Hydrochlorothiazide as add-on to Olmesartan/Amlodipine in Hypertension

Condition(s) targeted: Essential Hypertension

Intervention: 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 12.5mg (Drug); OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Daiichi Sankyo Inc.

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

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

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: 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

Secondary outcome:

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

Number of Subjects Achieving Blood Pressure (BP) Goal at Week 16.

Change in 24-hour Diastolic Blood Pressure (DBP) Assessed by 24-hour Ambulatory Blood Pressure Measurement (ABPM).

Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.

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.

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.

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.

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 Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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).

Graz, Austria

Salzburg, Austria

Wien, Austria

Antwerpen, Belgium

Lauwe, Belgium

Leuven, Belgium

Liege, Belgium

Massemen, Belgium

Oostham, Belgium

Haskovo, Bulgaria

Pleven, Bulgaria

Plovdiv, Bulgaria

Sofia, Bulgaria

Varna, Bulgaria

Bilovec, Czech Republic

Brno, Czech Republic

Havlickuv Brod, Czech Republic

Hodonin, Czech Republic

Kladno, Czech Republic

Kolin, Czech Republic

Ostrava-Vitkovice, Czech Republic

Ostrava, Czech Republic

Praha, Czech Republic

Copenhagen, Denmark

Frederiksberg, Denmark

Naestved, Denmark

Roskilde, Denmark

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

Berlin, Germany

Dresden, Germany

Einbeck, Germany

Hamburg, Germany

Magdeburg, Germany

Muenchen, Germany

Strasskirchen, Germany

Villingen-Schwenningen, Germany

Wermsdorf, Germany

Almere, Netherlands

Beek en Donk, Netherlands

Doetinchem, Netherlands

Groningen, Netherlands

Losser, Netherlands

Maastricht, Netherlands

Bytom, Poland

Gdansk, Poland

Katowice, Poland

Krakow, Poland

Piotrkow Trybunalski, Poland

Pulawy, Poland

Siemianowice Slaskie, Poland

Tarnow, Poland

Torun, Poland

Warszawa, Poland

Wroclaw, Poland

Brasov, Romania

Bucharest, Romania

Cluj-Napoca, Romania

Iasi, Romania

Oradea, Romania

Pitesti, Romania

Targoviste, Romania

Targu Mures, Romania

Timisoara, Romania

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

Banska Bysterica, Slovakia

Brastislava, Slovakia

Dolny Kubin, Slovakia

Kosice, Slovakia

Presov, Slovakia

Sahy, Slovakia

Alicante, Spain

Barcelona, Spain

Elche, Spain

Granada, Spain

Madrid, Spain

Palma de Mallorca, Spain

Sevilla, Spain

Valencia, Spain

Vizcaya, Spain

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

La Gineta, Albacete, Spain

La Roda, Albacete, Spain

Port de Sagunt, Valencia, Spain

Starting date: April 2009
Last updated: February 20, 2012