Phase 4 Study to Assess the Effect of Bisoprolol on Glycemic Level in Type II Diabetic Subjects With Suboptimal Blood Pressure Control (GIANT)

A Prospective, Multi-center, Open-label, Single Arm Study to Assess the Effect of Bisoprolol on Glycemic Level in Type II DIAbetic patieNTs With Suboptimal Blood Pressure Control (GIANT Study)

This is a 24-week, prospective, multicenter, open-label, single-arm study to assess the effect of bisoprolol on glycemic level in Type 2 diabetes mellitus (T2DM) controlled subjects with hypertension. The hypothesis of study is that there is no change in glycemic level and lipid metabolism as determined by glycosylated hemoglobin (HbA1c) using bisoprolol in T2DM subjects with suboptimal blood pressure (BP) control.

Study Overview

• Status: Completed
• Conditions: Hypertension; Diabetes Mellitus, Type II
• Intervention / Treatment: Drug: Bisoprolol

Detailed Description

Diabetes mellitus and hypertension are two of the most common chronic conditions, and each predisposes to accelerated atherosclerosis, cardiovascular disease, and death. There has been a concern that beta-blocker might have adverse effects in subjects with diabetes on glucose metabolism, but some data shows that highly beta-1 selective agents such as bisoprolol are essentially free of metabolic disturbances involving blood sugar, insulin sensitivity and lipids.

This is a prospective, multicenter, single-arm, open-label study to assess the glycemic effect of bisoprolol in T2DM subjects with suboptimal BP control.

After pre-screening period, each enrolled subject with T2DM and suboptimal BP control will undergo laboratory test for efficacy and safety measurement. After that, subject will continue his/her usual dosage of antihypertensive medication and bisoprolol will be added.

Subjects will be instructed to continue their diet and level of physical activity and to attempt to maintain current body weight until completion of the study.

Bisoprolol will be titrated upward until a dosage that lowers BP to less than 130/80 millimeter of mercury (mmHg) during the first 2 months of treatment. The maximum dosage of bisoprolol will be 10 mg once daily. Following 6 month of added bisoprolol therapy, all efficacy and safety measurements will be repeated.

The duration of study will be up to 24 weeks for each subject.

Objectives

Primary objective:

• To assess the effect of bisoprolol on glycemic control measured by change from baseline in HbA1c in T2DM subjects with suboptimal BP control

Secondary objectives:

• To evaluate the effects of bisoprolol, as add-on therapy, on BP in T2DM subjects with suboptimal BP control
• To evaluate the effects of bisoprolol, as add-on therapy, on insulin sensitivity as determined by Homeostasis Model Assessment-Insulin Resistance (HOMA-IR)
• To evaluate the effects of bisoprolol, as add-on therapy, on lipid metabolism as determined by lipid profile in T2DM subjects with suboptimal BP control
• To evaluate the safety and tolerability of bisoprolol in T2DM subjects with suboptimal BP control
• To assess the effects of bisoprolol combination therapy on insulin and c-peptide in T2DM subjects with suboptimal BP control compared to baseline
• To assess the effects of bisoprolol combination therapy on microalbumin and albumin/creatinine ratio in T2DM subjects with suboptimal BP control compared to baseline

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Seoul St. Mary´s Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age of 20 years or older and less than 80 years
• Subjects with T2DM
• Subjects who have failed to achieve an appropriate BP level as a result of treatment with any antihypertensive drug other than beta blockers - that is, with BP inadequately controlled to greater than or equal to (>=) 130/80 mmHg. However, those who have used a beta blocker before 12 weeks can be enrolled
• Subjects who underwent stable anti-diabetic regimen during the 12 weeks prior to screening
• Signed written informed consent

Exclusion Criteria:

• Ongoing insulin therapy
• Change in two HbA1c levels measured at an interval of 4 weeks or longer for the previous 6 months is at least 1% (the last HbA1c is measured within 4 weeks)
• Secondary hypertension
• Subjects with renal impairment (creatinine greater than 150 micromol per liter or 1.7 milligram per deciliter)
• Cardiovascular disease (uncontrolled or symptomatic arrhythmia, unstable angina, sick sinus syndrome, second or third degree atrioventricular (AV) block, bradycardia [less than 50 beats per minute], congestive heart failure, myocardial infarction, cerebral infraction attached within 12 weeks)
• Subjects requiring BP control by at least 3 different antihypertensive drugs, or with either systolic blood pressure (SBP) >=180 mmHg or diastolic blood pressure (DBP) >=110 mmHg at baseline
• Subjects with type 1 diabetes mellitus (T1DM)
• Uncontrolled diabetes with HbA1c >9%
• BMI >40 kilogram per square meter (kg/m^2)
• Pulmonary disease (chronic obstructive pulmonary disease [COPD], bronchial asthma)
• Other patients considered by the investigator to be not eligible for participation in this study for a legal or mental reason
• Contraindications for beta-blocker
• Pregnant or lactating women
• Use of an investigational drug within 30 days of entry to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bisoprolol

Drug: Bisoprolol; Bisoprolol tablet will be administered orally at dose of 5 milligram (mg) once daily for 24 weeks. If the blood pressure is not less than 130/80 millimeter of mercury (mmHg) during the first 8 weeks of treatment (up-titration), then the dose will be adjusted to 10 mg daily. In cases of hypotensive effect, symptomatic bradycardia or arrhythmia, the daily dose will be reduced to 2.5 mg.; Other Names: Concor; Concor Plus; ConcorCor; Lodoz

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 6	HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 6 was calculated as HbA1c at Month 6 minus HbA1c at baseline.	Baseline, Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 3	HbA1c represents the percentage of glycosylated hemoglobin. The change in HbA1c at Month 3 was calculated as HbA1c at Month 3 minus HbA1c at baseline.	Baseline, Month 3
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Blood Pressure (BP) at Month 6	The change in SBP, DBP, and mean BP at Month 6 were calculated as SBP, DBP, and mean BP at Month 6 minus SBP, DBP, and mean BP at baseline, respectively. Mean BP was calculated using the formula: (DBP plus [{SBP minus DBP} divided by 3]).	Baseline, Month 6
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Months 3 and 6	HOMA-IR is as an indicator of insulin resistance in participants with Type 2 diabetes mellitus and comorbid hypertension. HOMA-IR was derived from fasting plasma glucose (FPG) and fasting insulin (FI) using the formula: (FI [micro international units per milliliter {mcIU/mL}] * FPG [millimole per liter {mmol/L}]) divided by 22.5. The change in HOMA-IR at Months 3 and 6 was calculated as HOMA-IR at Months 3 and 6 minus HOMA-IR at baseline.	Baseline, Months 3 and 6
Change From Baseline in Insulin Level at Months 3 and 6	The change in insulin level at Months 3 and 6 was calculated as insulin level at Months 3 and 6 minus insulin level at baseline.	Baseline, Months 3 and 6
Change From Baseline in C-Peptide Level at Months 3 and 6	The change in C-peptide level at Months 3 and 6 was calculated as C-peptide level at Months 3 and 6 minus C-peptide level at baseline.	Baseline, Months 3 and 6
Change From Baseline in Total Cholesterol, Low Density Lipoprotein (LDL) Cholesterol, High Density Lipoprotein (HDL) Cholesterol and Triglyceride Level at Month 6	The change in total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride levels at Month 6 was calculated as total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at Month 6 minus total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels at baseline, respectively.	Baseline, Month 6
Change From Baseline in Albumin/Creatinine Ratio at Month 6	The change in albumin/creatinine ratio at Month 6 was calculated as albumin/creatinine ratio at Month 6 minus albumin/creatinine ratio at baseline.	Baseline, Month 6
Change From Baseline in Microalbumin Level at Month 6	The change in microalbumin level at Month 6 was calculated as microalbumin level at Month 6 minus microalbumin level at baseline.	Baseline, Month 6
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An Adverse Event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A Serious Adverse Event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.	Baseline up to Month 6

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Ltd.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: February 8, 2010
• First Submitted That Met QC Criteria: February 9, 2010
• First Posted (Estimate): February 10, 2010

Study Record Updates

• Last Update Posted (Estimate): July 4, 2014
• Last Update Submitted That Met QC Criteria: June 4, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension; Blood pressure; Bisoprolol; Diabetes mellitus, Type II; Glycemic level
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Bisoprolol
• Other Study ID Numbers: EMR 200006-509

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No