Postural Orthostatic Tachycardia Syndrome (POTS)Early Phase 1NCT03261570
Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS
A Early Phase 1 study testing Pyridostigmine and Digoxin in people with Postural Orthostatic Tachycardia Syndrome (POTS) and POTS, run by New York Medical College at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 15 to 30 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Postural Orthostatic Tachycardia Syndrome (POTS), POTS, Orthostatic Intolerance
- What is being tested?
- Pyridostigmine and Digoxin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 51 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jul 2017to 1 Jun 2022
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 to 30 years
- Women only
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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 :
- dizziness
- nausea and vomiting
- palpitations
- fatigue
- headache
Show all 14Show fewer
- exercise intolerance
- blurred vision
- abnormal sweating heat.
- Healthy control subjects:
- normal physical examination, and normal electrocardiographic and echocardiographic evaluations.
- Only those free from heart disease, and from systemic illness will be eligible to participate.
- This excludes patients with illnesses and disease states known to be associated with endothelial cell dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, morbid obesity and peripheral vascular disease.
- At the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks.
Who cannot join
- An active medical condition that may explain the diagnosis
- A previous medical condition with undocumented resolution that may explain the diagnosis
- any systemic or overt structural, arrhythmic or myopathic cardiovascular disease
- any illnesses known to produce autonomic dysfunction such as diabetes, heart disease, renal disease, systemic hypertension, acute and chronic inflammatory diseases, neoplastic disease, immune mediated disease, major trauma and burns, morbid obesity and peripheral vascular disease will also be excluded.
- Cigarette smokers will be excluded.
- Past or present major psychiatric disorder
- Substance abuse within 2 years before onset of symptoms.
Trial locations and contacts
1 site in 1 country.
United States1 site
New York Medical College/Bradhurst building
Hawthorne, New York, 10532
About this study
Official title: Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in Postural Tachycardia Syndrome
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.
Read the detailed description
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.
- Being tested
- Pyridostigmine, Digoxin, Placebo
- Keywords
- Postural Orthostatic Tachycardia Syndrome (POTS), POTS, Orthostatic Intolerance, Digoxin, Pyridostigmine, Mestinon
- Medical subject headings
- Postural Orthostatic Tachycardia Syndrome, Orthostatic Intolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PyridostigmineDrug
Also called Mestinon
60mg by mouth
DigoxinDrug
0.5 (500mcg) by mouth
PlaceboDrug
Lactulose 50mg by mouth
| Study group | Role | What they receive |
|---|---|---|
| Pyridostigmine and Placebo | Active comparator | Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day Receives: Drug: Pyridostigmine; Drug: Placebo |
| Digoxin and Placebo | Active comparator | Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day Receives: Drug: Digoxin; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 1 year
Secondary outcomes (4)
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.
Measured: 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.
Measured: 1 year
Heart rate
Measured: 1 year
systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2017
- Study start1 Jul 2017
- Primary completion1 Jun 2022
- Study completion1 Jun 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Postural Orthostatic Tachycardia Syndrome (POTS)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 51 participants (actual)
Sponsor and investigators
- Lead sponsor
- New York Medical College
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Responsible party
- Principal investigator, Julian Stewart, New York Medical College
- Investigators
- Julian M. Stewart, M.D., Ph.D., Principal investigator, New York Medical College
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03261570
- Sponsor's protocol ID
- 1R01HL134674-01A1
- Status last verified
- Aug 2021
- First submitted
- 14 Aug 2017
- Last updated
- 28 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in Postural Tachycardia Syndrome
- ClinicalTrials.gov ID
- NCT03261570
- Acronym / sponsor ID
- 1R01HL134674-01A1
- Keywords
- Postural Orthostatic Tachycardia Syndrome (POTS), POTS, Orthostatic Intolerance, Digoxin, Pyridostigmine, Mestinon
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 51 participants (actual)
- Lead sponsor
- New York Medical CollegeUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH)
- Study start
- 1 Jul 2017 (actual)
- Primary completion
- 1 Jun 2022 (actual)
- Study completion
- 1 Jun 2022 (actual)
- First posted
- 25 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pyridostigmine and Placebo | Active comparator | Drug: Pyridostigmine, Drug: PlaceboPyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day |
| Digoxin and Placebo | Active comparator | Drug: Digoxin, Drug: PlaceboDigoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day |
Who may qualify
- Ages
- 15 to 30 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (14 listed)
- 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 :
- dizziness
- nausea and vomiting
- palpitations
- fatigue
Key exclusion criteria (7 listed)
- An active medical condition that may explain the diagnosis
- A previous medical condition with undocumented resolution that may explain the diagnosis
- any systemic or overt structural, arrhythmic or myopathic cardiovascular disease
- any illnesses known to produce autonomic dysfunction such as diabetes, heart disease, renal disease, systemic hypertension, acute and chronic inflammatory diseases, neoplastic disease, immune mediated disease, major trauma and burns, morbid obesity and peripheral vascular disease will also be excluded.
- Cigarette smokers will be excluded.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PyridostigmineAlso: Mestinon60mg by mouth | Drug | Pyridostigmine and Placebo |
| Digoxin0.5 (500mcg) by mouth | Drug | Digoxin and Placebo |
| PlaceboLactulose 50mg by mouth | Drug | Digoxin and Placebo, Pyridostigmine and Placebo |
Primary outcome
Cardiovagal Baroreflex during orthostatic stress
Time frame: 1 year
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.
Cognitive ability during orthostatic stress
Time frame: 1 year
. 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.
4 secondary outcomes
Cardiac output measure by inert gas breathing technique
Time frame: 1 year
Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Julian M. Stewart, M.D., Ph.D. principal investigator
New York Medical College
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Pyridostigmine and Digoxin in people with Postural Orthostatic Tachycardia Syndrome (POTS) and POTS, run by New York Medical College at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Cardiovagal Baroreflex during orthostatic stress (time frame: 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2022.