A Phase 4 interventional study of Bisoprolol in Hypertension and Diabetes Mellitus, Type II, sponsored by Merck KGaA, Darmstadt, Germany. Completed at 1 site in Korea, Republic of. Open to participants aged 20 Years to 80 Years. Per ClinicalTrials.gov, last updated 2014-07-04.
Sponsored by Merck KGaA, Darmstadt, Germany · Phase 4, Interventional, and Treatment
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.
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:
Secondary objectives:
6,689 studies on the registry are indexed under Hypertension; 965 are open to participants now.
This study's enrollment of 202 is above the median of 90 across 4,995 interventional studies indexed under Hypertension.
Browse Hypertension studies →Merck KGaA, Darmstadt, Germany is the lead sponsor of 269 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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.
Also known as: Concor, Concor Plus, ConcorCor, Lodoz
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.
Time frame: Baseline, Month 6
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.
Time frame: 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 \[{SBP minus DBP} divided by 3\]).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline up to Month 6
| Milestone | Bisoprolol |
|---|---|
| Started | 202 |
| Treated | 200 |
| Completed | 158 |
| Not completed | 44 |
| Withdrew: Adverse event | 6 |
| Withdrew: Withdrawal by subject | 17 |
| Withdrew: Protocol violation | 2 |
| Withdrew: Inclusion/exclusion criteria violation | 9 |
| Withdrew: Investigator's request | 1 |
| Withdrew: Dropout due to insulin administration | 1 |
| Withdrew: Additional antihypertensive required | 4 |
| Withdrew: Volunteer failed to make the next visit | 2 |
| Withdrew: Failure to control blood pressure | 1 |
| Withdrew: Drug/dose adjustment required | 1 |
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.
| Percent HbA1c | Bisoprolol |
|---|---|
| Baseline | 6.79 ± 0.66 |
| Change at Month 6 | 0.26 ± 0.64 |
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.
| Percent HbA1c | Bisoprolol |
|---|---|
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Month 3 | 0.15 ± 0.51 |
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 \[{SBP minus DBP} divided by 3\]).
| mmHg | Bisoprolol |
|---|---|
| SBP: Baseline | 147.8 ± 11.5 |
| SBP: Change at Month 6 | -13.4 ± 15.4 |
| DBP: Baseline | 89.0 ± 7.3 |
| DBP: Change at Month 6 | -9.1 ± 9.0 |
| Mean BP: Baseline | 108.6 ± 6.9 |
| Mean BP: Change at Month 6 | -10.5 ± 10.2 |
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.
| mcIU/mL * mmol/L | Bisoprolol |
|---|---|
| Baseline | 2.3 ± 1.8 |
| Change at Month 3 | 0.1 ± 1.8 |
| Change at Month 6 | 0.4 ± 2.5 |
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.
| mcIU/mL | Bisoprolol |
|---|---|
| Baseline | 7.5 ± 4.8 |
| Change at Month 3 | 0.2 ± 4.5 |
| Change at Month 6 | 0.6 ± 6.0 |
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.
| nanogram per milliliter (ng/mL) | Bisoprolol |
|---|---|
| Baseline | 2.3 ± 0.9 |
| Change at Month 3 | 0.1 ± 0.8 |
| Change at Month 6 | 0.2 ± 1.0 |
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.
| milligram per deciliter (mg/dL) | Bisoprolol |
|---|---|
| Total Cholesterol: Baseline (n = 174) | 168.6 ± 32.3 |
| Total Cholesterol: Change at Month 6 (n = 173) | -0.8 ± 26.3 |
| LDL: Baseline (n = 174) | 93.3 ± 26.3 |
| LDL: Change at Month 6 (n = 173) | -1.6 ± 22.5 |
| HDL: Baseline (n = 174) | 49.2 ± 11.7 |
| HDL: Change at Month 6 (n = 173) | -3.4 ± 8.0 |
| Triglyceride: Baseline (n = 174) | 155.0 ± 96.3 |
| Triglyceride: Change at Month 6 (n = 173) | 13.5 ± 87.6 |
The change in albumin/creatinine ratio at Month 6 was calculated as albumin/creatinine ratio at Month 6 minus albumin/creatinine ratio at baseline.
| ratio | Bisoprolol |
|---|---|
| Baseline (n = 89) | 127.7 ± 630.9 |
| Change at Month 6 (n = 85) | 34.3 ± 186.6 |
The change in microalbumin level at Month 6 was calculated as microalbumin level at Month 6 minus microalbumin level at baseline.
| mg/dL | Bisoprolol |
|---|---|
| Baseline (n = 167) | 56.6 ± 261.6 |
| Change at Month 6 (n = 161) | -3.1 ± 204.4 |
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.
| participants | Bisoprolol |
|---|---|
| AEs | 68 |
| SAEs | 7 |
Collected over Baseline up to Month 6. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Bisoprolol | — | 7/200 (3.5%) | 61/200 (30.5%) |
| Event | Bisoprolol |
|---|---|
| Fracture lower limbMusculoskeletal and connective tissue disorders | 1/200 |
| Fracture ribMusculoskeletal and connective tissue disorders | 1/200 |
| Fracture upper limbMusculoskeletal and connective tissue disorders | 1/200 |
| Musculoskeletal disorderMusculoskeletal and connective tissue disorders | 1/200 |
| Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/200 |
| Gallbladder carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/200 |
| Hepatic neoplasm malignantNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/200 |
| Neoplasm metastaticNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/200 |
| Event | Bisoprolol |
|---|---|
| HeadacheNervous system disorders | 8/200 |
| DizzinessNervous system disorders | 6/200 |
| CoughingRespiratory, thoracic and mediastinal disorders | 4/200 |
| Weakness generalizedGeneral disorders | 3/200 |
| DiarrhoeaGastrointestinal disorders | 3/200 |
| Common coldInfections and infestations | 3/200 |
| NumbnessNervous system disorders | 2/200 |
| Abdominal discomfortGastrointestinal disorders | 2/200 |
| ConstipationGastrointestinal disorders | 2/200 |
| DyspepsiaGastrointestinal disorders | 2/200 |
Analysis population included all the participants who were enrolled in this study.
| Age, Continuous(years) | Bisoprolol |
|---|---|
| Mean | 59.1 ± 8.8 |
| Sex: Female, Male(Participants) | Bisoprolol |
|---|---|
| Female | 92 |
| Male | 110 |
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Merck KGaA, Darmstadt, Germany