An Early Phase 1 interventional study of Pyridostigmine and Digoxin in Postural Orthostatic Tachycardia Syndrome (POTS), POTS and Orthostatic Intolerance, sponsored by New York Medical College. Completed at 1 site in United States. Open to female participants aged 15 Years to 30 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-09-28.
Sponsored by New York Medical College · Early Phase 1, Interventional, and Diagnostic
Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance associated with excessive upright tachycardia, and occurs predominantly in young females (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory often called "brain fog" by patients. Task-related neurovascular coupling (NVC) links neural activity to an increase in CBF known as "functional hyperemia". Although memory task performance and NVC deteriorated with angle of tilt in POTS but not healthy controls, cerebral blood flow (CBF) remained similar to control. Instead, the investigators observed extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples BP to HR to buffer BP changes. The investigators hypothesize that the cardiovagal baroreflex becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF and Brain Fog in POTS.
Orthostatic intolerance is defined by debilitating upright symptoms that are relieved by sitting or lying. Symptoms include upright lightheadedness, fatigue, confusion, and decreased memory called 'Brain Fog' by patients. The most common chronic form is Postural Tachycardia Syndrome (POTS), characterized by excessive upright tachycardia without hypotension. Of note, >85% of POTS patients are female. The proposal that Brain Fog was caused by reduced cerebral blood flow (CBF) has been disproven, because graded incremental upright tilt failed to demonstrate difference in mean CBF compared to healthy volunteers. Nevertheless, memory task performance deteriorates with angle of tilt as does task-related neurovascular coupling (NVC), which links neural activity to an increase in CBF known as "functional hyperemia". The investigators have previously observed that large low frequency (0.07-0.13 Hz) oscillations in BP (OBP), which entrained and amplified oscillations in CBF (OCBF), increased with tilt angle and were associated with impaired working memory and reduced functional hyperemia.
The sympathetic baroreflex remains intact and HR is excessively increased in the absence of parasympathetic counterregulation. The cardiovagal baroreflex couples BP to HR to buffer BP changes. Large low frequency BP oscillations, representing a resonance within the sympathetic baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and reduced parasympathetic buffering of BP by HR; conditions found in upright POTS. This leads to the following hypothetical paradigm:
↓Cardiovagal Baroreflex → ↑OBP → ↑↑OCBF → ↓NVC → ↓working memory. Therefore, in this application, the investigators hypothesize that the cardiovagal baroreflex is impaired in POTS while supine, becomes further impaired with orthostasis, and accounts for OBP, OCBF, and loss of NVC. Further, the investigators propose that improving the cardiovagal baroreflex improves hemodynamics and Brain Fog in POTS patients.
136 studies on the registry are indexed under Postural Orthostatic Tachycardia Syndrome; 42 are open to participants now.
This study's enrollment of 51 is above the median of 36 across 102 interventional studies indexed under Postural Orthostatic Tachycardia Syndrome.
Browse Postural Orthostatic Tachycardia Syndrome studies →New York Medical College is the lead sponsor of 71 studies on the registry; 24 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
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Inclusion Criteria for POTS patients:
POTS patients referred for day to day orthostatic intolerance with greater than 3 symptoms for greater than 3 months and will have the diagnosis of symptomatic postural tachycardia made during a screening tilt table test :
Healthy control subjects:
At the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks.
Exclusion Criteria for both POTS and healthy controls:
Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
Drug: Pyridostigmine · Drug: Placebo
Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
Drug: Digoxin · Drug: Placebo
60mg by mouth
Also known as: Mestinon
0.5 (500mcg) by mouth
Lactulose 50mg by mouth
Cardiovagal Baroreflex during orthostatic stress
Cardiovagal Baroreflex during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. The unmedicated baroreflex measurement will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Baroreflex measurements will be obtained using the standard "modified Oxford" technique.
Time frame: 1 year
Cognitive ability during orthostatic stress
. Cognitive ability during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. Cognitive ability will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Cognitive ability will be assessed with a standard 2-Back test in which patients identify identical alphabetic characters appearing 2 characters before the current displayed character in a sequence of 29 characters.
Time frame: 1 year
Cardiac output measure by inert gas breathing technique
Cardiac output measure by inert gas breathing technique. Cardiac output is the amount of blood pumped by the heart in one minute. The technique uses the Innocor system in which the relative levels of two inert gases - one blood soluble and one insoluble component - are measured over a few respirations (about 5 breaths or 15 seconds). The rate of disappearance of the soluble gas from the alveolar space is proportional to the flow of blood perfusing the lungs and equals the cardiac output.
Time frame: 1 year
Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle
Arterial blood pressure in mmHg over each cardiac cycle will be collected using finger photoplethysmography. The arterial pressure is reported as an aggregate of 3 extracted quantities: the systolic blood pressure which is the maximum blood pressure over a cardiac cycle; the diastolic blood pressure which is the minimum blood pressure over a cardiac cycle; and the mean blood pressure which is the average blood pressure over a cardiac cycle.
Time frame: 1 year
Heart rate
Time frame: 1 year
systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output
Time frame: 1 year
Ran from Jul 2017 to primary completion in Jun 2022, 59 months.
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Studies of the drugs tested here: Pyridostigmine · Digoxin
Postural Orthostatic Tachycardia Syndrome →
New York Medical College