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

This study has been completed.
Sponsor:
Collaborator:
Merck Serono Co., Ltd., China
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01508325
First received: January 9, 2012
Last updated: April 28, 2015
Last verified: April 2015
  Purpose

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 Intervention Phase
Hypertension
Drug: Bisoprolol
Drug: Metoprolol
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Heart Rate in the Last 4 Hours After 12-week Treatment [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory 24-hour Blood Pressure at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory Daytime Blood Pressure at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory Night-time Blood Pressure at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory Daytime Heart Rate at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory Night-time Heart Rate at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in 24-hour Blood Pressure Variability at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.

  • Blood Pressure Response Rate [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    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.

  • Heart Rate Response Rate [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Mean Ambulatory 24-hour Heart Rate at Week 12 [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    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.


Enrollment: 186
Study Start Date: December 2011
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01508325

Locations
China
Merck Serono Investigational Site
Changsha City, China
Sponsors and Collaborators
Merck KGaA
Merck Serono Co., Ltd., China
Investigators
Study Director: Medical Director Merck Serono Co., Ltd., China
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01508325     History of Changes
Other Study ID Numbers: EMR200006-520
Study First Received: January 9, 2012
Results First Received: April 28, 2015
Last Updated: April 28, 2015
Health Authority: China: Ethics Committee

Keywords provided by Merck KGaA:
Bisoprolol
Hypertension
Blood pressure
Heart rate

Additional relevant MeSH terms:
Bisoprolol
Metoprolol
Metoprolol succinate
Adrenergic Agents
Adrenergic Antagonists
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Anti-Arrhythmia Agents
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sympatholytics
Therapeutic Uses

ClinicalTrials.gov processed this record on May 29, 2015