Hypertension
Conditions
Keywords
Hypertension, Bisoprolol, Atenolol
Brief summary
This is a Phase 4, prospective, multi-centric and randomized controlled study to compare the effects of bisoprolol and atenolol on resting heart rate (RHR) and sympathetic nervous system's (SNS) activity in subjects with essential hypertension.
Interventions
DRUGBisoprolol
Bisoprolol will be administered at a dose of 5 milligram (mg) once daily for 2 weeks. If heart rate is less than or equal to 65 beats per minute (bpm), then the initial dose will be administered for another 2 weeks. If the heart rate remains greater than 65 bpm, then the dose will be further increased to 7.5 mg once daily for 2 weeks. After 2 weeks, if the heart rate is less than or equal to 65 bpm, the increased dose will be administered for another 2 weeks. If the heart rate is still greater than 65 bpm, then the dose will be further increased to 10 mg once daily for 2 weeks. After 2 weeks, if the heart rate is less than or equal to 65 bpm, the increased dose will be administered for another 2 weeks.
DRUGAtenolol
Atenolol will be administered at a dose of 50 mg once daily for 2 weeks. If heart rate is less than or equal to 65 bpm, then the initial dose will be administered for another 2 weeks. If the heart rate remains greater than 65 bpm, then the dose will be further increased to 75 mg once daily for 2 weeks. After 2 weeks, if the heart rate is less than or equal to 65 bpm, the increased dose will be administered for another 2 weeks. If the heart rate still greater than 65 bpm, then the dose will be further increased to 100 mg once daily for 2 weeks. After 2 weeks, If the heart rate is less than or equal to 65 bpm, the increased dose will be administered for another 2 weeks.
Sponsors
Merck Serono Co., Ltd., China
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects aged between 25-65 years * Subjects with essential hypertension (EH) * Subjects with systolic blood pressure (SBP) 140-160 millimeter of mercury (mmHg) and diastolic blood pressure (DBP) 90-100 mmHg * Subjects with normal sinus rhythm * Subjects with resting heart rate (RHR) greater than 70 bpm * Subjects who give written informed consent
Exclusion criteria
* Subjects with atrial fibrillation (AF)/sick sinus syndrome (SSS)/atrioventricular block II-III Grade (AVB II-III) without pacemaker * Subjects with bradyarrhythmia/hypotension * Subjects with unstable angina pectoris (UAP)/acute myocardial infarction (AMI)/heart failure (HF) (New York Heart Association \[NYHA\] Class III - IV) * Subjects with uncontrolled diabetes mellitus (DM) * Subjects with bronchial asthma * Subjects with gastro-intestinal ulcer or skin ulcer * Subjects with liver dysfunction/renal impairment * Subjects treated with calcium channel blockers (except amlodipine) or other beta-blockers. * Subjects with glaucoma * Subjects with known allergic/intolerance to beta-blocker * Pregnant or lactating women * Subjects who had participated in another clinical study within the last 3 months * Subjects who have legal incapacity or limited legal capacity
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal | Baseline and attainment of heart rate goal (Week 2 or Week 4 or Week 6) | Baroreflex sensitivity (BRS) is an important characteristic of baroreflex control and often noninvasively assessed by relating heart rate (HR) fluctuations to blood pressure (BP) fluctuations. Heart rate goal was defined as attainment of heart rate less than or equal to 65 beats per minute (bpm). |
| Change From Baseline in Baroreflex Sensitivity (BRS) at End of Follow-up | Baseline and end of follow-up (Week 4 or Week 6 or Week 8) | Baroreflex sensitivity (BRS) is an important characteristic of baroreflex control and often noninvasively assessed by relating heart rate (HR) fluctuations to blood pressure (BP) fluctuations. Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Baseline up to attainment of heart rate goal (Week 2 or Week 4 or Week 6) | Dosage 1, 2 and 3 for bisoprolol group was defined as 5 mg, 7.5 mg and 10 mg once daily and for atenolol group as 50 mg, 75 mg and 100 mg once daily, respectively. Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm. |
| Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Attainment of heart rate goal (Week 2 or Week 4 or Week 6) | Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm. |
| Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Baseline, attainment of heart rate goal (Week 2 or Week 4 or Week 6) and end of follow-up (Week 4 or Week 6 or Week 8) | Heart rate variability (HRV) is used to describe the variations of both instantaneous HR and resting rate (RR) intervals and was evaluated for low frequency power (LF) and for high frequency power (HF). Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm. |
| Number of Participants Compliant With Study Treatment | Baseline up to end of follow-up (Week 4 or Week 6 or Week 8) | Participants compliant with study treatment were the participants who have completed the study treatment regimen. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to end of follow-up (Week 4 or Week 6 or Week 8) | AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition |
| Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Baseline, attainment of heart rate goal (Week 2 or Week 4 or Week 6) and end of follow-up (Week 4 or Week 6 or Week 8) | Heart rate variability (HRV) is used to describe the variations of both instantaneous HR and resting rate (RR) intervals and was evaluated for low frequency power (LF) and for high frequency power (HF). Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bisoprolol Bisoprolol was administered at a dose of 5 milligram (mg) once daily for 2 weeks. If the heart rate was less than or equal to 65 beats per minute (bpm) at Week 2, then the initial dose was administered for another 2 weeks (up to Week 4). If the heart rate was greater than 65 bpm at Week 2, then the dose was further increased to 7.5 mg once daily for 2 weeks (up to Week 4). If the heart rate was less than or equal to 65 bpm at Week 4, the increased dose was administered for another 2 weeks (up to Week 6). If the heart rate was still greater than 65 bpm at Week 4, then the dose was further increased to 10 mg once daily for 2 weeks (up to Week 6). If the heart rate was less than or equal to 65 bpm at Week 6, the increased dose was administered for another 2 weeks (up to Week 8). If the heart rate was still greater than 65 bpm, then the treatment was ceased. | 86 |
| Atenolol Atenolol was administered at a dose of 50 mg once daily for 2 weeks. If the heart rate was less than or equal to 65 bpm at Week 2, then the initial dose was administered for another 2 weeks (up to Week 4). If the heart rate was greater than 65 bpm at Week 2, then the dose was further increased to 75 mg once daily for 2 weeks (up to Week 4). If the heart rate was less than or equal to 65 bpm at Week 4, the increased dose was administered for another 2 weeks (up to Week 6). If the heart rate still greater than 65 bpm at Week 4, then the dose was further increased to 100 mg once daily for 2 weeks (up to Week 6). If the heart rate was less than or equal to 65 bpm at Week 6, the increased dose administered for another 2 weeks. If the heart rate was still greater than 65 bpm, then the treatment was ceased. | 91 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 10 |
Baseline characteristics
| Characteristic | Bisoprolol | Atenolol | Total |
|---|---|---|---|
| Age, Continuous | 45.44 years STANDARD_DEVIATION 9.78 | 46.30 years STANDARD_DEVIATION 9.87 | 45.88 years STANDARD_DEVIATION 9.81 |
| Sex: Female, Male Female | 31 Participants | 38 Participants | 69 Participants |
| Sex: Female, Male Male | 55 Participants | 53 Participants | 108 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 86 | 6 / 91 |
| serious Total, serious adverse events | 0 / 86 | 0 / 91 |
Outcome results
Primary
Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal
Baroreflex sensitivity (BRS) is an important characteristic of baroreflex control and often noninvasively assessed by relating heart rate (HR) fluctuations to blood pressure (BP) fluctuations. Heart rate goal was defined as attainment of heart rate less than or equal to 65 beats per minute (bpm).
Time frame: Baseline and attainment of heart rate goal (Week 2 or Week 4 or Week 6)
Population: Intention to treat (ITT) population included all randomized participants who received at least 1 dose of study medication. N signifies those participants who were evaluated for this measure. n signifies those participants who were evaluated for this measure at the specified time point for each treatment arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal | Baseline (n=75,79) | 7.78 millisecond per millimeter of mercury | Standard Deviation 2.92 |
| Bisoprolol | Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal | Change at attainment of heart rate goal (n=67,66) | 3.27 millisecond per millimeter of mercury | Standard Deviation 3.67 |
| Atenolol | Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal | Baseline (n=75,79) | 7.92 millisecond per millimeter of mercury | Standard Deviation 3.26 |
| Atenolol | Change From Baseline in Baroreflex Sensitivity (BRS) at Attainment of Heart Rate Goal | Change at attainment of heart rate goal (n=67,66) | 2.88 millisecond per millimeter of mercury | Standard Deviation 4.05 |
Primary
Change From Baseline in Baroreflex Sensitivity (BRS) at End of Follow-up
Baroreflex sensitivity (BRS) is an important characteristic of baroreflex control and often noninvasively assessed by relating heart rate (HR) fluctuations to blood pressure (BP) fluctuations. Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm.
Time frame: Baseline and end of follow-up (Week 4 or Week 6 or Week 8)
Population: ITT population included all randomized participants who received at least 1 dose of study medication. N signifies those participants who were evaluated for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bisoprolol | Change From Baseline in Baroreflex Sensitivity (BRS) at End of Follow-up | 4.08 millisecond per millimeter of mercury | Standard Deviation 3.79 |
| Atenolol | Change From Baseline in Baroreflex Sensitivity (BRS) at End of Follow-up | 3.31 millisecond per millimeter of mercury | Standard Deviation 3.83 |
Secondary
Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up
Heart rate variability (HRV) is used to describe the variations of both instantaneous HR and resting rate (RR) intervals and was evaluated for low frequency power (LF) and for high frequency power (HF). Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm.
Time frame: Baseline, attainment of heart rate goal (Week 2 or Week 4 or Week 6) and end of follow-up (Week 4 or Week 6 or Week 8)
Population: ITT population included all randomized participants who received at least 1 dose of study medication. N signifies those participants who were evaluated for this measure. n signifies those participants who were evaluated for this measure at the specified time point for each treatment arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | HRV for LF at Baseline (n=75,79) | 261.80 millisecond square (ms^2) | Standard Deviation 208.4 |
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change for LF: heart rate goal (n=71,71) | 90.04 millisecond square (ms^2) | Standard Deviation 352.97 |
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up for LF (n=71,66) | 89.40 millisecond square (ms^2) | Standard Deviation 330.26 |
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | HRV for HF at Baseline (n=75,79) | 171.26 millisecond square (ms^2) | Standard Deviation 161.43 |
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change for HF: heart rate goal (n=71,71) | 148.91 millisecond square (ms^2) | Standard Deviation 338.13 |
| Bisoprolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up for HF (n=71,66) | 186.46 millisecond square (ms^2) | Standard Deviation 288.53 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change for HF: heart rate goal (n=71,71) | 136.67 millisecond square (ms^2) | Standard Deviation 314.47 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | HRV for LF at Baseline (n=75,79) | 322.09 millisecond square (ms^2) | Standard Deviation 315.3 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | HRV for HF at Baseline (n=75,79) | 193.48 millisecond square (ms^2) | Standard Deviation 216.06 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change for LF: heart rate goal (n=71,71) | 26.14 millisecond square (ms^2) | Standard Deviation 416.51 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up for HF (n=71,66) | 178.05 millisecond square (ms^2) | Standard Deviation 375.7 |
| Atenolol | Change From Baseline in Heart Rate Variability (HRV) for Low Frequency Power (LF) and for High Frequency Power (HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up for LF (n=71,66) | -22.00 millisecond square (ms^2) | Standard Deviation 295.54 |
Secondary
Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up
Heart rate variability (HRV) is used to describe the variations of both instantaneous HR and resting rate (RR) intervals and was evaluated for low frequency power (LF) and for high frequency power (HF). Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm.
Time frame: Baseline, attainment of heart rate goal (Week 2 or Week 4 or Week 6) and end of follow-up (Week 4 or Week 6 or Week 8)
Population: ITT population included all randomized participants who received at least 1 dose of study medication. N signifies those participants who were evaluated for this measure. n signifies those participants who were evaluated for this measure at the specified time point for each treatment arm group respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bisoprolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Baseline (n=75,79) | 2.16 ratio | Standard Deviation 1.89 |
| Bisoprolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at attainment of heart rate goal (n=71,71) | -0.70 ratio | Standard Deviation 1.76 |
| Bisoprolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up (n=71,66) | -0.69 ratio | Standard Deviation 2.08 |
| Atenolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Baseline (n=75,79) | 2.40 ratio | Standard Deviation 1.96 |
| Atenolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at attainment of heart rate goal (n=71,71) | -0.90 ratio | Standard Deviation 1.62 |
| Atenolol | Change From Baseline in Ratio of Heart Rate Variability (HRV) for Low Frequency Power (LF) to Heart Rate Variability Power (HRV) for High Frequency (HF) (LF/HF) at Attainment of Heart Rate Goal and End of Follow-up | Change at end of follow-up (n=71,66) | -1.15 ratio | Standard Deviation 1.68 |
Secondary
Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment
Dosage 1, 2 and 3 for bisoprolol group was defined as 5 mg, 7.5 mg and 10 mg once daily and for atenolol group as 50 mg, 75 mg and 100 mg once daily, respectively. Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm.
Time frame: Baseline up to attainment of heart rate goal (Week 2 or Week 4 or Week 6)
Population: ITT population included all randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bisoprolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 1 | 72 participants |
| Bisoprolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 2 | 7 participants |
| Bisoprolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 3 | 1 participants |
| Atenolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 1 | 72 participants |
| Atenolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 2 | 6 participants |
| Atenolol | Number of Participants Attaining Heart Rate Goal at Dosage 1, 2 and 3 of Study Treatment | Dosage 3 | 0 participants |
Secondary
Number of Participants Compliant With Study Treatment
Participants compliant with study treatment were the participants who have completed the study treatment regimen.
Time frame: Baseline up to end of follow-up (Week 4 or Week 6 or Week 8)
Population: ITT population included all randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bisoprolol | Number of Participants Compliant With Study Treatment | 83 participants |
| Atenolol | Number of Participants Compliant With Study Treatment | 81 participants |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE: any new untoward medical occurrence/worsening of pre-existing medical condition, whether or not related to study drug. SAE: Any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was a medically important condition
Time frame: Baseline up to end of follow-up (Week 4 or Week 6 or Week 8)
Population: Safety population included all randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bisoprolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with AEs | 6 participants |
| Bisoprolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with SAEs | 0 participants |
| Atenolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with AEs | 6 participants |
| Atenolol | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with SAEs | 0 participants |
Secondary
Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6
Heart rate goal was defined as attainment of heart rate less than or equal to 65 bpm.
Time frame: Attainment of heart rate goal (Week 2 or Week 4 or Week 6)
Population: ITT population included all randomized participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bisoprolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 2 | 83.72 percentage of participants |
| Bisoprolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 4 | 91.86 percentage of participants |
| Bisoprolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 6 | 93.02 percentage of participants |
| Atenolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 2 | 79.12 percentage of participants |
| Atenolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 4 | 85.71 percentage of participants |
| Atenolol | Percentage of Participants Attaining Heart Rate Goal at Week 2, 4 and 6 | Week 6 | 85.71 percentage of participants |