Nebivolol Versus Metoprolol: Comparative Effects on Fatigue and Quality of Life

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00999102
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 37
• Location: 1
• Arms: 2
• Duration (Months): 15
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

Beta-blockers are prescribed to millions of people for treatment of hypertension. Fatigue is a recognized and common side effect of beta-blockers that can have significant effects on quality of life. Worse, many people taking a beta-blocker for years are not even aware of the reduction of energy with which they are living.

A new vasodilating beta-blocker, nebivolol, which is approved by the FDA for treatment of hypertension, appears to be far less associated with fatigue than are most currently available beta-blockers. The purpose of this study is to compare nebivolol with the current best-selling beta-blocker, metoprolol, and determine whether there is a significant difference in side effects including fatigue, reduced exertion tolerance, and reduced quality of life.

In this study, 30 subjects will take each of the 2 study drugs for 8 weeks, consisting of 4 weeks at a lower dose, and 4 weeks at a higher dose. All dosages are FDA-approved for treatment of hypertension. Subjects and investigators will not know which drug is being administered until completion of the study. Subjects will undergo a treadmill stress test and will complete fatigue and quality of life questionnaires after each 4 weeks of treatment. An echocardiogram and non-invasive measurement of aortic blood pressure will be performed after 8 weeks on each drug. Also, blood will be drawn and stored for possible measurement of drug levels, after 4 and 8 weeks on each drug. Results on each drug will then be compared. If nebivolol is found to cause significantly less fatigue, it would be of substantial importance to the many millions of people who are on life-long beta-blocker therapy, and are living with reduced energy.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Metoprolol; Drug: Nebivolol	Phase 4

Detailed Description

• Hypothesis: the beta-blocker nebivolol is associated with less fatigue than metoprolol, the most widely-prescribed beta-blocker

• Methods: a double-blinded crossover trial comparing nebivolol with metoprolol. Experimental procedures: Subjects will undergo electrocardiogram and routine blood testing, unless such tests have been performed within 6 months and are available for review. Subjects entered into the study will receive each of the two study drugs for 8 weeks. Metoprolol succinate will be given at a dose of 50 mg daily for 4 weeks, then 100 mg daily for 4 weeks. For nebivolol, dosage will be 5 mg daily for 4 weeks and 10mg daily for 4 weeks. Identical-appearing pills will be given, and the drugs will be given in randomized order without a placebo run-in period.

At the end of each 4-week treatment period on each drug, subjects will undergo a treadmill stress test (using the standard Cornell protocol), complete Quality of Life and fatigue questionnaires, and have blood drawn and frozen for later analysis for drug levels.

At the end of 8 weeks of treatment on each drug, subjects will undergo echocardiography and applanation tonometry (non-invasive measurement of aortic blood pressure) to assess heart function.

At the end of the study, the blinded subjects will be asked which of the two study drugs they preferred, and the extent to which their energy differed between the two drugs.

-Rationale: Millions of hypertensive patients are on life-long beta-blocker therapy. In many, it reduces cardiac output and increases peripheral resistance to blood flow (1). It is well-established that beta-blockers cause fatigue in many patients and reduce exertion tolerance. Every physician knows this, and tacitly accepts that many patients are living with this unwelcome side effect.

A new beta-blocker, nebivolol, has the standard beta-blocking effects, but also produces blood vessel relaxation (vasodilation), probably through increased secretion of the vasodilator nitric oxide. Studies indicate that nebivolol, unlike most beta-blockers, does not cause constriction of peripheral blood vessels, and is associated with improved heart function (2). Studies suggest that it is also less likely to cause fatigue (3).

Personal experience is consistent with this, as I have observed marked improvement in energy in patients in whom I have prescribed nebivolol in place of a different beta-blocker. The possibility of placebo effect of course cannot be excluded. Nevertheless, the known hemodynamic differences between nebivolol and other beta-blockers, and the positive clinical experience, warrant formal study to determine whether nebivolol is kinder than other beta-blockers in terms of the important side effect of fatigue.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Nebivolol Vs. Metoprolol: Comparative Effects on Fatigue and Quality of Life
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nebivolol, followed by Metoprolol Participants first received Nebivolol at a dose of 5 mg daily for 4 weeks, followed by 10 mg daily for another 4 weeks (i.e., weeks 1-8 in total). The participants then received Metoprolol at a dose of 50 mg daily for 4 weeks, followed by 100 mg daily for another 4 weeks (i.e., weeks 9-16 in total).	Drug: Metoprolol; Metoprolol 50 mg, Metoprolol 100 mg,; Other Names: Lopressor, Toprol-XL ; Drug: Nebivolol; Nebivolol 5 mg, Nebivolol 10 mg.; Other Names: Bystolic
Experimental: Metoprolol, followed by Nebivolol Participants first received Metoprolol at a dose of 50 mg daily for 4 weeks, followed by 100 mg daily for another 4 weeks (i.e., weeks 1-8 in total). The participants then received Nebivolol at a dose of 5 mg daily for 4 weeks, followed by 10 mg daily for another 4 weeks (i.e., weeks 9-16 in total)	Drug: Metoprolol; Metoprolol 50 mg, Metoprolol 100 mg,; Other Names: Lopressor, Toprol-XL ; Drug: Nebivolol; Nebivolol 5 mg, Nebivolol 10 mg.; Other Names: Bystolic

Outcome Measures

Primary Outcome Measures

1. Multidimensional Assessment of Fatigue (MAF) Questionnaire: Global Fatigue Score After 4 Weeks of Treatment on Each Drug/Dose Combination. [After 4 weeks of treatment on each drug/dose combination]

   A 16 item scale that measures 4 dimensions of fatigue: severity, distress, timing, and degree of interference in activities of daily living. Range: 1 (no fatigue) to 50 (extreme fatigue).

2. Treadmill Exercise Time After 4 Weeks of Treatment on Each Drug/Dose Combination. [After 4 weeks of treatment on each drug/dose combination]

   Treadmill Exercise Time After 4 Weeks of Treatment on Each Drug/Dose Combination (in minutes). The Treadmill Test was Performed at the 4-week Visit of Each Drug/Dose Combination.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Individuals who are taking, or are about to begin taking, a beta-blocker, and who have the approved indication of hypertension

Exclusion Criteria:

• Orthopedic ailments that would interfere with performance of treadmill testing

• Stroke or heart attack within the previous 1 year

• Symptomatic coronary disease within the past year (angina, shortness of breath)

• Clinically significant pulmonary disease (e.g. emphysema or asthma).

• Poorly controlled hypertension (blood pressure above 160 systolic or 100 diastolic)

• Patients with contra-indications to taking a beta-blocker (asthma or bradyarrhythmia)

• History of tachyarrhythmia (abnormal rapid heart rate)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10065

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Forest Laboratories

Investigators

• Principal Investigator: Samuel J Mann, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT00999102
• Other Study ID Numbers: 0901010162
• First Posted: Oct 21, 2009
• Last Update Posted: Oct 19, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Weill Medical College of Cornell University: hypertension; beta blockers; Metoprolol; blood pressure, high; antihypertensive agents; vascular resistance; adrenergic beta-receptor blockaders; beta-Adrenergic blockers; beta-Adrenergic Blocking Agents; beta-Adrenergic Receptor Blockaders; beta-Blockers, Adrenergic; Bystolic; Nebivolol; Nebivololum; Nebivololum [Latin]; R65,824; Beloc- Zok; H 93/26 succinate; Metoprolol succinate; Seloken ZOC; Selozok; Spesicor Dos; Toprol XL; Toprol-XL; UNII-TH25PD4CCB
• Additional relevant MeSH terms: Hypertension; Metoprolol; Nebivolol

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the patient population of the Hypertension Center, and from an announcement at the medical center. Subjects were entered from 10/09 to 9/10, and the final subject completed the protocol in 1/11.
Pre-assignment Detail	Subjects who were on anti-hypertensives were instructed to continue their medications. Subjects taking a beta-blocker were instructed to stop them. There was no washout period. Individuals with a contraindication to beta-blockers were excluded. 4 subjects dropped out before starting medication for reasons unrelated to the study.

Arm/Group Title	Nebivolol, Followed by Metoprolol	Metoprolol, Followed by Nebivolol
Arm/Group Description	Participants first received Nebivolol at a dose of 5 mg daily for 4 weeks, followed by 10 mg daily for another 4 weeks (i.e., weeks 1-8 in total). The participants then received Metoprolol at a dose of 50 mg daily for 4 weeks, followed by 100 mg daily for another 4 weeks (i.e., weeks 9-16 in total).	Participants first received Metoprolol at a dose of 50 mg daily for 4 weeks, followed by 100 mg daily for another 4 weeks (i.e., weeks 1-8 in total). The participants then received Nebivolol at a dose of 5 mg daily for 4 weeks, followed by 10 mg daily for another 4 weeks (i.e., weeks 9-16 in total)
Period Title: 4 Weeks at Lower Dose of First Drug
STARTED	16	17
COMPLETED	15	16
NOT COMPLETED	1	1
Period Title: 4 Weeks at Lower Dose of First Drug
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0
Period Title: 4 Weeks at Lower Dose of First Drug
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0
Period Title: 4 Weeks at Lower Dose of First Drug
STARTED	15	16
COMPLETED	15	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Participants who were randomized to receive either Nebivolol followed by Metoprolol or Metoprolol followed by Nebivolol.
Overall Participants	33
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 63.6%
>=65 years	12 36.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.6 (13.4)
Sex: Female, Male (Count of Participants)
Female	14 42.4%
Male	19 57.6%
Region of Enrollment (Count of Participants)
United States	33 100%

Outcome Measures

1. Primary Outcome

Title	Multidimensional Assessment of Fatigue (MAF) Questionnaire: Global Fatigue Score After 4 Weeks of Treatment on Each Drug/Dose Combination.
Description	A 16 item scale that measures 4 dimensions of fatigue: severity, distress, timing, and degree of interference in activities of daily living. Range: 1 (no fatigue) to 50 (extreme fatigue).
Time Frame	After 4 weeks of treatment on each drug/dose combination

Outcome Measure Data

Analysis Population Description

All participants who received both interventions and completed all study visits were included in the efficacy analysis.

Arm/Group Title	Nebivolol 5 mg for 4 Weeks	Metoprolol 50 mg for 4 Weeks	Nebivolol 10 mg for 4 Weeks	Metoprolol 100 mg for 4 Weeks
Arm/Group Description	31 subjects received Nebivolol 5 mg daily for 4 weeks.	31 subjects received Metoprolol 50 mg daily for 4 weeks	31 subjects received Nebivolol 10 mg daily for 4 weeks.	31 subjects received Metoprolol 100 mg daily for 4 weeks
Measure Participants	31	31	31	31
Mean (Standard Deviation) [units on a scale]	18.5 (11.2)	18.0 (11.2)	21.0 (11.8)	20.3 (11.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol 5 mg for 4 Weeks, Metoprolol 50 mg for 4 Weeks
	Comments	The null hypothesis is that there is no difference in the Global Fatigue Score after 4 weeks of Nebivolol 5 mg (lower dose) vs. 4 weeks of Metoprolol 50 mg (lower dose).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was performed since each participant received both interventions in a crossover design.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -1.86 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of Comparison: Mean Global Fatigue Score for Nebivolol 5 mg minus Mean Global Fatigue Score for Metoprolol 50 mg.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nebivolol 10 mg for 4 Weeks, Metoprolol 100 mg for 4 Weeks
	Comments	The null hypothesis is that there is no difference in the Global Fatigue Score after 4 weeks of Nebivolol 10 mg (higher dose) vs. 4 weeks of Metoprolol 100 mg (higher dose).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was performed since each participant received both interventions in a crossover design.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -3.17 to 4.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of Comparison: Mean Global Fatigue Score for Nebivolol 10 mg minus Mean Global Fatigue Score for Metoprolol 100 mg.

2. Primary Outcome

Title	Treadmill Exercise Time After 4 Weeks of Treatment on Each Drug/Dose Combination.
Description	Treadmill Exercise Time After 4 Weeks of Treatment on Each Drug/Dose Combination (in minutes). The Treadmill Test was Performed at the 4-week Visit of Each Drug/Dose Combination.
Time Frame	After 4 weeks of treatment on each drug/dose combination

Outcome Measure Data

Analysis Population Description

All participants who received both interventions and completed all study visits were included in the efficacy analysis.

Arm/Group Title	Nebivolol 5 mg for 4 Weeks	Metoprolol 50 mg for 4 Weeks	Nebivolol 10 mg for 4 Weeks	Metoprolol 100 mg for 4 Weeks
Arm/Group Description	31 subjects received Nebivolol 5 mg daily for 4 weeks.	31 subjects received Metoprolol 50 mg daily for 4 weeks	31 subjects received Nebivolol 10 mg daily for 4 weeks.	31 subjects received Metoprolol 100 mg daily for 4 weeks
Measure Participants	31	31	31	31
Mean (Standard Deviation) [minutes]	833.9 (266.1)	840.9 (288.6)	841.2 (265.4)	867.1 (249.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nebivolol 5 mg for 4 Weeks, Metoprolol 50 mg for 4 Weeks
	Comments	The null hypothesis is that there is no difference in Treadmill Exercise Time after 4 weeks of Nebivolol 5 mg (lower dose) vs. 4 weeks of Metoprolol 50 mg (lower dose).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.89
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was performed since each participant received both interventions in a crossover design.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.03
	Confidence Interval	(2-Sided) 95%; -108.99 to 94.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of Comparison: Mean Treadmill Exercise Time for Nebivolol 5 mg minus Mean Treadmill Exercise Time for Metoprolol 50 mg.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Nebivolol 10 mg for 4 Weeks, Metoprolol 100 mg for 4 Weeks
	Comments	The null hypothesis is that there is no difference in Treadmill Exercise Time after 4 weeks of Nebivolol 10 mg (higher dose) vs. 4 weeks of Metoprolol 100 mg (higher dose).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was performed since each participant received both interventions in a crossover design.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.90
	Confidence Interval	(2-Sided) 95%; -91.55 to 39.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Direction of Comparison: Mean Treadmill Exercise Time for Nebivolol 10 mg minus Mean Treadmill Exercise Time for Metoprolol 100 mg.

Adverse Events

Time Frame	After 4 weeks on either study drug.
Adverse Event Reporting Description	All-Cause Mortality; Serious; Other.
Arm/Group Title	Nebivolol 5 mg for 4 Weeks		Metoprolol 50 mg for 4 Weeks		Nebivolol 10 mg for 4 Weeks		Metoprolol 100 mg for 4 Weeks
Arm/Group Description	31 subjects received Nebivolol 5 mg daily for 4 weeks.		31 subjects received Metoprolol 50 mg daily for 4 weeks		31 subjects received Nebivolol 10 mg daily for 4 weeks.		31 subjects received Metoprolol 100 mg daily for 4 weeks
All Cause Mortality
	Nebivolol 5 mg for 4 Weeks		Metoprolol 50 mg for 4 Weeks		Nebivolol 10 mg for 4 Weeks		Metoprolol 100 mg for 4 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/33 (0%)		0/33 (0%)		0/33 (0%)
Serious Adverse Events
	Nebivolol 5 mg for 4 Weeks		Metoprolol 50 mg for 4 Weeks		Nebivolol 10 mg for 4 Weeks		Metoprolol 100 mg for 4 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/33 (0%)		0/33 (0%)		0/33 (0%)
Other (Not Including Serious) Adverse Events
	Nebivolol 5 mg for 4 Weeks		Metoprolol 50 mg for 4 Weeks		Nebivolol 10 mg for 4 Weeks		Metoprolol 100 mg for 4 Weeks
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/33 (3%)		1/33 (3%)		0/31 (0%)		0/31 (0%)
General disorders
Fatigue	1/33 (3%)		1/33 (3%)		0/31 (0%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.