Clinical trial NCT02398929: BRAVE Study With Uncontrolled Essential Hypertension (BRAVE Study)
Official title: An Open Label, Pharmacogenetic Study of Bisoprolol Treatment in Patients With Uncontrolled Essential Hypertension (BRAVE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Lead sponsor: Chinese University of Hong Kong
Sponsor class: OTHER
First posted: 2015-03-26
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 After informed consent is obtained, subjects will be withdrawn from previous antihypertensive therapy and given placebo for at least 2 weeks.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.

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.

Primary outcomes:
measure: 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.
timeFrame: 6 weeks
Secondary outcomes:
measure: Change of blood pressure from baseline to 6 weeks by clinic sitting blood pressure according to other genotypes.
timeFrame: 6 weeks
measure: Change of blood pressure from baseline to 24 weeks by clinic sitting blood pressure according to other genotypes.
timeFrame: 24 weeks
measure: 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.
timeFrame: 6 weeks
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Brian Tomlinson
Study officials:
affiliation: Chinese University of Hong Kong
name: Brian Tomlinson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hiltunen TP, Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Virolainen J, Kontula K. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007 Mar;20(3):311-8. doi: 10.1016/j.amjhyper.2006.09.006.
citation: Suonsyrja T, Donner K, Hannila-Handelberg T, Fodstad H, Kontula K, Hiltunen TP. Common genetic variation of beta1- and beta2-adrenergic receptor and response to four classes of antihypertensive treatment. Pharmacogenet Genomics. 2010 May;20(5):342-5. doi: 10.1097/FPC.0b013e328338e1b8.
citation: de Groote P, Helbecque N, Lamblin N, Hermant X, Mc Fadden E, Foucher-Hossein C, Amouyel P, Dallongeville J, Bauters C. Association between beta-1 and beta-2 adrenergic receptor gene polymorphisms and the response to beta-blockade in patients with stable congestive heart failure. Pharmacogenet Genomics. 2005 Mar;15(3):137-42. doi: 10.1097/01213011-200503000-00001.