Hydrochlorothiazide as add-on to Olmesartan/Amlodipine in Hypertension

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

Conditions
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Essential Hypertension

Intervention / Treatment
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* 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 12.5mg
* Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olmesartan (OLM) 40mg-Amlodipine (AML) 10mg<br>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<br>* Oral tablets containing Olmesartan medoxomil-Amlodipine 40-10 mg, given once daily<br>|
| Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg<br>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<br>* 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.<br>|
| Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg<br>Participants could start receiving this combination in randomized, double-blind, 8- week Period 2. | Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg<br>* Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablets. All tablets are given once a day.<br>* Other names: Olmesartan 40mg-Amlodipine 10mg tablet + 2 Hydrochlorothiazide 12.5mg tablets;|
| Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Responders)<br>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<br>* 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.<br>|
| Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Non-responders)<br>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<br>* 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.<br>|
| Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg (Non-responders)<br>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<br>* Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablet. All tablets are given once a day.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Add on treatment, essential hypertension