Hypertension
Conditions
Keywords
Bisoprolol, Amlodipine, Fixed dose combination (FDC), Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP)
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).
Interventions
DRUGBisoprolol/Amlodipine (Bisoprolol failed group)
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).
DRUGBisoprolol/Amlodipine (Amlodipine failed group)
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).
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Baseline, Week 18 | Baseline was defined as the latest SBP under monotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Baseline, Week 18 | Baseline was defined as the latest DBP before study treatment administration. |
| 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, Week 18 | Baseline was defined as the latest HR before study treatment administration |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | Baseline up to Day 127 (end of trial) | 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. |
Countries
Germany
Participant flow
Recruitment details
The study was conducted at 10 clinical trial sites in Guatemala.
Pre-assignment details
A total of 200 subjects (100 subjects in the amlodipine failed group, and 100 subjects in the bisoprolol failed group) were enrolled and randomized in the trial. Out of which 196 subjects (97 subjects in amlodipine failed group and 99 subjects in bisoprolol failed group) were included in modified intent-to-treat (MITT) analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Amlodipine Failed Group Subjects who failed monotherapy with amlodipine 5 mg before trial inclusion were randomized to amlodipine failed group to receive Bisoprolol/Amlodipine FDC tablet. Bisoprolol/Amlodipine FDC tablet was orally administered at an initial dose of 5 mg/5 mg once daily for 6 weeks. If BP was controlled at Week 6 (Day 43), the same dose was continued for next 6 weeks. If the BP was not controlled at Day 43, the dose was increased to Bisoprolol/Amlodipine 5 mg/10 mg or 10 mg/5 mg for next 6 weeks. Subjects who had controlled BP at Week 12 (Day 85), continued with the same dose that they were receiving for next 6 weeks. If their BP was not controlled at Day 85, dose was increased to the next level (Bisoprolol/Amlodipine 5 mg/10 mg for subjects receiving Bisoprolol/Amlodipine 5 mg/5 mg dose and Bisoprolol/Amlodipine and 10 mg/10 mg for subjects receiving Bisoprolol/Amlodipine 5 mg/10 mg dose) until Week 18 (Day 127). Controlled BP= SBP \<140 mmHg and DBP \<90 mmHg. | 97 |
| Bisoprolol Failed Group Subjects who failed monotherapy with bisoprolol 5 mg before trial inclusion were randomized to bisoprolol failed group to receive Bisoprolol/Amlodipine FDC tablet. Bisoprolol/Amlodipine FDC tablet was orally administered at an initial dose of 5 mg/5 mg once daily for 6 weeks. If BP was controlled at Week 6 (Day 43), the same dose was continued for next 6 weeks. If the BP was not controlled at Day 43, the dose was increased to Bisoprolol/Amlodipine 5 mg/10 mg or 10 mg/5 mg for next 6 weeks. Subjects who had controlled BP at Week 12 (Day 85), continued with the same dose that they were receiving for next 6 weeks. If their BP was not controlled at Day 85, dose was increased to the next level (Bisoprolol/Amlodipine 5 mg/10 mg for subjects receiving Bisoprolol/Amlodipine 5 mg/5 mg dose and Bisoprolol/Amlodipine and 10 mg/10 mg for subjects receiving Bisoprolol/Amlodipine 5mg/10mg dose) until Week 18 (Day 127). Controlled BP= SBP \<140 mmHg and DBP \<90 mmHg. | 99 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrew consent | 2 | 1 |
Baseline characteristics
| Characteristic | Amlodipine Failed Group | Bisoprolol Failed Group | Total |
|---|---|---|---|
| Age, Continuous | 63.4 years STANDARD_DEVIATION 11.62 | 59.6 years STANDARD_DEVIATION 12.05 | 61.5 years STANDARD_DEVIATION 11.96 |
| Gender Female | 77 Participants | 72 Participants | 149 Participants |
| Gender Male | 20 Participants | 27 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 63 / 100 | 53 / 100 |
| serious Total, serious adverse events | 1 / 100 | 2 / 100 |
Outcome results
Primary
Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline
Baseline was defined as the latest SBP under monotherapy.
Time frame: Baseline, Week 18
Population: MITT analysis set was defined as all randomized and treated subjects with at least 1 SBP measurement after the date of first dose of IMP. Here Number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amlodipine Failed Group | Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Baseline | 150.6 millimeters of mercury (mmHg) | Standard Deviation 8.21 |
| Amlodipine Failed Group | Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Change at Week 18 | -24.7 millimeters of mercury (mmHg) | Standard Deviation 11.67 |
| Bisoprolol Failed Group | Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Baseline | 151.6 millimeters of mercury (mmHg) | Standard Deviation 11.57 |
| Bisoprolol Failed Group | Mean Reduction In Systolic Blood Pressure (SBP) After 18 Weeks of Treatment From Baseline | Change at Week 18 | -25.9 millimeters of mercury (mmHg) | Standard Deviation 12.82 |
Comparison: For each group (Amlodipine failed and Bisoprolol failed) SBP after 18 weeks compared to baseline (under monotherapy). Superiority was assessed between FDC and monotherapies.p-value: <0.001Paired t test
Secondary
Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment
Baseline was defined as the latest DBP before study treatment administration.
Time frame: Baseline, Week 18
Population: MITT analysis set was defined as all randomized and treated subjects with at least 1 SBP measurement after the date of first dose of IMP. Here Number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amlodipine Failed Group | Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Baseline | 90.5 mmHg | Standard Deviation 6.92 |
| Amlodipine Failed Group | Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Change at Week 18 | -13.0 mmHg | Standard Deviation 9.38 |
| Bisoprolol Failed Group | Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Baseline | 92.0 mmHg | Standard Deviation 8.81 |
| Bisoprolol Failed Group | Change From Baseline in Diastolic Blood Pressure (DBP) After 18 Weeks of Treatment | Change at Week 18 | -14.0 mmHg | Standard Deviation 7.73 |
Secondary
Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment
Baseline was defined as the latest HR before study treatment administration
Time frame: Baseline, Week 18
Population: MITT analysis set was defined as all randomized and treated subjects with at least 1 SBP measurement after the date of first dose of IMP. Here Number of subjects analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Amlodipine Failed Group | Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment | Baseline | 73.6 beats per minute | Standard Deviation 8.96 |
| Amlodipine Failed Group | Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment | Change from baseline at Week 18 | -11.5 beats per minute | Standard Deviation 8.65 |
| Bisoprolol Failed Group | Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment | Baseline | 69.9 beats per minute | Standard Deviation 9.7 |
| Bisoprolol Failed Group | Change From Baseline in Heart Rate (HR) After 18 Weeks of Treatment | Change from baseline at Week 18 | -6.6 beats per minute | Standard Deviation 9.67 |
Secondary
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.
Time frame: Baseline up to Day 127 (end of trial)
Population: Safety analysis set included all subjects who received at least 1 dose of IMP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amlodipine Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | TEAEs | 78 subjects |
| Amlodipine Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | Serious TEAEs | 1 subjects |
| Amlodipine Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | AEs leading to discontinuation | 3 subjects |
| Amlodipine Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | AEs leading to death | 1 subjects |
| Bisoprolol Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | AEs leading to death | 1 subjects |
| Bisoprolol Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | TEAEs | 71 subjects |
| Bisoprolol Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | AEs leading to discontinuation | 3 subjects |
| Bisoprolol Failed Group | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Discontinuation and AEs Leading to Death | Serious TEAEs | 2 subjects |
Secondary
Percentage of Subjects With Controlled Blood Pressure
Time frame: Baseline up to Week 18
Population: MITT analysis set included all randomized and treated subjects with at least 1 SBP measurement after the date of first dose of IMP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Amlodipine Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 6 | 85.6 percentage of subjects |
| Amlodipine Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 12 | 86.8 percentage of subjects |
| Amlodipine Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 18 | 86.7 percentage of subjects |
| Bisoprolol Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 6 | 80.8 percentage of subjects |
| Bisoprolol Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 12 | 87.9 percentage of subjects |
| Bisoprolol Failed Group | Percentage of Subjects With Controlled Blood Pressure | Week 18 | 89.0 percentage of subjects |