Hypertension, Type 2 Diabetes Mellitus
Conditions
Keywords
nebivolol, Bystolic ™, Hypertension, Diabetes
Brief summary
This study will evaluate the effects of nebivolol on glycemic control compared with metoprolol and HCTZ in patients with hypertension and type 2 diabetes mellitus
Interventions
DRUGNebivolol
* Nebivolol 5 mg (overencapsulated 5-mg marketed tablet), oral administration * Nebivolol 10 mg (overencapsulated 10-mg marketed tablet), oral administration * Nebivolol 20 mg (overencapsulated 20-mg marketed tablet) oral administration * Nebivolol 40 mg (two overencapsulated 20-mg tablets) oral administration
DRUGMetoprolol ER
* Metoprolol ER 50 mg (overencapsulated 50-mg tablet) oral administration * Metoprolol ER 100 mg (two overencapsulated 50-mg tablets) oral administration * Metoprolol ER 200 mg (overencapsulated 200-mg tablet) oral administration * Metoprolol ER 400 mg (two overencapsulated 200-mg tablets) oral administration
DRUGHCTZ
* HCTZ 12.5 mg (overencapsulated 12.5 capsule), oral administration * HCTZ 25 mg (two capsules, overencapsulated 12.5-mg capsules), oral administration
Sponsors
Forest Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 18-85 years of age * Blood pressure in the range of 130 to 179/80 to 109 mmHg * Currently using either an ACE inhibitor or an ARB alone or (an ACE inhibitor or an ARB and up to two other drugs for treatment of high blood pressure). (Patients may be on both an ACE inhibitor and ARB, but would need to be taken off one.) * Stable medication regimen for high blood pressure for at least one month prior to screening * Stable type 2 diabetes mellitus for at least 3 months prior to screening that is controlled by any or all of the following: diet and antidiabetic medications that may include fixed-dose insulin * HgbA1c 6.5 to 8.5% (This is measured at the screening visit)
Exclusion criteria
* Use of any beta blocker within one month prior to screening * Use of clonidine within 3 months prior to screening * Diagnosis of hyperthyroidism as evidenced by abnormal lab markers * Any disorder requiring the intermittent or chronic use of systemic corticosteroids * Diagnosis of hyperthyroidism as determined by lab markers done at screening * Active liver disease as determined by lab markers * Kidney impairment; estimated GFR \< 60 mL/min/1.73 m2 * History of heart attack, clinically significant arrhythmia, unstable angina, coronary angioplasty/bypass surgery, stroke, or TIA in 3 months prior to screening * Chronic heart failure * Drug or alcohol abuse within 2 years prior to screening * History of sensitivity to any beta blocker, HCTZ, sulfa drug, or calcium channel blocker * Participation in another research study within 30 days prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Glycosylated Hemoglobin (HbA1c) at Week 26 | visit 5(week 0) and visit 14(week 26) | Change from baseline in glycosylated hemoglobin (HbA1c) over 26 weeks, Last Observation Carried Forward. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | [visit 5(week 0) and visit 14(week 26)] | Change from Baseline in Insulin Resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at week 26, Last Observation Carried Forward (LOCF). The HOMA-IR is the the product of the blood Glucose and Insulin levels, divided by a constant. HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (μU/ml) × fasting plasma glucose (mmol/l) / 22.5 |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Recruitment occured from September 2008 through December 2009 at 69 US sites
Pre-assignment details
Placebo washout phase was required for patients currently on any anti-hypertensives at screening exclusive of background ACE inhibitor or ARB before assignment to HCTZ or Metoprolol ER or Nebivolol arms.
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol * Nebivolol 5 mg (overencapsulated 5-mg marketed tablet), oral administration
* Nebivolol 10 mg (overencapsulated 10-mg marketed tablet), oral administration
* Nebivolol 20 mg (overencapsulated 20-mg marketed tablet) oral administration
* Nebivolol 40 mg (two overencapsulated 20-mg tablets) oral administration
* Open-label amlodipine may be given | 83 |
| Metoprolol ER * Metoprolol ER 50 mg (overencapsulated 50-mg tablet) oral administration
* Metoprolol ER 100 mg (two overencapsulated 50-mg tablets) oral administration
* Metoprolol ER 200 mg (overencapsulated 200-mg tablet) oral administration
* Metoprolol ER 400 mg (two overencapsulated 200-mg tablets) oral administration
* Open-label amlodipine may be given | 73 |
| Hydrochlorothiazide (HCTZ) * HCTZ 12.5 mg (overencapsulated 12.5 capsule), oral administration
* HCTZ 25 mg (two capsules, overencapsulated 12.5-mg capsules), oral administration
* Open-label amlodipine may be given | 74 |
| Total | 230 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative. Site Closed | 1 | 1 | 1 |
| Overall Study | Adverse Event | 9 | 13 | 5 |
| Overall Study | Dosing Error | 1 | 0 | 1 |
| Overall Study | Inclusion/Exclusion criteria not met | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 |
| Overall Study | Poor Compliance | 0 | 2 | 0 |
| Overall Study | Prohibited Concomitant Medication | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 4 | 3 |
| Overall Study | Study Drug Error | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 5 | 3 |
Baseline characteristics
| Characteristic | Nebivolol | Metoprolol ER | Hydrochlorothiazide (HCTZ) | Total |
|---|---|---|---|---|
| Age Continuous | 58.2 years STANDARD_DEVIATION 9.3 | 59.2 years STANDARD_DEVIATION 8.3 | 59.5 years STANDARD_DEVIATION 9 | 58.9 years STANDARD_DEVIATION 8.9 |
| Age, Customized Patients 18 to 64 years of age | 61 participants | 51 participants | 53 participants | 165 participants |
| Age, Customized Patients greater than or equal to 65 years of age. | 22 participants | 22 participants | 21 participants | 65 participants |
| Region of Enrollment Puerto Rico | 5 participants | 4 participants | 2 participants | 11 participants |
| Region of Enrollment United States | 78 participants | 69 participants | 72 participants | 219 participants |
| Sex: Female, Male Female | 30 Participants | 30 Participants | 29 Participants | 89 Participants |
| Sex: Female, Male Male | 53 Participants | 43 Participants | 45 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 83 | 17 / 73 | 17 / 74 |
| serious Total, serious adverse events | 2 / 83 | 3 / 73 | 2 / 74 |
Outcome results
Primary
Change From Baseline in Mean Glycosylated Hemoglobin (HbA1c) at Week 26
Change from baseline in glycosylated hemoglobin (HbA1c) over 26 weeks, Last Observation Carried Forward.
Time frame: visit 5(week 0) and visit 14(week 26)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change From Baseline in Mean Glycosylated Hemoglobin (HbA1c) at Week 26 | 0.12 Percentage | Standard Deviation 0.78 |
| Metoprolol ER | Change From Baseline in Mean Glycosylated Hemoglobin (HbA1c) at Week 26 | 0.00 Percentage | Standard Deviation 0.65 |
| Hydrochlorothiazide (HCTZ) | Change From Baseline in Mean Glycosylated Hemoglobin (HbA1c) at Week 26 | 0.40 Percentage | Standard Deviation 0.96 |
Secondary
Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR)
Change from Baseline in Insulin Resistance based on homeostasis model assessment of insulin resistance (HOMA-IR) at week 26, Last Observation Carried Forward (LOCF). The HOMA-IR is the the product of the blood Glucose and Insulin levels, divided by a constant. HOMA-IR is expressed as the following: HOMA-IR = fasting serum insulin (μU/ml) × fasting plasma glucose (mmol/l) / 22.5
Time frame: [visit 5(week 0) and visit 14(week 26)]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nebivolol | Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 0.011 Unit on a scale | Standard Deviation 9.828 |
| Metoprolol ER | Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | 1.156 Unit on a scale | Standard Deviation 9.628 |
| Hydrochlorothiazide (HCTZ) | Change From Baseline in Insulin Resistance Based on Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) | -0.662 Unit on a scale | Standard Deviation 10.178 |