Hydrochlorothiazide as add-on to Olmesartan/Amlodipine in Hypertension

Add-on Study of Hydrochlorothiazide in Patients With Moderate to Severe Hypertension Not Achieving Target Blood Pressure on Olmesartan/Amlodipine Alone

Both Olmesartan (OLM)/Amlodipine (AML) combination and Hydrochlorothiazide (HCTZ) have proven to be efficacious and safe in lowering blood pressure, but may not always be sufficient. This study is to test efficacy and safety of the combination of OLM/AML and HCTZ in hypertensive patients whose blood pressure is not adequately controlled with OLM/AML alone. The following treatments will be included in the trial: OLM 40mg/AML 10mg; OLM 40mg/AML 10 mg/HCTZ 12.5 mg; OLM 40 mg/AML 10 mg/HCTZ 25 mg. The trial has four periods. The treatments that will be used are as follows:

Period 1 - OLM 40mg/AML 10mg; Period 2 - OLM 40mg/AML 10mg or OLM 40mg/AML 10 mg/HCTZ 12.5 mg or OLM 40 mg/AML 10 mg/HCTZ 25 mg; Period 3 - OLM 40mg/AML 10 mg/HCTZ 12.5 mg; Period 4 - Period 3 responders: OLM 40mg/AML 10 mg/HCTZ 12.5 mg; Period 4 - Period 3 non-responders: OLM 40mg/AML 10 mg/HCTZ 12.5 mg or OLM 40 mg/AML 10 mg/HCTZ 25 mg

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: Olmesartan medoxomil 40 mg - Amlodipine 10 mg; Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg; Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg; Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg

• Study Type: Interventional
• Enrollment (Actual): 2204
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
  • Salzburg, Austria
  • Wien, Austria
• Belgium
  • Antwerpen, Belgium
  • Lauwe, Belgium
  • Leuven, Belgium
  • Liege, Belgium
  • Massemen, Belgium
  • Oostham, Belgium
• Bulgaria
  • Haskovo, Bulgaria
  • Pleven, Bulgaria
  • Plovdiv, Bulgaria
  • Sofia, Bulgaria
  • Varna, Bulgaria
• Czechia
  • Bilovec, Czechia
  • Brno, Czechia
  • Havlickuv Brod, Czechia
  • Hodonin, Czechia
  • Kladno, Czechia
  • Kolin, Czechia
  • Ostrava, Czechia
  • Ostrava-Vitkovice, Czechia
  • Praha, Czechia
• Denmark
  • Copenhagen, Denmark
  • Frederiksberg, Denmark
  • Naestved, Denmark
  • Roskilde, Denmark
• France
  • Albi, France
  • Angers, France
  • Brest, France
  • Cambrai, France
  • Creteil, France
  • Dijon, France
  • Dinard, France
  • Lyon, France
  • Nancy, France
  • Pessac, France
  • Roubaix, France
  • Strasbourg, France
  • Tierce, France
  • Vandoeuvre, France
  • Villefranche de Rouergue, France
• Germany
  • Berlin, Germany
  • Dresden, Germany
  • Einbeck, Germany
  • Hamburg, Germany
  • Magdeburg, Germany
  • Muenchen, Germany
  • Strasskirchen, Germany
  • Villingen-Schwenningen, Germany
  • Wermsdorf, Germany
• Netherlands
  • Almere, Netherlands
  • Beek en Donk, Netherlands
  • Doetinchem, Netherlands
  • Groningen, Netherlands
  • Losser, Netherlands
  • Maastricht, Netherlands
• Poland
  • Bytom, Poland
  • Gdansk, Poland
  • Katowice, Poland
  • Krakow, Poland
  • Piotrkow Trybunalski, Poland
  • Pulawy, Poland
  • Siemianowice Slaskie, Poland
  • Tarnow, Poland
  • Torun, Poland
  • Warszawa, Poland
  • Wroclaw, Poland
• Romania
  • Brasov, Romania
  • Bucharest, Romania
  • Cluj-Napoca, Romania
  • Iasi, Romania
  • Oradea, Romania
  • Pitesti, Romania
  • Targoviste, Romania
  • Targu Mures, Romania
  • Timisoara, Romania
• Russian Federation
  • Ekaterinburg, Russian Federation
  • Moscow, Russian Federation
  • Novosibirsk, Russian Federation
  • Orenburg, Russian Federation
  • Ryazan, Russian Federation
  • Saratov, Russian Federation
  • Smolensk, Russian Federation
  • St. Petersburg, Russian Federation
  • Tomsk, Russian Federation
  • Yaroslavl, Russian Federation
• Slovakia
  • Banska Bysterica, Slovakia
  • Brastislava, Slovakia
  • Dolny Kubin, Slovakia
  • Kosice, Slovakia
  • Presov, Slovakia
  • Sahy, Slovakia
• Spain
  • Alicante, Spain
  • Barcelona, Spain
  • Elche, Spain
  • Granada, Spain
  • Madrid, Spain
  • Palma de Mallorca, Spain
  • Sevilla, Spain
  • Valencia, Spain
  • Vizcaya, Spain
  • Albacete
    • La Gineta, Albacete, Spain
    • La Roda, Albacete, Spain
  • Valencia
    • Port De Sagunt, Valencia, Spain
• Ukraine
  • Dnipropetrovsk, Ukraine
  • Donetsk, Ukraine
  • Ivano-Frankivsk, Ukraine
  • Kharkiv, Ukraine
  • Kiev, Ukraine
  • Lviv, Ukraine
  • Mykolayiv, Ukraine
  • Odesa, Ukraine
  • Simferopol, Ukraine
  • Uzhorod, Ukraine
  • Vinnytsya, Ukraine
  • Yalta, 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 aged 18 years or older.
• Mean trough seated systolic blood pressure (SeSBP) of ≥ 160/100 mmHg (SeSBP of ≥ 160 mmHg and seated diastolic blood pressure (SeDBP) ≥ 100 mmHg) at screening if not currently on antihypertensive medication (e.g. newly diagnosed subjects)

OR:

For subjects on monotherapy: mean trough SeSBP of ≥ 150/95 mmHg (SeSBP of ≥ 150 mmHg and SeDBP ≥ 95 mmHg) at screening

OR:

For subjects on any combination of antihypertensive medications that includes either hydrochlorothiazide or amlodipine or olmesartan for a duration of at least four weeks: mean trough SeSBP of ≥ 140/90 mmHg (SeSBP of ≥ 140 mmHg and SeDBP ≥ 90 mmHg) at screening

OR:

For subjects on any other combination of antihypertensive medications that includes neither hydrochlorothiazide, amlodipine nor olmesartan: mean trough SeSBP ≥ 160 mmHg, mean trough SeDBP ≥ 100mmHg, at the end of the taper-off period

• Subject freely signs 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]). Females taking oral contraceptives should have been on therapy for at least three months. 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. If a female becomes pregnant during the study, she has to be withdrawn immediately.

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, haematological or oncological, neurological, 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-glutamyltransferase (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 excipients.
• Subjects with a mean SeSBP > 200 mmHg or mean SeDBP > 115 mmHg or 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 2).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Olmesartan (OLM) 40mg-Amlodipine (AML) 10mg; The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Drug: Olmesartan medoxomil 40 mg - Amlodipine 10 mg; Oral tablets containing Olmesartan medoxomil-Amlodipine 40-10 mg, given once daily
Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg; Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg; Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.	Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablets. All tablets are given once a day.; Other Names: Olmesartan 40mg-Amlodipine 10mg tablet + 2 Hydrochlorothiazide 12.5mg tablets
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Responders); Participants who meet their blood pressure goals in Period 3 and continued into the 8-week, double-blind Period 4 continued to receive this combination.	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Non-responders); Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg (Non-responders); Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablet. All tablets are given once a day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Seated Diastolic Blood Pressure (SeDBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg	Three cuff blood pressure measurements were taken at each visit.	baseline (8 weeks) to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Seated Systolic Blood Pressure (SeSBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg	Three cuff blood pressure measurements were taken at each visit.	baseline (8 weeks) to week 16
Number of Subjects Achieving Blood Pressure (BP) Goal at Week 16.	Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.	baseline (week 8) to week 16
Change in 24-hour Diastolic Blood Pressure (DBP) Assessed by 24-hour Ambulatory Blood Pressure Measurement (ABPM).	Three cuff blood pressure measurements were taken at each visit.	Baseline (8 weeks) to 16 weeks
Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.	Three cuff blood pressure measurements were taken at each visit.	Baseline (8 weeks) to 16 weeks
In Non-responders, the Change in Seated Diastolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.	Change in seated diastolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.	week 24 to week 32
In Non-responders, the Change in Seated Systolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.	Change in seated systolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.	week 24 to week 32
In Non-responders, the Number of Subject Meeting Their Blood Pressure Goals Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.	The number of non-responding participants who achieved their blood pressure goals at the end of Period 4. Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.	week 24 to week 32
In Non-responders, the Change in 24-hour Diastolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.	In non-responders, the change in 24-hour diastolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.	Week 16 to week 32
In Non-responders, the Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.	In non-responders, the change in 24-hour systolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.	Week 16 to week 32

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): September 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: May 13, 2009
• First Submitted That Met QC Criteria: May 14, 2009
• First Posted (Estimate): May 15, 2009

Study Record Updates

• Last Update Posted (Actual): January 11, 2019
• Last Update Submitted That Met QC Criteria: December 20, 2018
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: essential hypertension; Add on treatment
• 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
• Other Study ID Numbers: CS8635-A-E303

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; SAP; ICF; ANALYTIC_CODE; CSR