Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 4 of 133 for:    Recruiting, Not yet recruiting, Available Studies | Tachycardia

Gastrointestinal Symptoms in Postural Orthostatic Tachycardia Syndrome (POTS-GUT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03263819
Recruitment Status : Recruiting
First Posted : August 28, 2017
Last Update Posted : August 20, 2019
Sponsor:
Information provided by (Responsible Party):
Cyndya Shibao, Vanderbilt University Medical Center

Tracking Information
First Submitted Date August 24, 2017
First Posted Date August 28, 2017
Last Update Posted Date August 20, 2019
Actual Study Start Date June 20, 2017
Estimated Primary Completion Date January 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: August 25, 2017)
Gastrointestinal hormones plasma levels after oral glucose tolerance test [ Time Frame: 0-120 minutes. ]
The plasma levels of GI peptides (GLP-1, GLP-2, PPY, glucagon, C-peptide, insulin) and their pattern of secretion after ingestion of 75 g glucose.
Original Primary Outcome Measures
 (submitted: August 24, 2017)
Gastrointestinal hormones plasma levels after oral glucose tolerance test [ Time Frame: 0-120 minutes. ]
The plasma levels of GI peptides (GLP-1, GLP-2, PPY, glucagon, C-peptide, insulin) and their pattern of secetion after ingestion of 75 g glucose.
Change History Complete list of historical versions of study NCT03263819 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures
 (submitted: August 25, 2017)
  • Gastric emptying after oral glucose [ Time Frame: 0-120 minutes. ]
    Gastric emptying time will be measured by acetaminophen absorption test after ingestion of 75 grams glucose.
  • Gastrointestinal symptoms [ Time Frame: 0-120 minutes ]
    The gastrointestinal symptoms will be evaluated by questionnaire after ingestion of 75 grams glucose.
  • POTS related symptoms [ Time Frame: 0-120 minutes. ]
    Symptoms related to postural orthostatic tachycardia symptoms will be evaluated by specific questionnaire after ingestion of 75 grams glucose.
Original Secondary Outcome Measures
 (submitted: August 24, 2017)
  • Gastric emptying after oral glucose [ Time Frame: 0-120 minutes. ]
    Gastric emptying time will be measured by acetaminophen absorption test after ingestion of 75 grams glucose.
  • Gastrointestinal symptoms [ Time Frame: 0-120 minutes ]
    The gastrointestinal symptoms will be evaluated by questionnaire after ingestion of 75 grams glucose.
  • POTS related symtoms [ Time Frame: 0-120 minutes. ]
    Symptoms related to postural orthostatic tachycardia symptoms will be evaluated by specific questionnaire after ingestion of 75 grams glucose.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Gastrointestinal Symptoms in Postural Orthostatic Tachycardia Syndrome
Official Title POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME AND GASTROINTESTINAL SYMPTOMS: Contribution of Gastrointestinal Peptides
Brief Summary

Patients with POTS experience significant gastrointestinal symptoms. Current evidence suggesting that abnormal post-ganglionic sympathetic function could play a role in the pathophysiology of these GI abnormalities. Sympathetic fiber regulate motor and the postprandial GI peptides secretion.

The focus of the present proposal is to determine glucose homeostasis, GI motility, and their association with GI and cardiovascular symptoms in POTS patients versus healthy controls. Furthermore, we will determine differences in these outcomes in POTS patients with and without evidence of postganglionic sympathetic fiber neuropathy.

As a long-term goal, this study can lead us to understand the pathophysiology of common co-morbidities in patients with POTS to provide new treatment approaches and prevention strategies.

Detailed Description

Postural Tachycardia Syndrome (POTS) is a disabling condition that mostly affects young women in their reproductive age. It is characterized by chronic (>6 months) orthostatic intolerance symptoms (palpitation, lightheadedness, blurred vision and mental clouding) triggered by assuming an upright posture and that improved upon recumbency. These symptoms are associated with a rapid increase in heart rate (≥30 bpm) that occur within 10 minutes upon standing. POTS is estimated to affect up to 3 million persons in the United States and is considered a syndrome rather than a single disease.

The pathophysiology of POTS is complex, and are related to abnormal cardiovascular autonomic adaptation to postural changes. Under normal conditions, the assumption of upright posture does not result in major changes in blood pressure due to the integration of complex autonomic, circulatory and neurohumoral responses. Upright posture-induced a fluid shift of approximately 700 mL of blood from the upper thorax to the splanchnic circulation and lower extremities, which result in decrease in venous return to the heart, ventricular filling, and stroke volume. These changes cause unloading of the arterial baroreceptors and increase in sympathetic activity, vasoconstriction and restoration of stroke volume and cardiac output.

In POTS patients, multiple mechanisms have been proposed to explain the exaggerated increase in heart rate. The orthostatic tachycardia could be a compensatory phenomenon to hypovolemia, impaired sympathetic-mediated vasoconstriction or increased vascular compliance. The later could induce an exaggerated fluid shift upon standing from thorax to lower body. Depending on the mechanism involved different POTS phenotype has been described: (i) hypovolemic POTS; (ii) neuropathic POTS; and (iii) POTS associated with Ehlers-Danlos and joint hypermobility syndrome (EDS/JHS). Of note, there is overlapping in the pathophysiology of POTS with patients having more than one etiology.

In addition to the cardiovascular symptoms, patients with POTS experience significant gastrointestinal symptoms namely nausea, bloating, diarrhea or even severe constipation. Furthermore, large meals or high carbohydrate meals exacerbates the feelings of palpitations, weakness, and fatigue in these patients.

Multiple studies have reported the presence of alterations in the gastrointestinal motility. Pooled data from 352 patients recruited from 6 different studies, showed 21-80% prevalence of nausea, vomiting, and abdominal pain. In four of these studies that measured gastric motility, they found that 43% prevalence of rapid gastric emptying and 20% prevalence of delayed gastric emptying. Furthermore, Al-Shekhlee et al. reported a high prevalence of impaired sudomotor function in the POTS patients who reported GI symptoms suggesting that abnormal post-ganglionic sympathetic function could play a role in the pathophysiology of these GI abnormalities.

We previously defined a subgroup of POTS patients in whom we detected a partial peripheral autonomic neuropathy primarily affecting lower extremities (neuropathic POTS). These subjects had decreased norepinephrine spillover in response to sympathetic activation and abnormal sweat volumes and prolonged latency detected by quantitative sudomotor axon reflex (QSART). Recently, Gibbons and Freeman (2013) strengthen the definition by providing histological evidence of neuronal damage with the inclusion of skin biopsies with specific staining for autonomic dense fiber and sensitivity assessment.

In Neuropathic POTS there is evidence of impaired vasomotor tone in different specific vascular bed, particularly the splanchnic circulation. Tani et al. reported reduced splanchnic vascular resistance and increase in resting mesenteric blood flow providing evidence of splanchnic denervation.

In summary, there is evidence of post-ganglionic sympathetic denervation is a subset of patients with POTS. The most current definition are based on the presence of abnormal sudomotor and sensitivity assessment.

The sympathetic nervous system (SNS) provide innervation to the enteric ganglia, the circular muscles of sphincters, and the mucosa of the stomach and intestines. The SNS also negatively regulate the motor and secretory functions of the gastrointestinal (GI) tract. Browning and Travagli (2014) reported that the absence of sympathetic inhibitory innervation causes excessive and uncoordinated activity in the GI tract. Indicating that a preserved ANS (autonomic nervous system) regulation of the GI tract is crucial for the maintenance of normal GI motility.

In addition to regulating the motor function, the SNS and parasympathetic nervous system (PNS) regulate the postprandial GI peptides secretion by enteroendocrine cells (EEC). EECs are the first line components of the Brain-Gut axis. Multiple peptides, such as incretins (GLP-1, GLP-2, GIP), and PYY (peptide YY) are important for the maintenance of glucose homeostasis. They are secreted by a different type of EEC in the GI tract. Prior to their absorption, nutrients in the GI lumen are important stimuli for peptide secretion in the ileum in rats, pigs , and humans. These peptides are secreted before the bulk of ingested meal reaches to the ileum, suggesting the presence of a neuronal/endocrine pathway in GI tract.

In summary, the SNS through innervation the gut smooth muscle; ENS (enteric nervous system) and EECs negatively regulate the GI motor function and incretins secretion which impact glucose homeostasis.

Evidence from animal models showed that when rats underwent removal of the superior autonomic mesenteric ganglia that contains mostly SNS neurons and were challenged with an oral glucose gavage; plasma insulin and C-peptide secretion were increased compared with controls (non-ganglionectomised rats). Furthermore, glucose levels were much lower in the ganglionectomised rats suggesting that the SNS splanchnic innervation plays a critical role in the maintenance of glucose homeostasis. The increased secretion of insulin and C-peptide levels in this model could be explained by an increase in incretin hormonal release. Additional studies using isolated guineas pig ileum (in vitro model) showed that GLP-1 secretion is inhibited by SNS nerve stimulation which is mediated by α-adrenergic receptors.

In summary, in the absence of sympathetic tone on ENS and EECs the incretins secretion increases which may cause low levels of plasma glucose.

The focus of the present proposal is to determine glucose homeostasis, GI motility, and their association with GI and cardiovascular symptoms in POTS patients versus healthy controls. Furthermore, we will determine differences in these outcomes in POTS patients with and without evidence of postganglionic sympathetic fiber neuropathy.

The glucose homeostasis will be evaluated by a modified oral glucose tolerance test (OGTT). In addition, we will assess GI symptoms and hemodynamics before and after oral glucose (at minute 0, 30, 60, 90, and 120). The plasma levels of GI peptides (GLP-1, GLP-2, PYY, glucagon, C-peptide, insulin) will be measured in different time points after oral glucose. Gastric emptying will be evaluated by acetaminophen absorption test (AAT). The LPS (lipopolysaccharide), LBP (lipopolysaccharid-binding protein), sCD14, and I-FABP (faty acid-binding protein) as GUT cells damage markers will be measured at baseline. The following technics will be used in this study:

  1. Oral glucose tolerance test (OGTT): In the case of OGTT, subjects will be given a ready-to-use test solution (TRUTOL® 75, Thermo Scientific, USA) containing 75 g glucose dissolved in 300 mL water, immediately after fasting blood sampling. They will be instructed to drink the test solution within 5 mins. Blood samples will be drawn at 5, 10, 15, 30, 60, 90, and 120 minutes after drinking the ready-to-use test solution. Gastric emptying will be measured by acetaminophen absorption test.
  2. Acetaminophen absorption test (AAT): Acetaminophen (20 mg/kg) will be given to patients. Serum acetaminophen will be determined by fluorescence polarization immunoassay. This assay uses a six-point calibration curve, and the detection limit is 4 µmol/L. The coefficient of variation is less than 5%. Estimation of the rate of gastric emptying was based on serum concentrations of acetaminophen in the blood samples collected. An algorithm that transforms serum concentrations of paracetamol into estimates of gastric emptying was applied. This algorithm adjusts for first-pass metabolism, unequal distribution and individual rate of elimination, and provides estimates for the percentage of meal emptied from the stomach as a function of time.
  3. Gastrointestinal symptoms scoring: The 2-page questionnaire is based on elements from a questionnaire that have been validated with some modifications. The questionnaire contains 17 questions on the frequency of GI symptoms that have been troublesome in the preceding 6 months. The frequency of each symptom is rated on seven-point Likert scale from no discomfort to very severe discomfort.
  4. Hemodynamic symptoms scoring: Hemodynamic symptoms will be measured by using the Vanderbilt POTS Symptom Score. The patients will be asked to rate the severity of 9 symptoms on a 0-10 scale (with 0 reflecting an absence of symptoms). The sum of the scores at each time point will be used as a measure of symptom burden. The 9 symptoms are: mental clouding, blurred vision, shortness of breath, rapid heartbeat, tremulousness, chest discomfort, headache, lightheadedness, and nausea. This symptom score has been previously used by our center, and the symptoms were chosen as they reflect common complaints of patients with POTS.
  5. Glucose and insulin levels: Glucose levels will be measured with a glucose analyzer (YSI Life Sciences, Yellow Springs, OH).
  6. GI peptides measurements: The plasma designated for GLP-1 measurement will be supplemented with aprotinin (1,000 kallikrein inactivation unit (KIU)/ml) and dipeptidyl peptidase-4 inhibitor (20 μl/ml plasma; Millipore, St. Charles, MO). Plasma insulin, c-peptide, glucagon, GIP, active GLP-1 (7-37 and 7-36 amide), peptide YY, pancreatic polypeptide, and leptin were measured by multiplex immunoassays (Luminex, Millipore).
Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Whole blood will be retain for DNA extraction.
Sampling Method Non-Probability Sample
Study Population The participants with POTS and "complete autonomic failure" will be recruited from patients referred to the Vanderbilt University Autonomic Dysfunction Center. Additional patients will be recruited from the POTS registry in ResearchMatch, and information about the study will be posted on websites associated with POTS support groups. Healthy volunteers will be recruited from a population of previous participants in autonomic studies, through the ResearchMatch.org database, Subject Locator, and through advertising and emails around the Vanderbilt community.
Condition Postural Tachycardia Syndrome
Intervention Diagnostic Test: Oral glucose tolerance test
75 grams of glucose
Study Groups/Cohorts
  • POTS
    patients with postural orthostatic tachycardia syndrome diagnosis.
    Intervention: Diagnostic Test: Oral glucose tolerance test
  • Healthy controls
    Patients with Postural orthostatic tachycardia syndrome who has peripheral neuropathy
    Intervention: Diagnostic Test: Oral glucose tolerance test
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: August 24, 2017)
48
Original Estimated Enrollment Same as current
Estimated Study Completion Date January 30, 2020
Estimated Primary Completion Date January 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • 18-60 years old
  • Postural Tachycardia Syndrome: Heart rate increase >30 bpm from supine within 10 min of standing, in the absence of orthostatic hypotension (>20/10 mmHg fall in blood pressure), with chronic symptoms (> 6 months), and in the absence of other acute cause of orthostatic tachycardia.
  • Able and willing to provide informed consent
  • Female premenopausal subjects must utilize adequate birth control and willingness to undergo serum beta-hCG (human chorionic gonadotropin) testing

Exclusion Criteria:

  • Use of acetaminophen or acetaminophen-related drugs (over-the-counter) in the 24 hours prior to the study.
  • Hypertension (>150 mmHg systolic and >100 mmHg diastolic) based on history or findings on screening.
  • Orthostatic hypotension (consistent decrease in BP >20/10 mmHg with 10 min stand)
  • Pregnancy
  • History of type 1 or type 2 diabetes mellitus
  • Cardiovascular disease, such as myocardial infarction within 6 months, angina pectoris, significant arrhythmia (sinus tachycardia is not excluded), deep vein thrombosis, pulmonary embolism
  • History of serious neurologic disease
  • Impaired hepatic function (aspartate amino transaminase and/or alanine amino transaminase >1.5 x upper limit of normal range)
  • Impaired renal function (serum creatinine >1.5 mg/dL)
  • Hematocrit <28%
  • Any underlying or acute disease requiring regular medication that could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
  • Inability to comply with the protocol

Healthy control subjects

Defined as subjects without any significant past medical history, non-smokers, and on no chronic medications at the time of the study. Healthy control subjects will be age- and BMI-matched to the POTS patients.

Positive control

Patients with complete autonomic neuropathy (pure autonomic failure) will be enrolled as positive control. This condition is defined as complete autonomic failure based on AFT (autonomic function test) and norepinephrine plasma levels less than 100 pg/ml.

Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers Not Provided
Contacts
Contact: Cyndya Shibao, MD 6159364584 cyndya.shibao@vumc.org
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03263819
Other Study ID Numbers 170052
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Cyndya Shibao, Vanderbilt University Medical Center
Study Sponsor Vanderbilt University Medical Center
Collaborators Not Provided
Investigators
Principal Investigator: cyndya shibao Vanderbilt University Medical Center
PRS Account Vanderbilt University Medical Center
Verification Date August 2019