Clinical trial NCT01044693: Nebivolol in the Supine Hypertension of Autonomic Failure
Official title: Effect of Nebivolol on Blood Pressure in a Model of Hypertension Sensitive to Potentiation of Nitric Oxide Bioactivity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Hypertension
Pure Autonomic Failure
Multiple System Atrophy
Keywords: supine Hypertension
autonomic failure
nitric oxide
nebivolol
Lead sponsor: Vanderbilt University
Sponsor class: OTHER
Collaborators: name: Forest Laboratories
First posted: 2010-01-08
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: The purpose of this study is to evaluate the effect of the antihypertensive drug, nebivolol (Bystolic), compared to metoprolol (Lopressor) and sildenafil (Viagra) on blood pressure in patients with autonomic failure and supine hypertension.

Detailed description: Nebivolol is distinct among beta-blockers by its ability to increase nitric oxide (NO) bioactivity. The contribution of this effect to the pharmacological actions of the drug, however, is difficult to ascertain in normal subjects because of the confounding contribution of the autonomic nervous system. Autonomic failure patients provide a unique model of hypertension devoid of autonomic modulation but sensitive to NO mechanisms. We propose to determine the effect of nebivolol on blood pressure in this patient population. A decrease in blood pressure will imply increased bioactivity of NO. Comparisons will be made with placebo, metoprolol (as a negative control) and sildenafil (as a positive control).

Eligibility criteria: Inclusion Criteria:

* Male or female and aged 18 years or over.
* Clinical diagnosis of orthostatic hypotension associated with Primary Autonomic Failure (Parkinson Disease, Multiple System Atrophy and Pure Autonomic Failure).
* A documented fall in systolic blood pressure of at least 20 mmHg, or in diastolic blood pressure of at least 10 mmHg, within 3 minutes after standing.
* Supine hypertension, defined as a systolic blood pressure \>150 mm Hg or diastolic blood pressure \> 90 mm Hg.
* Provide written informed consent to participate in the study and understand that they may withdraw their consent at any time without prejudice to their future medical care.

Exclusion Criteria:

* Have changed dose, frequency and or type of prescribed medication, within two weeks of study start.
* Women of childbearing potential who are not using a medically accepted contraception.
* Have, in the investigator's opinion, any significant cardiac, systemic, hepatic, or renal illness.
* Diabetes mellitus or insipidus.
* In the investigator's opinion, have clinically significant abnormalities on clinical examination or laboratory testing.
* In the investigator's opinion, are unable to adequately co-operate because of individual or family situation.
* In the investigator's opinion, are suffering from a mental disorder that interferes with the diagnosis and/or with the conduct of the study, e.g. schizophrenia, major depression, dementia.
* Are not able or willing to comply with the study requirements for the duration of the study.
* Persons on drugs with beta-blocking potential (e.g., amiodarone), persons taking scheduled or as needed nitrates and persons on drugs with alpha-blocking potential (e.g. tamsulosin).

Primary outcomes:
measure: Change in Systolic Blood Pressure During the Night
timeFrame: 8 pm - 8 am
Secondary outcomes:
measure: Nocturnal Urinary Sodium Excretion
timeFrame: 8 pm - 8 am
measure: Orthostatic Tolerance the Following Morning
timeFrame: 10 min standing
measure: Change in Heart Rate During the Night
timeFrame: 8 pm - 8 am
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
Study officials:
affiliation: Vanderbilt University
name: Italo Biaggioni, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Biaggioni I, Garcia F, Inagami T, Haile V. Hyporeninemic normoaldosteronism in severe autonomic failure. J Clin Endocrinol Metab. 1993 Mar;76(3):580-6. doi: 10.1210/jcem.76.3.7680352.
citation: Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, Wooding SJ, Ritter JM. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995 Sep;274(3):1067-71.
citation: Gamboa A, Shibao C, Diedrich A, Paranjape SY, Farley G, Christman B, Raj SR, Robertson D, Biaggioni I. Excessive nitric oxide function and blood pressure regulation in patients with autonomic failure. Hypertension. 2008 Jun;51(6):1531-6. doi: 10.1161/HYPERTENSIONAHA.107.105171. Epub 2008 Apr 21.
citation: Gupta S, Wright HM. Nebivolol: a highly selective beta1-adrenergic receptor blocker that causes vasodilation by increasing nitric oxide. Cardiovasc Ther. 2008 Fall;26(3):189-202. doi: 10.1111/j.1755-5922.2008.00054.x.
citation: Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hypertension of autonomic failure and its treatment. Hypertension. 1997 Nov;30(5):1062-7. doi: 10.1161/01.hyp.30.5.1062.
citation: Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001 Jul 31;104(5):511-4. doi: 10.1161/hc3001.094207.