Comparison of Bisoprolol With Metoprolol Succinate Sustained-release on Heart Rate and Blood Pressure in Hypertensive Patients (CREATIVE)

Comparison of Bisoprolol With Metoprolol Succinate Sustained-release on Heart Rate and Blood Pressure in Hypertensive Patients (CREATIVE Study)

This is a multicentre, randomized, open-label parallel trial to demonstrate the superiority and/or non-inferiority of bisoprolol on metoprolol succinate sustained-release (SR) tablet in subjects with mild to moderate primary hypertension.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Bisoprolol; Drug: Metoprolol

Detailed Description

Primary objectives:

To demonstrate that bisoprolol is superior in mean ambulatory heart rate and/or non-inferior in mean ambulatory DBP as compared with metoprolol SR in the last 4 hours after 12-week active treatment in subjects with mild to moderate essential hypertension (EH).

Secondary objectives:

1. To compare the efficacy of the 2 study drugs by 24h ambulatory monitoring by several parameters at different times (Example: blood pressure, heart rate, their variability, etc...) after 12-week treatment from baseline among subjects with mild to moderate EH
2. To evaluate safety of the two drugs
3. To evaluate the treatment compliance of the two drugs

• Study Type: Interventional
• Enrollment (Actual): 186
• Phase: Phase 4

Contacts and Locations

Study Locations

• China
  • Changsha City, China
    • Merck Serono Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subjects aged: >=18 years and =<70 years old
2. EH who are suitable for mono-therapy, either mild to moderate EH patients who have not been treated with anti-hypertension drugs, or mild EH subjects who have taken anti-hypertension drug.
3. Clinic resting Heart Rate >=70 beats per minute (bpm)
4. Patients who have signed informed consent

Exclusion Criteria:

1. Subjects with contraindications according to the China Summary of Product Characteristics (SmPCs) of both bisoprolol and metoprolol SR, such as acute heart failure, second or third degree atrioventricular block (without a pacemaker), sick sinus syndrome, symptomatic bradycardia or symptomatic hypotension, severe bronchial asthma or severe chronic obstructive pulmonary disease, metabolic acidosis, etc.
2. Moderate EH patients who have used anti-hypertension drugs
3. Secondary hypertension
4. Subjects with history of coronary heart disease
5. Chronic or acute heart failure
6. Cerebrovascular events within 6 months before screening
7. Impaired hepatic or renal function (according to local lab standard)
8. Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bisoprolol	Drug: Bisoprolol; Subjects will receive bisoprolol fumarate (Concor®) at a dose of 5 milligram (mg) once daily orally as sustained release (SR) tablets for a period of 4 weeks. The dose of bisoprolol will be escalated to 7.5 mg orally once daily for next 4 weeks (Weeks 4 to 8) and to 10 mg orally once daily for the next 4 weeks (Weeks 8 to 12), if clinic systolic blood pressure (SBP) was greater than or equal to (>=) 140 millimeters of mercury (mmHg) and/or diastolic blood pressure (DBP) was >=90 mmHg measured every 4 weeks.; Other Names: Concor
Active Comparator: Metoprolol	Drug: Metoprolol; Subjects will receive metoprolol succinate (Betaloc SR) at a dose of 47.5 mg once daily orally as SR tablets for a period of 4 weeks. The dose of metoprolol will be escalated to 71.25 mg orally once daily for next 4 weeks (Weeks 4 to 8) and to 95 mg orally once daily for the next 4 weeks (Weeks 8 to 12) if clinic SBP was >=140 mmHg and/or DBP was >=90 mmHg measured every 4 weeks.; Other Names: Betaloc SR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (DBP) in the Last 4 Hours After 12-week Treatment	Ambulatory blood pressure monitoring (ABPM) determined blood pressure 3 times hourly in the daytime and once hourly in the nighttime. Only monitoring data with valid data greater than or equal to (>=) 80 percent (%) was used for analysis. Each ABPM lasted for at least 24 hours. The first dynamic blood pressure monitoring was used as baseline. The difference between the mean ambulatory DBP observed in the last 4 hours after 12-week treatment and baseline was calculated to find out the change of mean ambulatory DBP at the end of the treatment.	Baseline and Week 12
Change From Baseline in Mean Heart Rate in the Last 4 Hours After 12-week Treatment	Pulse rate was measured by palpation on radial artery for 1 minute. Two measurements were made at least 1 to 2 minutes apart. Finally mean heart rate was recorded. The first measured heart rate was used as baseline heart rate. The difference between the last 4 hours heart rate after 12-week treatment and of the baseline heart rate was calculated to measure the change in mean heart rate at the end of the treatment.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Ambulatory Systolic Blood Pressure (SBP) in the Last 4 Hours After 12-week Treatment	The ABPM determined blood pressure 3 times hourly in the daytime and once hourly in the nighttime. Only monitoring data with valid data >=80% was used for analysis. Each ABPM lasted for at least 24 hours. The first dynamic blood pressure monitoring was used as baseline. The difference between the mean ambulatory SBP observed in the last 4 hours after 12-week treatment and baseline was calculated to find out the change of mean ambulatory SBP at the end of the treatment.	Baseline and Week 12
Change From Baseline in Mean Ambulatory 24-hour Blood Pressure at Week 12	The ABPM determined blood pressure 3 times hourly in the daytime and once hourly in the nighttime. Only monitoring data with valid data >=80% was used for analysis. Each ABPM lasted for at least 24 hours. The first dynamic blood pressure monitoring was used as baseline. The difference between the mean ABPM observed in the last 24 hours at Week 12 and baseline was calculated to find out the change of mean ABPM at the end of the treatment.	Baseline and Week 12
Change From Baseline in Mean Ambulatory Daytime Blood Pressure at Week 12	The ABPM determined blood pressure 3 times hourly in the daytime. Only monitoring data with valid data >=80% was used for analysis. Each ABPM lasted for at least 24 hours. The first dynamic daytime blood pressure monitoring was used as baseline. The difference between the mean ambulatory daytime blood pressure observed at Week 12 and baseline was calculated to find out the change of mean ambulatory daytime blood pressure at the end of the treatment. Daytime in this study was defined as time between 06:00 am to 10:00 pm.	Baseline and Week 12
Change From Baseline in Mean Ambulatory Night-time Blood Pressure at Week 12	The ABPM determined blood pressure once hourly in the nighttime. Only monitoring data with valid data >=80% was used for analysis. Each ABPM lasted for at least 24 hours. The first nighttime blood pressure monitoring was used as baseline. The difference between the mean ambulatory nighttime blood pressure observed at Week 12 and baseline was calculated to find out the change of mean ambulatory nighttime blood pressure at the end of the treatment. Nighttime in this study was defined as 10:00 pm to 06:00 am.	Baseline and Week 12
Change From Baseline in Mean Ambulatory Daytime Heart Rate at Week 12	Pulse rate was measured by palpation on radial artery for 1 minute. Two measurements were made at least 1 to 2 minutes apart. Finally mean heart rate was recorded. The first measured daytime heart rate was used as baseline heart rate. The difference between the daytime heart rate at Week 12 treatment and of the baseline heart rate was calculated to measure the change of mean ambulatory daytime heart rate at the end of the treatment. Daytime in this study was defined as 06:00 am to 10:00 pm.	Baseline and Week 12
Change From Baseline in Mean Ambulatory Night-time Heart Rate at Week 12	Pulse rate was measured by palpation on radial artery for 1 minute. Two measurements were made at least 1 to 2 minutes apart. Finally mean heart rate was recorded. The first measured heart rate was used as baseline heart rate. The difference between the nighttime heart rate at Week 12 treatment and of the baseline heart rate was calculated to measure the change of mean ambulatory nighttime heart rate at the end of the treatment. Nighttime was defined as 10:00 pm to 06:00 am.	Baseline and Week 12
Change From Baseline in 24-hour Blood Pressure Variability at Week 12	The ABPM determined blood pressure 3 times hourly in the daytime and once hourly in the nighttime. Only monitoring data with valid data >=80% was used for analysis. Each ABPM lasted for at least 24 hours. The first dynamic blood pressure monitoring was used as baseline. The mean change in the blood pressure variability between the 24-hour blood pressure observed at Week 12 and baseline was calculated.	Baseline and Week 12
Blood Pressure Response Rate	Blood pressure response was defined as DBP less than or equal to (=<) 90 mmHg or >=10 mmHg decrease in DBP from baseline. Blood pressure response rate was calculated as: number of subjects with blood pressure response divided by total number of subjects and multiplied by 100.	Week 12
Heart Rate Response Rate	Heart rate response was defined as decrease in heart rate from baseline >=10 percent (%). Heart rate response rate was calculated by using the number of subjects with heart rate response divided by total number of subjects and multiplied by 100.	Week 12
Change From Baseline in Mean Ambulatory 24-hour Heart Rate at Week 12	Pulse rate was measured by palpation on radial artery for 1 minute. Two measurements were made at least 1 to 2 minutes apart. Finally mean heart rate was recorded. The first measured heart rate was used as baseline heart rate. The difference between the last 24 hours heart rate at Week 12 and of the baseline heart rate was calculated.	Baseline and Week 12

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Serono Co., Ltd., China
• Investigators: Study Director: Medical Director, Merck Serono Co., Ltd., China

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: January 9, 2012
• First Submitted That Met QC Criteria: January 9, 2012
• First Posted (Estimate): January 11, 2012

Study Record Updates

• Last Update Posted (Estimate): May 13, 2015
• Last Update Submitted That Met QC Criteria: April 28, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: Hypertension; Blood pressure; Bisoprolol; Heart rate
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Bisoprolol; Metoprolol
• Other Study ID Numbers: EMR200006-520