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

• ClinicalTrials.gov Identifier: NCT01508325
• Recruitment Status: Completed
• First Posted: January 11, 2012
• Results First Posted: May 13, 2015
• Last Update Posted: May 13, 2015
• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborator: Merck Serono Co., Ltd., China
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Bisoprolol; Drug: Metoprolol	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 186 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Comparison of Bisoprolol With Metoprolol Succinate Sustained-release on Heart Rate and Blood Pressure in Hypertensive Patients (CREATIVE Study)
• Study Start Date: December 2011
• Actual Primary Completion Date: April 2014
• Actual Study Completion Date: April 2014

Arms and Interventions

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 Name: 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 Name: Betaloc SR

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Mean Ambulatory Diastolic Blood Pressure (DBP) in the Last 4 Hours After 12-week Treatment [ Time Frame: Baseline and Week 12 ]
   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.
2. Change From Baseline in Mean Heart Rate in the Last 4 Hours After 12-week Treatment [ Time Frame: Baseline and 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 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.

Secondary Outcome Measures :

1. Change From Baseline in Mean Ambulatory Systolic Blood Pressure (SBP) in the Last 4 Hours After 12-week Treatment [ Time Frame: Baseline and 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 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.
2. Change From Baseline in Mean Ambulatory 24-hour Blood Pressure at Week 12 [ Time Frame: Baseline and 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.
3. Change From Baseline in Mean Ambulatory Daytime Blood Pressure at Week 12 [ Time Frame: Baseline and 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.
4. Change From Baseline in Mean Ambulatory Night-time Blood Pressure at Week 12 [ Time Frame: Baseline and 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.
5. Change From Baseline in Mean Ambulatory Daytime Heart Rate at Week 12 [ Time Frame: Baseline and 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.
6. Change From Baseline in Mean Ambulatory Night-time Heart Rate at Week 12 [ Time Frame: Baseline and 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.
7. Change From Baseline in 24-hour Blood Pressure Variability at Week 12 [ Time Frame: Baseline and 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.
8. Blood Pressure Response Rate [ Time Frame: Week 12 ]
   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.
9. Heart Rate Response Rate [ Time Frame: Week 12 ]
   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.
10. Change From Baseline in Mean Ambulatory 24-hour Heart Rate at Week 12 [ Time Frame: Baseline and 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

China

Merck Serono Investigational Site

Changsha City, China

Sponsors and Collaborators

Merck KGaA, Darmstadt, Germany

Merck Serono Co., Ltd., China

Investigators

• Study Director: Medical Director; Merck Serono Co., Ltd., China

More Information

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01508325
• Other Study ID Numbers: EMR200006-520
• First Posted: January 11, 2012
• Results First Posted: May 13, 2015
• Last Update Posted: May 13, 2015
• Last Verified: April 2015

Keywords provided by Merck KGaA, Darmstadt, Germany:

Bisoprolol; Hypertension; Blood pressure; Heart rate

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Metoprolol; Bisoprolol; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action