Fixed Dose Combination of Bisoprolol and Amlodipine in the Treatment of Hypertension

Study Overview
=================
Brief Summary
-----------------
This is a randomized, comparative Phase 3 trial to investigate the efficacy of fixed dose combination (FDC) of bisoprolol and amlodipine in hypertensive subjects (superiority of FDC over monotherapies).

Official Title
-----------------
A Randomized, Comparative Trial of Concor AM, a Fixed Dose Combination of Bisoprolol and Amlodipine, on the Treatment of Essential Hypertensive Patients Whose Blood Pressure is Not Well Controlled by Monotherapy of Bisoprolol 5mg or Amlodipine 5mg

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

Intervention / Treatment
-----------------
* Drug: Bisoprolol/Amlodipine (Bisoprolol failed group)
* Drug: Bisoprolol/Amlodipine (Amlodipine failed group)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Essential hypertension not controlled at 5 mg bisoprolol or 5 mg amlodipine at least 4 weeks (definition of not controlled: SBP greater than or equal to (>=) 140 millimeter of mercury (mmHg) with or without DBP >= 90 mmHg) Male or female subjects >=18 years of age, without limitation on race Medically accepted effective contraception if procreative potential exists (applicable for both male and female subjects until at least 90 days after the last dose of trial treatment) Subjects who have signed the informed consent form before any trial related assessment Exclusion Criteria: General contraindications of beta-blockers and/or calcium channel blockers Previous and concurrent acute heart failure or during episodes of heart failure decompensation requiring intravenous inotropic therapy Concurrent cardiogenic shock Previous and concurrent second or third degree atrioventricular (AV) block (without a pacemaker) Previous and concurrent sick sinus syndrome Previous and concurrent sinoatrial block Concurrent symptomatic bradycardia Concurrent symptomatic hypotension Previous and concurrent severe bronchial asthma or chronic obstructive pulmonary diseases Previous and concurrent severe peripheral arterial occlusive diseases and Raynaud's syndrome Untreated pheochromocytoma Concurrent metabolic acidosis Known hypersensitivity to bisoprolol, amlodipine, dihydropyridine derivates or to any of the excipients Seated pulse rate less than 60 beats per minute (bpm) at screening Any other anti-hypertensive drugs (other than bisoprolol and amlodipine) are used within 4 weeks prior to the screening visit Use of any enzyme-modifying drugs acting on cytochrome P450 (CYP) 3A4 enzymes via inhibition (such as ketoconazole, itraconazole, ritonavir) or induction (such as rifampicin or hypericum perforatum) within 28 days before Day 1 of the trial Other significant disease that in the Investigator's opinion that would exclude the subject from the trial, such as uncontrolled diabetes mellitus, severe liver and/or kidney dysfunction, decompensated cardiac failure Any other condition or therapy which in the Investigator's opinion would pose a risk to the subject or interfere with the trial objectives Concurrent alcohol and/or drug abuse Known hypersensitivity to the trial treatments Pregnancy and lactation period. All female subjects with reproductive potential must have a negative pregnancy serum test within the 7 days prior to enrollment Known lack of subject compliance Legal incapacity or limited legal capacity Participation in another clinical trial within the previous 30 days Persons directly involved in the execution of the protocol

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

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bisoprolol failed group<br>Subjects who failed monotherapy with bisoprolol 5 milligram (mg) before trial inclusion will be randomized to bisoprolol failed group to receive Bisoprolol/Amlodipine FDC tablet | Drug: Bisoprolol/Amlodipine (Bisoprolol failed group)<br>* Bisoprolol/Amlodipine FDC tablet will be orally administered at an initial dose of 5 mg/5 mg once daily for 6 weeks. If blood pressure (BP) is controlled at Week 6 (Day 43), the same dose will continue for next 6 weeks. If the BP is not controlled at Day 43, the dose will be increased to Bisoprolol/Amlodipine 5mg/10mg or 10mg/5mg for next 6 weeks. Subjects who have controlled BP at Week 12 (Day 85), will continue with the same dose for next 6 weeks. If their BP is not controlled at Day 85, dose will be increased to the next level (Bisoprolol/Amlodipine 5mg/10mg for subjects receiving Bisoprolol/Amlodipine 5mg/5mg dose and Bisoprolol/Amlodipine and 10mg/10mg for subjects receiving Bisoprolol/Amlodipine 5mg/10mg dose) until Week 18 (Day 127).<br>* Other names: Concor AM;|
| Experimental: Amlodipine failed group<br>Subjects who failed monotherapy with amlodipine 5 mg before trial inclusion will be randomized to amlodipine failed group to receive Bisoprolol/Amlodipine FDC tablet. | Drug: Bisoprolol/Amlodipine (Amlodipine failed group)<br>* Bisoprolol/Amlodipine FDC tablet will be orally administered at an initial dose of 5 milligram (mg)/5 mg once daily for 6 weeks. If BP is controlled at Week 6 (Day 43), the same dose will continue for next 6 weeks. If the BP is not controlled at Day 43, the dose will be increased to Bisoprolol/Amlodipine 5mg/10mg or 10mg/5mg for next 6 weeks. Subjects who have controlled BP at Week 12 (Day 85), will continue with the same dose for next 6 weeks. If their BP is not controlled at Day 85, dose will be increased to the next level (Bisoprolol/Amlodipine 5mg/10mg for subjects receiving Bisoprolol/Amlodipine 5mg/5mg dose and Bisoprolol/Amlodipine and 10mg/10mg for subjects receiving Bisoprolol/Amlodipine 5mg/10mg dose) until Week 18 (Day 127).<br>* Other names: Concor AM;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Baseline was defined as the latest SBP under monotherapy. | Baseline, Week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Baseline was defined as the latest DBP before study treatment administration. | Baseline, Week 18 | 
| Percentage of Subjects With Controlled Blood Pressure |  | Baseline up to Week 18 | 
| Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment | Baseline was defined as the latest HR before study treatment administration | Baseline, Week 18 | 
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment emergent AEs was AEs that started or worsened in severity on or after the date of first dose of IMP until the end of the study. AEs leading to death and discontinued were also presented. | Baseline up to Day 127 (end of trial) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bisoprolol, Amlodipine, Fixed dose combination (FDC), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)