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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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)

Conditions
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Hypertension, Diabetes Mellitus, Type II

Intervention / Treatment
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* Drug: Bisoprolol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bisoprolol<br> | Drug: Bisoprolol<br>* 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.<br>* Other names: Lodoz;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bisoprolol, Hypertension, Diabetes mellitus, Type II, Blood pressure, Glycemic level