Orthostatic Intolerance After Bariatric Surgery

NCT03808740 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 180499
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Orthostatic Intolerance

Outcome Measures

Primary Outcomes (4)

• 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

  To assess the hemodynamic (Blood Pressure) changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.

  0- 3 months

• 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

  To assess the hemodynamic (cardiac output \[CO\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.

  0- 3 months

• 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

  To assess the hemodynamic (stroke volume \[SV\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope Orthostatic hemodynamics were analyzed as the area under the curve (AUC) after baseline-correction during HUT.

  0- 3 months

• 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

  To assess the hemodynamic ( total peripheral resistance \[TPR\]) and cardiovascular autonomic changes during an orthostatic challenge with a head up tilt (HUT at 60 degrees) before and after bariatric surgery, at two time-points: after 10% weight loss (10% WL) and after 3 months, in morbidly obese patients. Our primary endpoint (orthostatic tolerance, OT) is defined as the time between the start of the 60 degree HUT until pre-syncope

  0- 3 months

Study Arms (4)

Roux-en-Y gastric bypass (RYGB)/Atomoxetine

EXPERIMENTAL

Participants with standard of care RYGB will receive atomoxetine, 0.5 mg/kg/day for 3 days

Drug: Atomoxetine

Vertical sleeve gastrectomy (VSG) /Atomoxetine

EXPERIMENTAL

Participants with standard of care VSG will receive atomoxetine 0.5 mg/kg/day for 3 days

Drug: Atomoxetine

Roux-en-Y gastric bypass (RYGB)/Placebo

PLACEBO COMPARATOR

Participants with standard of care RYGB will receive placebo 0.5 mg/kg/day for 3 days

Drug: Placebo

Vertical sleeve gastrectomy (VSG)/ Placebo

PLACEBO COMPARATOR

Participants with standard of care VSG will receive placebo 0.5 mg/kg/day for 3 days

Drug: Placebo

Interventions

Atomoxetine DRUG

atomoxetine 0.5 mg/kg/day.

Also known as: strattera

Roux-en-Y gastric bypass (RYGB)/Atomoxetine; Vertical sleeve gastrectomy (VSG) /Atomoxetine

Placebo DRUG

sugar pill

Also known as: sugar pill

Roux-en-Y gastric bypass (RYGB)/Placebo; Vertical sleeve gastrectomy (VSG)/ Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Cyndya Shibao

Nashville, Tennessee, 37027, United States

Location

MeSH Terms

Conditions

Orthostatic Intolerance

Interventions

Atomoxetine Hydrochloride; Sugars

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Carbohydrates

Results Point of Contact

• Title: Dr Cyndya Shibao
• Organization: Vanderbilt University Medical Center

cyndya.shibao@vumc.org

6159364584

Study Officials

• Cyndya Shiabao, M.D.

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: January 16, 2019
• First Posted: January 18, 2019
• Study Start: July 1, 2018
• Primary Completion: May 31, 2021
• Study Completion: May 31, 2021
• Last Updated: September 27, 2024
• Results First Posted: September 27, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)