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| Name | Class |
|---|---|
| Forest Laboratories | INDUSTRY |
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This is a 26-week, prospective double-blind, randomized pilot trial of nebivolol versus an active control, metoprolol succinate, in patients with established lower-extremity peripheral artery disease, hypertension, and at least moderate risk for coronary artery disease.
Peripheral arterial disease (PAD) affects up to an estimated 16-29% of men and women over age 50, and is associated with increased cardiovascular morbidity and mortality. Beta-blockers have been shown to reduce the risk of myocardial infarction and death in patients with coronary artery disease (CAD) and are indicated for the treatment of hypertension in patients with PAD. However, there is a theoretical risk that antihypertensive therapy may decrease limb perfusion pressure and therefore exacerbate symptoms of claudication or limb ischemia. Patients with CAD and concomitant PAD are less likely to be prescribed beta-blockers, even though most patients are able to tolerate antihypertensive therapy without worsening of symptoms.
The third generation beta-blocker, nebivolol, has vasodilating properties in addition to beta-adrenergic blockade. This vasodilatory effect is mediated through the L-arginine-nitric oxide-dependent pathway. Nitric oxide is a critical modulator of vascular disease with effects that lead to vasodilatation, endothelial regeneration, inhibition of leukocyte chemotaxis and inhibition of platelet adhesion. This combination of beta-blockade and nitric oxide-dependent vasodilation may enhance effectiveness and tolerability of nebivolol versus other beta-blockers in patients with hypertension, CAD or high-risk state, and PAD.
This study will be a pilot comparative effectiveness study to examine the effect of nebivolol versus metoprolol succinate in patients with lower-extremity PAD and at least moderate risk for CAD on PAD symptoms as measured by both functional and quality of life measures.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| nebivolol | Experimental | nebivolol 1 to 4 capsules daily |
|
| metoprolol succinate | Active Comparator | metoprolol 1 to 4 capsules daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| nebivolol | Drug | Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing). |
| Measure | Description | Time Frame |
|---|---|---|
| Peak Walking Time (PWT) | Change in peak walking time (PWT) is measured in seconds. The PWT is defined as when walking on a treadmill cannot continue due to maximal leg pain, resulting in the discontinuation of the treadmill test. | Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks. |
| Measure | Description | Time Frame |
|---|---|---|
| Ankle-brachial Index (ABI) | Change in measurement of Ankle-brachial index (ABI). The ABI is the ratio of the blood pressure measured in the lower legs to the blood pressure measured in the arms. | Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks |
| Claudication Onset Time (COT) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Danielle Duffy, MD | Thomas Jefferson University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Thomas Jefferson University | Philadelphia | Pennsylvania | 19107 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Nebivolol | nebivolol 1 to 4 capsules daily nebivolol: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing). |
| FG001 | Metoprolol Succinate | metoprolol 1 to 4 capsules daily Metoprolol succinate: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Original sample size for pilot study was fixed at 40 subjects. Lagging enrollment necessitated completion at 17 subjects.
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| ID | Title | Description |
|---|---|---|
| BG000 | Nebivolol | nebivolol 1 to 4 capsules daily nebivolol: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Peak Walking Time (PWT) | Change in peak walking time (PWT) is measured in seconds. The PWT is defined as when walking on a treadmill cannot continue due to maximal leg pain, resulting in the discontinuation of the treadmill test. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | seconds | Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks. |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Nebivolol | nebivolol 1 to 4 capsules daily nebivolol: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at the study visits. Nebivolol is approved for hypertension treatment at a dose of 5-40 mg daily. Based on the study titration schedule, the maximum doses used will be 20 mg of nebivolol (each maximum dose being contained in 4 capsules for daily dosing). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Decrease in hemoglobin | Blood and lymphatic system disorders | Systematic Assessment | The patient had a decrease in hemoglobin and was sent to outside hospital where upper endoscopy and colonoscopy found no bleeding. The patient received 2 units of packed red blood cells started on a regimen of ferrous sulfate 320 mg PO BID. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Danielle Duffy MD | Thomas Jefferson University | 215 955 5050 | Danielle.Duffy@jefferson.edu |
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| ID | Term |
|---|---|
| D058729 | Peripheral Arterial Disease |
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D050197 | Atherosclerosis |
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D000068577 | Nebivolol |
| D008790 | Metoprolol |
| ID | Term |
|---|---|
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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|
|
| Metoprolol succinate | Drug | Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). |
|
|
Change in measurement of claudication onset time (COT). The COT is defined as the time when a patient first experienced pain walking during a treadmill test. |
| Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks. |
| Walking Impairment Questionnaire (WIQ) - Change Calf Pain | Change in calf pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
| Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain | Change in buttock pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score | Change in distance score as captured by the Walking Impairment Questionnaire (WIQ) distance score subscale. The degree of difficulty in the walking of specific distances is ranked on a 0 to 4 Likert scale, in which 0 represents the inability to walk the distance and 4 represents no difficulty. A Likert scale is an ordinal scale of consecutive, equidistant, numerical values (ie, 0 to 4). The distances assessed in the WIQ range from walking indoors around the home to walking 5 blocks (1500 feet). The items on the subscale are weighted according to the difficulty of walking. The distance score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score | Change in speed score as captured by the Walking Impairment Questionnaire (WIQ) speed score subscale. In the walking speed component, the degree of difficulty walking is ranked on a 0 to 4 scale where speed is assessed for each of the following speeds: at the following speeds: 1, slowly; 2, average speed; 3, quickly; or 4, running or jogging 1 block. Zero represents the inability to walk the specified speed, and 4 represents no difficulty. The items on the subscale are weighted according to the difficulty of the task. The speed score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
| Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score | Change in stairs score as captured by the Walking Impairment Questionnaire (WIQ) stairs subscale. This scale item asks the subject to describe the degree of difficulty climbing one, two, or three flights of stairs in the past week. A flight of stairs is defined as 14 steps. A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, 5) Unable to Do, or 6) Didn Do for Other Reasons. The items on the subscale are weighted according to the difficulty of the task. The stairs score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
| BG001 | Metoprolol Succinate | metoprolol 1 to 4 capsules daily Metoprolol succinate: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Metoprolol Succinate | metoprolol 1 to 4 capsules daily Metoprolol succinate: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). |
|
|
|
| Secondary | Ankle-brachial Index (ABI) | Change in measurement of Ankle-brachial index (ABI). The ABI is the ratio of the blood pressure measured in the lower legs to the blood pressure measured in the arms. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | Ankle-Brachial Index | Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks |
|
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|
|
| Secondary | Claudication Onset Time (COT) | Change in measurement of claudication onset time (COT). The COT is defined as the time when a patient first experienced pain walking during a treadmill test. | Final measurements of COT in the metoprolol succinate group excludes one subject who did not experience claudication while walking during the treadmill test, and one subject who withdrew consent prior to the end of the study, therefore, only 6 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | seconds | Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks. |
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|
|
| Secondary | Walking Impairment Questionnaire (WIQ) - Change Calf Pain | Change in calf pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | units on a scale | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
|
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|
|
| Secondary | Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain | Change in buttock pain as captured by the Walking Impairment Questionnaire (WIQ). A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, and 5) Great Difficulty. The scores are determined by dividing the score by the maximum possible score and then multiplying by 100. The score ranges from 0-100 with lower scores indicating greater pain. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | units on a scale | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
|
|
|
|
| Secondary | Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score | Change in distance score as captured by the Walking Impairment Questionnaire (WIQ) distance score subscale. The degree of difficulty in the walking of specific distances is ranked on a 0 to 4 Likert scale, in which 0 represents the inability to walk the distance and 4 represents no difficulty. A Likert scale is an ordinal scale of consecutive, equidistant, numerical values (ie, 0 to 4). The distances assessed in the WIQ range from walking indoors around the home to walking 5 blocks (1500 feet). The items on the subscale are weighted according to the difficulty of walking. The distance score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. | Posted | Mean | Standard Deviation | units on a scale | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
|
|
|
|
| Secondary | Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score | Change in speed score as captured by the Walking Impairment Questionnaire (WIQ) speed score subscale. In the walking speed component, the degree of difficulty walking is ranked on a 0 to 4 scale where speed is assessed for each of the following speeds: at the following speeds: 1, slowly; 2, average speed; 3, quickly; or 4, running or jogging 1 block. Zero represents the inability to walk the specified speed, and 4 represents no difficulty. The items on the subscale are weighted according to the difficulty of the task. The speed score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | One patient in the metoprolol succinate group withdrew consent prior to the end of the study, therefore, only 7 participants are included in the analysis for this group. One patient in the nebivolol group failed to complete the items in the WIQ speed score subscale, therefore, only 8 patients were included in the analysis for this outcome. | Posted | Mean | Standard Deviation | units on a scale | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
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|
| Secondary | Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score | Change in stairs score as captured by the Walking Impairment Questionnaire (WIQ) stairs subscale. This scale item asks the subject to describe the degree of difficulty climbing one, two, or three flights of stairs in the past week. A flight of stairs is defined as 14 steps. A 5 point Likert scale scoring ranges from 1) No Difficulty, 2) Slight Difficulty, 3) Some Difficulty, 4) Much Difficulty, 5) Unable to Do, or 6) Didn Do for Other Reasons. The items on the subscale are weighted according to the difficulty of the task. The stairs score is determined by dividing the total weighted score by the greatest possible weighted score and multiplying by 100. Scores range from 0-100. | Four people in the nebivolol group and 1 person in the metoprolol group did not complete the items in the "Stairs" WIQ subscale therefore they were excluded from the analysis. One person in the metoprolol succinate group withdrew consent before the end of the study so they were also excluded from the final analysis. | Posted | Mean | Standard Deviation | units on a scale | Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks. |
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|
|
| 2 |
| 9 |
| 0 |
| 9 |
| EG001 | Metoprolol Succinate | metoprolol 1 to 4 capsules daily Metoprolol succinate: Study medication will initially be dispensed as one capsule daily and the dose will be titrated at study visits. Metoprolol succinate at 25-400 mg daily. Based on the study titration schedule, the maximum dose used will be 200 mg of metoprolol succinate (each maximum dose being contained in 4 capsules for daily dosing). | 0 | 8 | 0 | 8 |
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| Peripheral stent placed | Vascular disorders | Systematic Assessment | The patient had elective left femoral and popliteal artery angioplasty with stent placed in left leg due to disabling claudication. |
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| D002318 |
| Cardiovascular Diseases |
| D016491 | Peripheral Vascular Diseases |
| D000588 |
| Amines |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D020005 | Propanols |