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| Name | Class |
|---|---|
| Forest Laboratories | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Nebivolol, followed by Metoprolol | Experimental | 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). |
|
| Metoprolol, followed by Nebivolol | Experimental | 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) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metoprolol | Drug | Metoprolol 50 mg, Metoprolol 100 mg, |
|
| Measure | Description | Time Frame |
|---|---|---|
| Multidimensional Assessment of Fatigue (MAF) Questionnaire: Global Fatigue Score 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). | After 4 weeks of treatment on each drug/dose combination |
| Treadmill Exercise Time 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. | After 4 weeks of treatment on each drug/dose combination |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Samuel J Mann, MD | Weill Medical College of Cornell University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Weill Cornell Medical College | New York | New York | 10065 | United States |
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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). |
| FG001 | 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) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 4 Weeks at Lower Dose of First Drug |
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| 4 Weeks at Higher Dose of First Drug |
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| 4 Weeks at Lower Dose of Second Drug |
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| 4 Weeks at Higher Dose of Second Drug |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Participants who were randomized to receive either Nebivolol followed by Metoprolol or Metoprolol followed by Nebivolol. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Multidimensional Assessment of Fatigue (MAF) Questionnaire: Global Fatigue Score 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). | All participants who received both interventions and completed all study visits were included in the efficacy analysis. | Posted | Mean | Standard Deviation | units on a scale | After 4 weeks of treatment on each drug/dose combination |
|
After 4 weeks on either study drug.
All-Cause Mortality; Serious; Other.
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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 5 mg for 4 Weeks | 31 subjects received Nebivolol 5 mg daily for 4 weeks. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | Systematic Assessment | 1 subject on each drug dropped out of the study with complaint of fatigue. The symptom ceased with discontinuation of the drug. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Samuel Mann, PI | NY Presbyterian Hospital - Weill Cornell Medical Center | 212-746-2200 | sjmann@med.cornell.edu |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D008790 | Metoprolol |
| D000068577 | Nebivolol |
| ID | Term |
|---|---|
| D050198 | Phenoxypropanolamines |
| D011412 | Propanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
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| Nebivolol | Drug | Nebivolol 5 mg, Nebivolol 10 mg. |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| NOT COMPLETED |
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| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
31 subjects received Metoprolol 50 mg daily for 4 weeks |
| OG002 | Nebivolol 10 mg for 4 Weeks | 31 subjects received Nebivolol 10 mg daily for 4 weeks. |
| OG003 | Metoprolol 100 mg for 4 Weeks | 31 subjects received Metoprolol 100 mg daily for 4 weeks |
|
|
|
| Primary | Treadmill Exercise Time 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. | All participants who received both interventions and completed all study visits were included in the efficacy analysis. | Posted | Mean | Standard Deviation | minutes | After 4 weeks of treatment on each drug/dose combination |
|
|
|
|
| 0 |
| 33 |
| 0 |
| 33 |
| 1 |
| 33 |
| EG001 | Metoprolol 50 mg for 4 Weeks | 31 subjects received Metoprolol 50 mg daily for 4 weeks | 0 | 33 | 0 | 33 | 1 | 33 |
| EG002 | Nebivolol 10 mg for 4 Weeks | 31 subjects received Nebivolol 10 mg daily for 4 weeks. | 0 | 33 | 0 | 33 | 0 | 31 |
| EG003 | Metoprolol 100 mg for 4 Weeks | 31 subjects received Metoprolol 100 mg daily for 4 weeks | 0 | 33 | 0 | 33 | 0 | 31 |
|
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| D009930 |
| Organic Chemicals |
| D020005 | Propanols |
| D000588 | Amines |
| D004983 | Ethanolamines |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| 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). | t-test, 2 sided | Paired t-test was performed since each participant received both interventions in a crossover design. | 0.43 | Mean Difference (Final Values) | -25.90 | 2-Sided | 95 | -91.55 | 39.75 | Direction of Comparison: Mean Treadmill Exercise Time for Nebivolol 10 mg minus Mean Treadmill Exercise Time for Metoprolol 100 mg. | Superiority |