ENCOMPASS: Comparison of 2 Beta Blocker Drugs on Peripheral Arterial Disease in Patients With High Blood Pressure

• Sponsor: Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01499134
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 17
• Location: 1
• Arms: 2
• Duration (Months): 34
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Peripheral Artery Disease; Hypertension	Drug: nebivolol; Drug: Metoprolol succinate	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Nebivolol Compared With Metoprolol in Hypertensive Patients With Peripheral Arterial Disease
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: nebivolol nebivolol 1 to 4 capsules daily	Drug: 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).; Other Names: Bystolic
Active Comparator: metoprolol succinate metoprolol 1 to 4 capsules daily	Drug: 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).; Other Names: Toprol XL

Outcome Measures

Primary Outcome Measures

1. Peak Walking Time (PWT) [Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

Secondary Outcome Measures

1. Ankle-brachial Index (ABI) [Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks]

   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.

2. Claudication Onset Time (COT) [Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

3. Walking Impairment Questionnaire (WIQ) - Change Calf Pain [Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

4. Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain [Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

5. Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score [Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

6. Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score [Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

7. Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score [Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and non-pregnant, non-lactating women 45 years of age or older

• Able to give informed consent and complete scheduled visits

• Mild-moderate bilateral lower extremity peripheral arterial disease as defined by an ankle-brachial index (ABI measurement of 0.6-0.9. If a subject has baseline claudication symptoms, the symptoms must be stable for the 3 months preceding enrollment.

• History of hypertension. Blood pressure at the screening visit must be ≤160/100 mmHg and ≥100/60 mmHg for all subjects. If a subject is currently prescribed beta-blocker therapy, BP at the screening visit must be ≤140/90 mmHg. In addition, heart rate must be ≥55 beats per minute if currently prescribed a beta-blocker and ≤60 beats per minute if not currently prescribed a beta-blocker.

• At least moderate risk for CAD.

Exclusion Criteria:

• Participation in another clinical trial

• Ongoing ischemic (resting) limb pain, or lower extremity ulceration due to arterial insufficiency, or an ABI indicating <0.6 indicating disease potentially requiring revascularization

• History of limb or digit amputation due to arterial insufficiency

• Revascularization of peripheral vessels within the preceding 6 months

• Uncontrolled hypertension as defined by systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg

• Contraindication or allergy to beta blocker therapy

• History of myocardial infarction , coronary revascularization, or a cerebrovascular event within the preceding 6 months

• Class III or IV angina

• Current or past history of New York Heart Association (NYHA) class III or IV heart failure

• Inability to walk on a treadmill for any reason

• Regular use of nitroglycerin or nitrates including oral, transdermal ointment or patch, or sublingual, translingual spray and/or combination agents containing nitrates

• Active liver, pulmonary, infectious or inflammatory process

• History of malignancy within preceding 5 years (excluding basal or squamous cell skin cancer)

• History of any other condition that, in the opinion of the investigators, renders it unsafe for the subject to be enrolled

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107

Sponsors and Collaborators

• Thomas Jefferson University
• Forest Laboratories

Investigators

• Principal Investigator: Danielle Duffy, MD, Thomas Jefferson University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT01499134
• Other Study ID Numbers: 11C.18
• First Posted: Dec 26, 2011
• Last Update Posted: Dec 17, 2014
• Last Verified: Dec 1, 2014

• Additional relevant MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases; Metoprolol; Nebivolol

Study Results

Participant Flow

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Period Title: Overall Study
STARTED	9	8
COMPLETED	9	7
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Nebivolol	Metoprolol Succinate	Total
Arm/Group Description	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).	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).	Total of all reporting groups
Overall Participants	9	8	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (8)	65 (8)	66 (8)
Sex: Female, Male (Count of Participants)
Female	7 77.8%	2 25%	9 52.9%
Male	2 22.2%	6 75%	8 47.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	9 100%	8 100%	17 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 55.6%	3 37.5%	8 47.1%
White	4 44.4%	5 62.5%	9 52.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%	8 100%	17 100%

Outcome Measures

1. Primary Outcome

Title	Peak Walking Time (PWT)
Description	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.
Time Frame	Baseline PWT is measured at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	7
Mean (Standard Deviation) [seconds]	110.4 (89.7)	-19.4 (110.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Ankle-brachial Index (ABI)
Description	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.
Time Frame	Baseline ABI is measured at the time of enrollment and again at the final study visit at 26 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	7
Mean (Standard Deviation) [Ankle-Brachial Index]	0.03 (0.14)	0.06 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.585
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Claudication Onset Time (COT)
Description	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.
Time Frame	Baseline COT is measured at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	6
Mean (Standard Deviation) [seconds]	155.7 (217.5)	148.7 (173.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	This p-value is correct, confirmed with report from statistician.
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Walking Impairment Questionnaire (WIQ) - Change Calf Pain
Description	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.
Time Frame	Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	7
Mean (Standard Deviation) [units on a scale]	25 (28)	10.7 (40.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.363
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Walking Impairment Questionnaire (WIQ) - Change in Buttock Pain
Description	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.
Time Frame	Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	7
Mean (Standard Deviation) [units on a scale]	-8.3 (12.5)	14.3 (19.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Walking Impairment Questionnaire (WIQ) - Change in WIQ Distance Score
Description	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.
Time Frame	Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	9	5
Mean (Standard Deviation) [units on a scale]	13.52 (27.37)	28.28 (31.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.476
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Walking Impairment Questionnaire (WIQ) - Change in WIQ Speed Score
Description	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.
Time Frame	Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	8	7
Mean (Standard Deviation) [units on a scale]	21.88 (30.08)	-6.83 (35.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.170
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Walking Impairment Questionnaire (WIQ) - Change in WIQ Stairs Score
Description	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.
Time Frame	Baseline WIQ is completed at the time of enrollment and again at the final study visit at 26 weeks.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Nebivolol	Metoprolol Succinate
Arm/Group Description	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).	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).
Measure Participants	5	6
Mean (Standard Deviation) [units on a scale]	21.67 (37.20)	24.31 (38.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol, Metoprolol Succinate
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.595
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	6 months
Arm/Group Title	Nebivolol		Metoprolol Succinate
Arm/Group Description	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).		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).
All Cause Mortality
	Nebivolol		Metoprolol Succinate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nebivolol		Metoprolol Succinate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		0/8 (0%)
Blood and lymphatic system disorders
Decrease in hemoglobin	1/9 (11.1%)	1	0/8 (0%)	0
Vascular disorders
Peripheral stent placed	1/9 (11.1%)	1	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	Nebivolol		Metoprolol Succinate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.