Parallel-Group Comparison of Olmesartan (OLM), Amlodipine (AML) and Hydrochlorothiazid (HCTZ) in Hypertension

Randomised, Double-Blind, Parallel-Group Study Evaluating Efficacy and Safety of Co-Administration of Triple Combinations of Olmesartan Medoxomil, Amlodipine Besylate, and Hydrochlorothiazide Compared With Corresponding Olmesartan - Amlodipine Combination in Subjects With Hypertension

This study is to determine the change in blood pressure from the administration of Olmesartan/Amlodipine/Hydrochlorothiazide triple combinations compared to dual combinations with Olmesartan/Amlodipine.

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide + placebo; Drug: Olmesartan medoxomil + amlodipine + hydrochlorothiazide + placebo; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; Drug: olmesartan medoxomil + amlodipine; Drug: olmesartan medoxomil + amlodipine; Drug: olmesartan medoxomil + amlodipine

• Study Type: Interventional
• Enrollment (Actual): 2689
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium
  • Buizingen, Belgium
  • De Pinte, Belgium
  • Drongen, Belgium
  • Gent, Belgium
  • Gilly, Belgium
  • Merksem, Belgium
  • Mouscron, Belgium
  • Tremelo, Belgium
  • Wichelen, Belgium
• Bulgaria
  • Burgas, Bulgaria
  • Pleven, Bulgaria
  • Plovdiv, Bulgaria
  • Sofia, Bulgaria
  • Stara Zagora, Bulgaria
  • Veliko Tarnovo, Bulgaria
• Czechia
  • Benatky nad Jizerou, Czechia
  • Brodce, Czechia
  • Havirov, Czechia
  • Jicin, Czechia
  • Mlada Boleslav, Czechia
  • Moravska Ostrava, Czechia
  • Plzen, Czechia
  • Prachatice, Czechia
  • Praha, Czechia
  • Sokolov, Czechia
• Denmark
  • Copenhagen, Denmark
  • Frederiksberg, Denmark
  • Roskilde, Denmark
• Germany
  • Berlin, Germany
  • Cloppenburg, Germany
  • Delitzsch, Germany
  • Dresden, Germany
  • Erfurt, Germany
  • Essen, Germany
  • Hamburg, Germany
  • Heidelberg, Germany
  • Leipzig, Germany
  • Northeim, Germany
  • Simmern, Germany
  • Wallerfing, Germany
  • Wiesbaden, Germany
• Hungary
  • Budapest, Hungary
  • Debrecen, Hungary
  • Hodmezovasarhely, Hungary
  • Jaszbereny, Hungary
  • Kaposvar, Hungary
  • Kecskemet, Hungary
  • Oroshaza, Hungary
  • Pecs, Hungary
  • Szekesfehervar, Hungary
  • Veszprem, Hungary
  • Zalaegerszeg, Hungary
• Italy
  • Bologna, Italy
  • Brescia, Italy
  • Chieti, Italy
  • Ferrara, Italy
  • Foggia, Italy
  • Genova, Italy
  • Palermo, Italy
  • Parma, Italy
  • Perugia, Italy
  • Pisa, Italy
  • Roma, Italy
  • Sassari, Italy
  • Stradella Pavia, Italy
• Latvia
  • Cesis, Latvia
  • Daugavpils, Latvia
  • Jekabpils, Latvia
  • Ogre, Latvia
  • Riga, Latvia
  • Tukums, Latvia
  • Varaklani, Latvia
  • Ventspils, Latvia
• Netherlands
  • Deurne, Netherlands
  • Eindhoven, Netherlands
  • Lichtenvoorde, Netherlands
  • Lieshout, Netherlands
  • Rotterdam, Netherlands
  • Utrecht, Netherlands
• Poland
  • Bialystok, Poland
  • Debica, Poland
  • Gdansk, Poland
  • Gdynia, Poland
  • Jastrzebia Zdroj, Poland
  • Krakow, Poland
  • Lublin, Poland
  • Mielec, Poland
  • Opole, Poland
  • Szczecin, Poland
  • Warsaw, Poland
  • Wroclaw, Poland
• Romania
  • Arad, Romania
  • Bucharest, Romania
  • Craiova, Romania
  • Iasi, Romania
  • Pitesti, Romania
  • Ploiesti, Romania
  • Sibiu, Romania
  • Suceava, Romania
  • Timisoara, Romania
• Russian Federation
  • Barnaul, Russian Federation
  • Moscow, Russian Federation
  • Novosibirsk, Russian Federation
  • Saint Petersburg, Russian Federation
  • Tyumen, Russian Federation
  • Yaroslavl, Russian Federation
• Slovakia
  • Banska Bysterica, Slovakia
  • Bratilslava, Slovakia
  • Nitra, Slovakia
  • Povazska Bystrica, Slovakia
  • Rimavska Sobota, Slovakia
  • Zilina, Slovakia
• Spain
  • Badalona, Spain
  • Barcelona, Spain
  • Ferrol, Spain
  • Lleida, Spain
  • Madrid, Spain
  • Petrer, Spain
  • Salamanca, Spain
  • Santiago de Compostela, Spain
  • Valencia, Spain
• Ukraine
  • Dnipropetrovsk, Ukraine
  • Donetsk, Ukraine
  • Kharkiv, Ukraine
  • Kyiv, Ukraine
  • Lutsk, Ukraine
  • Lviv, Ukraine
  • Odesa, Ukraine
  • Simferopol, Ukraine
  • Vinnytsya, Ukraine
  • Zaporizhzhya, Ukraine
  • Zhytomyr, Ukraine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female subjects aged 18 years or older.
• Subjects with mean trough seated blood pressure (SeBP) ≥ 160/100 mmHg, (seated systolic blood pressure(SeSBP) ≥ 160 mmHg and seated diastolic blood pressure (SeDBP) ≥ 100 mmHg) at Screening if not currently on antihypertensive medication (newly diagnosed subjects or subjects who are not taking any antihypertensive medication for at least 3 weeks); Or Subjects with mean trough SeBP ≥ 160/100 mmHg, SeSBP ≥ 160 mmHg and SeDBP ≥ 100 mmHg) after washout of prior antihypertensive medication in subjects who discontinued their previous antihypertensive medication.

The difference in mean SeSBP/SeDBP between the visit prior to randomisation and the randomisation visit must be ≤ 20/10 mmHg. Subjects not currently on antihypertensive (HTN) medication may meet this requirement at the screening visit (Visit 1) and the randomization visit (Visit 3). Subjects washing out of HTN medication must meet this requirement at least by Visit 2 (or Visit 2.1, if needed) and Visit 3. All subjects undergoing washout of their prior antihypertensive medication will have the opportunity to re-visit the study sites for additional visits during washout (Visits 2 and 2.1) to assess eligibility for randomisation.

• Subjects freely sign the informed consent form (ICF) after the nature of the study and the disclosure of his/her data has been explained.
• Female subjects of childbearing potential must be using adequate contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study [Visit 1]). Adequate contraceptives include hormonal intra-uterine devices, hormonal contraceptives (oral, depot, patch or injectable), and double barrier methods such as condoms or diaphragms with spermicidal gel or foam.

Exclusion Criteria:

• Female subjects of childbearing potential who are pregnant or lactating.
• Subjects with serious disorders which may limit the ability to evaluate the efficacy or safety of the investigational products, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematologic or, neurologic, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic subjects.
• Subjects having a history of the following within the last six months: myocardial infarction (MI), unstable angina pectoris, percutaneous coronary intervention, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischaemic attack.

• Subjects with clinically significant abnormal laboratory values at Screening, including subjects with one or more of the following:

  • Aspartate aminotransferase (AST) > 3 times upper limit of normal (ULN).
  • Alanine aminotransferase (ALT) > 3 times ULN.
  • Gamma-glutamyl transferase (GGT) > 3 times ULN.
  • Potassium above ULN (unless high value is due to haemolytic blood sample).
• Subjects with secondary hypertension of any aetiology such as renal disease, phaeochromocytoma, or Cushing's syndrome.
• Subjects with contraindication to olmesartan, amlodipine, hydrochlorothiazide, or any of the tablet's excipients.
• Newly diagnosed subjects with a mean trough SeSBP > 200 mmHg or mean trough SeDBP > 115 mmHg or any subjects with bradycardia (heart rate < 50 beats/min at rest documented by mean radial pulse rate [PR] or electrocardiogram [ECG]) at Screening (Visit 1) or immediately before taking Period I study medication (Visit 3).
• Subjects already taking four or more antihypertensive medications.
• Subjects with a mean trough SeSBP > 145 mmHg or mean trough SeDBP > 95 mmHg while taking three antihypertensive medications.
• Subjects with a mean trough SeSBP > 160 mmHg or mean trough SeDBP > 100 mmHg while taking two antihypertensive medications.
• Subjects with a mean trough SeSBP > 180 mmHg or mean trough SeDBP > 110 mmHg while taking one antihypertensive medication.
• Subjects with electrocardiogram evidence of 2nd or 3rd degree atrio ventricular (AV) block, atrial fibrillation, or other cardiac arrhythmia (requiring treatment).
• Subjects with severe heart failure (New York Heart Association stage III-IV), clinically significant aortic or mitral valve stenosis, uncorrected coarctation of the aorta, obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy) or symptomatic coronary disease.
• Subjects with clinical evidence of renal disease including reno-vascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery stenosis, unilateral renal artery stenosis in a solitary kidney, or severe renal impairment as evidenced by CrCl of < 30 mL/min calculated using the Cockcroft and Gault formula.
• Subjects with clinically relevant hepatic impairment.
• Subjects with biliary obstruction.
• Subjects with uncontrolled Type 1 or Type 2 diabetes defined as HbA1c > 9.0%. Diabetics must have documentation of HbA1c within 6 months of the Screening Visit, or must have their HbA1c assessed prior to randomisation. Note: subjects with Type 1 or Type 2 diabetes controlled with insulin, diet or oral hypoglycaemic agents on a stable dose for at least 30 days may be included.
• Subjects with a history of a wasting disease (e.g. cancer), autoimmune diseases, connective tissue diseases, major allergies or angioneurotic oedema.
• Subjects who require or are taking any concomitant medication which may interfere with the objectives of the study.
• Subjects on beta blockers or calcium channel blockers (CCBs) for both hypertension and either ischemia, post-MI prophylaxis or tachyarrhythmias.
• Subjects with known malabsorption syndromes.
• Subjects with psychiatric or emotional problems, which would invalidate the giving of informed consent or limit the ability of the subject to comply with study requirements.
• Subjects with a history of alcohol and/or drug abuse.
• Subjects who have received any investigational agent within 30 days prior to Screening.
• Subjects who are unwilling or unable to provide informed consent or to participate satisfactorily for the entire study.
• Subjects with malignancy during the past 2 years excluding squamous cell or basal cell carcinoma of the skin.
• Subjects with signs or symptoms which could exacerbate the occurrence of hypotension such as volume and salt depletion.
• Subjects with any medical condition, which in the judgment of the Investigator would jeopardise the evaluation of efficacy or safety and/or constitute a significant safety risk to the subject.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: olmesartan/amlodipine/hydrochlorothiazide 20mg/5mg/12.5mg; olmesartan medoxomil 20mg / amlodipine besylate 5 mg / hydrochlorothiazide 12.5mg	Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide + placebo; One olmesartan medoxomil 20 mg + amlodipine 5 mg combination oral tablet taken once per day. One hydrochlorothiazide 12.5 mg tablet + one hydrochlorothiazide 12.5 mg placebo tablet taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine/hydrochlorothiazide 40mg/5mg/12.5mg	Drug: Olmesartan medoxomil + amlodipine + hydrochlorothiazide + placebo; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day. One hydrochlorothiazide 12.5 mg tablet + one hydrochlorothiazide 12.5 mg placebo tablet taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine/hydrochlorothiazide 40mg/5mg/25mg	Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Norvasc; Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. One hydrochlorothiazide 12.5 mg tablet + one hydrochlorothiazide 12.5 mg placebo tablet taken once per day.; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine/hydrochlorothiazide 40mg/10mg/12.5mg	Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Norvasc; Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. One hydrochlorothiazide 12.5 mg tablet + one hydrochlorothiazide 12.5 mg placebo tablet taken once per day.; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine/hydrochlorothiazide 40mg/10mg/25mg	Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Norvasc; Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. One hydrochlorothiazide 12.5 mg tablet + one hydrochlorothiazide 12.5 mg placebo tablet taken once per day.; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine + hydroclororthiazide; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day. Two hydrochlorothiazide 12.5 mg tablets taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine 20mg/5mg; olmesartan medoxomil 20mg / amlodipine besylate 5mg	Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 20 mg + amlodipine 5 mg combination oral tablet taken once per day; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day.; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine 40mg/5mg	Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 20 mg + amlodipine 5 mg combination oral tablet taken once per day; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day.; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day.; Other Names: Azor
Experimental: olmesartan/amlodipine 40mg/10mg	Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 20 mg + amlodipine 5 mg combination oral tablet taken once per day; Other Names: Azor; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 5 mg combination oral tablet taken once per day.; Drug: olmesartan medoxomil + amlodipine; One olmesartan medoxomil 40 mg + amlodipine 10 mg combination oral tablet taken once per day.; Other Names: Azor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Seated Diastolic Blood Pressure (SeDBP).	Baseline blood pressure was defined as the average values obtained at the randomization visit and at the visit prior to randomization	Baseline to week 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Seated Systolic Blood Pressure (SeDBP).		Baseline to week 10
Number of Subjects Reaching Blood Pressure Goal at Week 10	Blood pressure treatment goal was defined as blood pressure <140/90 mmHg or <130/80 mmHg for subjects with diabetes, chronic renal disease, or chronic cardiovascular disease.	baseline to week 10
Change in Seated Diastolic Blood Pressure From Week 18 to Week 22		Week 18 to week 22
Change in Seated Systolic Blood Pressure From Week 18 to Week 22		Week 18 to week 22
Number of Subjects Reaching Blood Pressure Goal From Week 18 to Week 22	Blood pressure treatment goal was defined as blood pressure <140/90 mmHg or <130/80 mmHg for subjects with diabetes, chronic renal disease, or chronic cardiovascular disease.	Week 18 to week 22
Change in Seated Diastolic Blood Pressure From Week 22 to Week 26		Week 22 to week 26
Change in Seated Systolic Blood Pressure From Week 22 to Week 26		Week 22 to week 26
Number of Subjects Reaching Blood Pressure Goal at Week 26	Blood pressure treatment goal was defined as blood pressure <140/90 mmHg or <130/80 mmHg for subjects with diabetes, chronic renal disease, or chronic cardiovascular disease.	Week 22 to week 26
Change in Seated Systolic Blood Pressure (SeDBP) During Open-Label Period VI (Titration Effect From OM/AML/HCTZ 40/5/25 to 40/10/25.		Week 26 to week 54

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Publications and helpful links

General Publications

• Marques da Silva P, Haag U, Guest JF, Brazier JE, Soro M. Health-related quality of life impact of a triple combination of olmesartan medoxomil, amlodipine besylate and hydrochlorotiazide in subjects with hypertension. Health Qual Life Outcomes. 2015 Feb 21;13:24. doi: 10.1186/s12955-015-0216-6.
• Volpe M, de la Sierra A, Ammentorp B, Laeis P. Open-label study assessing the long-term efficacy and safety of triple olmesartan/amlodipine/hydrochlorothiazide combination therapy for hypertension. Adv Ther. 2014 May;31(5):561-74. doi: 10.1007/s12325-014-0117-9. Epub 2014 Apr 24.
• Volpe M, Christian Rump L, Ammentorp B, Laeis P. Efficacy and safety of triple antihypertensive therapy with the olmesartan/amlodipine/hydrochlorothiazide combination. Clin Drug Investig. 2012 Oct 1;32(10):649-64. doi: 10.1007/BF03261919.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): January 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: June 16, 2009
• First Submitted That Met QC Criteria: June 16, 2009
• First Posted (Estimate): June 18, 2009

Study Record Updates

• Last Update Posted (Actual): January 10, 2019
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: parallel group; triple combination; dual combination
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Amlodipine; Olmesartan; Olmesartan Medoxomil; Hydrochlorothiazide; Amlodipine Besylate, Olmesartan Medoxomil Drug Combination
• Other Study ID Numbers: CS8635-A-E302

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No