh BH, Hong TJ, Park CG, Kim BS, Chung WB; Investigators. Efficacy and Safety Study of Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide Combination Therapy in Patients with Hypertension Not Controlled with Olmesartan Medoxomil and Hydrochlorothiazide Combination Therapy: Results of a Randomized, Double-Blind, Multicenter Trial. Am J Cardiovasc Drugs. 2016 Apr;16(2):129-38. doi: 10.1007/s40256-015-0156-x. Erratum In: Am J Cardiovasc Drugs. 2016 Apr;16(2):139.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: April 22, 2013
• First Posted (Estimate): April 24, 2013

Study Record Updates

• Last Update Posted (Actual): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Olmesartan Medoxomil
• Other Study ID Numbers: CS8635-SIT-11-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code