BRAVE Study With Uncontrolled Essential Hypertension (BRAVE Study)

Study Overview
=================
Brief Summary
-----------------
This is an open-label, placebo run-in study to investigate the genetic and biomedical predictors of blood pressure response to bisoprolol. After informed consent is obtained, subjects will be withdrawn from previous antihypertensive therapy and given placebo for at least 2 weeks. Compliance will be assessed using pill counting, and any subject will a compliance less than 80% during the placebo run-in period will be excluded from the study. Bisoprolol 2.5 mg will be given once daily for 6 weeks. At baseline and after 6 weeks on bisoprolol 2.5 mg the clinic sitting blood pressure, 24-hour ambulatory blood pressure (if the patient is willing to do this), clinical characteristics and biochemical profile will be measured. Central aortic blood pressure will be measured with the A-PULSE device at baseline and after 6 weeks treatment. After completing 6 weeks treatment with bisoprolol 2.5 mg daily, the patient will continue treatment with bisoprolol for a total of 24 weeks unless there is any adverse event that requires discontinuation of bisoprolol.

Detailed Description
-----------------
Patients with uncontrolled essential hypertension aged 18-79 years on no antihypertensive treatment with sitting clinic systolic blood pressure of 140-169 mmHg and/or a sitting clinic diastolic blood pressure of 90-109 mmHg, or for patients with diabetes mellitus or with chronic kidney disease with sitting clinic systolic blood pressure of 130-169 mmHg and / or a sitting clinic diastolic blood pressure of 80-109 mmHg and heart rate > 70 at baseline (before starting bisoprolol treatment) will be enrolled. Patients on other antihypertensive treatments who are experiencing side effects or whose blood pressure may not be well controlled can also enter if they can continue on a stable dose of a calcium channel blocker, either amlodipine or nifedipine retard throughout the study. Patients will be treated with bisoprolol 2.5mg daily for a total of 26 weeks. The primary endpoint will be the influence of common genetic polymorphisms on clinic sitting blood pressure or ambulatory blood pressure (ABP) response to bisoprolol 2.5 mg after 6 weeks treatment.

Official Title
-----------------
An Open Label, Pharmacogenetic Study of Bisoprolol Treatment in Patients With Uncontrolled Essential Hypertension (BRAVE)

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Bisoprolol 2.5 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with essential hypertension For uncomplicated hypertensive patients on no antihypertensive treatment, sitting clinic systolic blood pressure of 140-169 mmHg and / or a sitting clinic diastolic blood pressure of 90-109 mmHg. For patients with diabetes mellitus or with chronic kidney disease, sitting clinic systolic blood pressure of 130-169 mmHg and / or a sitting clinic diastolic blood pressure of 80-109 mmHg. Patient has a heart rate >70 b/min at baseline (before starting bisoprolol treatment) Exclusion Criteria: Secondary Hypertension Pregnant or lactating women and women with childbearing potential not using adequate method of contraception or agreeing to maintain sexual abstinence throughout the study; Unstable angina, history of myocardial infarction, stroke or coronary heart disease (coronary by-pass or angioplasty) in the previous 3 months; Heart failure (New York Heart Association [NYHA] III-IV); Haemodynamically relevant aortic or mitral valve disease; Obstructive hypertensive cardiomyopathy; Symptomatic bradycardia, second or third degree atrio-ventricular (AV) block, sick sinus syndrome, sinoatrial block, or heart rate <70 b/min at baseline (before starting bisoprolol treatment); Primary hyperaldosteronism; Renal artery stenosis; Impairment of hepatic or renal function as defined by liver function values of ALT ≥1.5-fold the upper normal limit or serum creatinine >150 µmol/L or upon investigator decision; History of intolerance to beta-blockers the drug classes used in the study. Patients with a known contraindication to beta-blockers, e.g. bradycardia, asthma, severe peripheral vascular disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 79 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Bisoprolol 2.5 mg<br>Bisoprolol 2.5 mg will be given once daily following run-in placebo for 2 weeks | Drug: Bisoprolol 2.5 mg<br>* Bisoprolol 2.5 mg will be given once daily<br>* Other names: Concor;Drug: Placebo<br>* Placebo tablets will be given once daily for 2 weeks during the run-in period.<br>* Other names: Run-in;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Influence of the two common polymorphisms in the beta1-adrenoceptor (ADRB1) gene on changes in sitting clinic blood pressure after 6 weeks treatment with bisoprolol 2.5 mg daily. | Subjects will be divided according to the Gly389Arg and Ser49Gly polymorphisms in ADRB1 gene and the clinic blood pressure changes at 6 weeks compared between these groups. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of blood pressure from baseline to 6 weeks by clinic sitting blood pressure according to other genotypes. | Patients will be divided into groups according to genotypes of the Fok+/Fok- polymorphism in the G-protein alpha subunit (GNAS) gene and the T393C polymorphism in the G-protein alpha subunit 1 (GNAS1) gene, and changes in blood pressure after 6 weeks treatment compared. | 6 weeks | 
| Change of blood pressure from baseline to 24 weeks by clinic sitting blood pressure according to other genotypes. | Patients will be divided into groups according to genotypes of the Fok+/Fok- polymorphism in the G-protein alpha subunit (GNAS) gene and the T393C polymorphism in the G-protein alpha subunit 1 (GNAS1) gene, and changes in blood pressure after 24 weeks treatment compared. | 24 weeks | 
| Influence of the two common polymorphisms in the beta1-adrenoceptor (ADRB1) gene on changes in ambulatory blood pressure (ABP) after 6 weeks treatment with bisoprolol 2.5 mg daily. | Subjects will be divided according to the Gly389Arg and Ser49Gly polymorphisms in the ADRB1 gene and the ambulatory blood pressure changes at 6 weeks compared between these groups. | 6 weeks |