Clinical trial NCT03808740: Orthostatic Intolerance After Bariatric Surgery
Official title: Orthostatic Intolerance After Bariatric Surgery
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Orthostatic Intolerance
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2019-01-18
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: More than 78 million adults in the U.S. are obese. Bariatric surgery is the only modality that results in sustained weight loss along with reversal of diabetes mellitus, and a decrease in cardiovascular events. Obesity is associated with increased sympathetic nervous system (SNS) activity that contributes to blood pressure regulation; sympathetic vasoconstrictor activity is maximally activated upon standing and is fundamental for the maintenance of orthostatic tolerance. After bariatric surgery, there is a significant and sustained reduction in SNS activity at three and six months after the procedure, which is related to weight loss. Recently, multiple retrospective studies have reported an orthostatic intolerance (OI) syndrome after bariatric surgery characterized by chronic pre-syncopal symptoms, syncope and orthostatic hypotension. In the Vanderbilt University Medical Center bariatric surgical center, 741 post-bariatric surgery patients reported OI symptoms, 98 (13.2%) of these patients, progressed to chronic OI and in17 cases, the OI was so disabling that patients initiated treatment with pressor agents. More than 50% of OI cases in the cohort developed the condition during a weight-stable period. Hence, investigators propose the novel hypothesis that after bariatric surgery, the persistent reduction in SNS activity contributes to impaired orthostatic tolerance, which is independent of weight loss.

Detailed description: Considering that SNS vasoconstrictor activity depends on synaptic norepinephrine concentrations, investigators propose a proof-of-concept study to test the hypothesis that the norepinephrine transporter (NET) inhibitor, atomoxetine, which increases synaptic norepinephrine concentrations, will improve post-bariatric OI. Understanding the changes in SNS activity and its contribution to orthostatic tolerance after bariatric surgery is of utmost importance to unravel the mechanisms of a novel and unrecognized syndrome, post-bariatric OI. In 2014, nearly 200,000 individuals in the US underwent bariatric surgery, and the number of bariatric surgery procedures is expected to increase by 22% each year. It is projected, therefore, an increase in the incidence of post-bariatric OI.

Participants with Roux-en-Y gastric bypass (RYGB) and Vertical sleeve gastrectomy (VSG) will be studied.

OI is a chronic and disabling condition; treatment is challenging because current therapies have debatable efficacy.

The proposed application will not only provide central knowledge on the pathophysiology of this new syndrome but also will fill an unmet therapeutic need by repurposing NET inhibitors for the treatment of OI.

Eligibility criteria: Inclusion Criteria:

* Obese subjects that will undergo bariatric surgery or medical weight loss.
* Age 18-60 years
* BMI \>35 kg/m2
* Weight \< 400 lbs

Exclusion Criteria:

* Diabetes type 1
* Use of an alpha blockers, clonidine, beta-blockers.
* Pregnancy or breast-feeding. Women of childbearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control.
* The use of any strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine, tipranavir).
* Use of selective NET inhibitors.
* Use of monoamine oxidase inhibitors.
* Cardiovascular disease such as myocardial infarction within six months prior to the study, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
* History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack
* Hematocrit \< 34%
* Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
* Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study
* Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and investigator discretion

Primary outcomes:
measure: Blood Pressure Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
timeFrame: 0- 3 months
measure: Cardiac Output During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
timeFrame: 0- 3 months
measure: Stroke Volume Measurements During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
timeFrame: 0- 3 months
measure: Calculated Total Peripheral Resistance During Orthostatic Challenge With a Head up Tilt (HUT at 60 Degrees) Before and After Bariatric Surgery: at 2 Timepoints: After 10% Weight Loss and After 3 Months
timeFrame: 0- 3 months
Secondary outcomes:
Other outcomes:
Locations:
city: Nashville
country: United States
facility: Cyndya Shibao
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Cyndya Shiabao, M.D.
role: PRINCIPAL_INVESTIGATOR
References: