Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000476831
Ethics application status
Approved
Date submitted
18/04/2021
Date registered
21/04/2021
Date last updated
23/10/2023
Date data sharing statement initially provided
21/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Postural orthostatic tachycardia syndrome (POTS) in Long COVID syndrome: A detailed profiling study
Scientific title
Postural orthostatic tachycardia syndrome (POTS) in Long COVID syndrome: A detailed profiling study
Secondary ID [1] 303992 0
Nil known
Universal Trial Number (UTN)
Trial acronym
(POTS-LCS)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postural Orthostatic Tachycardia Syndrome 321604 0
Long Covid Syndrome 321605 0
Condition category
Condition code
Cardiovascular 319343 319343 0 0
Other cardiovascular diseases
Infection 319344 319344 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Participants:
Cohort One: 150 consecutive patients with Long Covid Syndrome: defined as unexplained lingering symptoms greater than 3 months post SARS-CoV-2 infection

Cohort Two: 34 consecutive patients with POTS: defined as orthostatic intolerance with a postural delta heart rate change of greater than 30 beats per minute in the absence of orthostatic hypotension.

Cohort Three (Controls): 34 healthy, matched age and gender controls

Subject preparation:

48 hr before examination the following will be discontinued
• Anticholinergics
• Sympathomimetics (a and ß agonists)
• Mineralcorticoids (Fludrocortisone)

24hr before examination the following will be discontinued
• Alcohol
• Salt tablets
• Caffeine
• Beta Blockers (propranolol, metoprolol) Ivabradine

8 hrs before testing
• Fast from food
• Drink only water ‘to thirst’ and abstain from fluid ‘loading’

On the morning of testing
• No wearing of compression wear
• No abdominal binders
• No support stockings


The Exposure
The comprehensive nature of this exercise will allow subjects to complete various tools/questionnaires at their leisure via online portal links to a secure REDCap data base, to reduce the impact of fatigue on the accuracy of findings. Subjects will be required to return urine samples and Holter monitor to the clinical testing site. All autonomic testing will be undertaken by experienced clinical staff including Clinical Nurses and Doctors with greater than 5 years experience.

On Line Surveys (10-20 minutes online)
-Demographic Survey
-Health History including medications, past medical history, condition onset and symptom course

Before Study Day

1. Holter Monitor: All patients will undergo 24 hour ambulatory ECG, at home (adhesive electrodes placed on the skin and attached to a recording device). This measure will be used to determine heart rate variability; which is a measure of baseline autonomic tone. It will also help to exclude other alternative cardiac arrhythmias.

2. Echocardiogram requires the subject to undertake an ultrasound of the heart previous to the day of testing at the subject’s convenience. This test is important for determining other secondary causes of symptoms due to structural cardiac changes. Passive leg raise will be undertaken during echo assessment. It requires a non-invasive ultra-sound of the heart and generally takes 15 minutes to complete.

Online surveys are likely to take 40-60 minutes and will be accessed through online secure links. Participants can sign in and out and save data to reduce completion fatigue. Surveys include:

3. Demographic survey and Medical Health History including alcohol consumption, tobacco use. Past medical history, medications and allergies. Condition onset and clinical course

4. Rand SF-36: 36 item short form survey which is commonly utilised to measure self-reported quality of life measures in adult patients.

5. EQ-5D/5L: Is a short survey utilised and validated to describe and value health across 5 domains.

6. COMPASS-31: 31 question composite autonomic scale which is utilised widely for use in autonomic research and practice. It addresses the domains of : orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor function.

7. Fatigue Severity Score: A 9 item questionnaire that reports how fatigue interferes with certain activities and rates the severity of fatigue.

8. 5 Point hypermobility screen: Five questions related to hypermobility. A score >2/5 suggests hypermobility (sens 85%, spec 90%)

9. Orthostatic Hypotension Questionnaire: A validated tool used to determine the burden and severity of orthostatic hypotension. It has two components: a 6-item symptom assessment scale and a 4 item activity scale.

10. Hospital Anxiety Depression Scale: 14 item scale with 7 items relating to anxiety and 7 to depression. A cut off score of 8 in either domain has been widely validated as a reliable indicator of anxiety or depression.

STUDY DAY

Subjects will be invited to attend in person to facilitate detailed history and examination including autonomic testing, blood draw and associated investigations (see below). The total time of this visit is estimated to be 2.5 hours. Non-invasive measurements of continuous arterial pressure and heart rate will be obtained using finger photoplethysmography (non-invasive blood pressure testing; NIBP) for 5 minutes before testing (rest) and then during each reflex test. This involves application of a small cuff to either of the 2nd to 5th digits of one hand. The cuff is inflated to allow measurement of finger arterial blood pressure. This technique is well validated in a variety of clinical and experimental conditions.


1. Physical assessment including vital signs, height, weight and BMI. 5 minutes

2. Valsalva manoeuvre is used to assess normal or disordered autonomic control of blood pressure and heart rate. The test requires the maintenance of forced expiration against resistance for 15 seconds and beat to beat, non-invasive blood pressure and heart rate monitoring. 5 minutes

3. Deep breathing test requires the subject to breathe at 6 breaths per minute while undergoing non-invasive ‘beat to beat’ blood pressure and heart rate monitoring to determine cardiovagal function. 10 minutes

4. Sudomotor function testing requires the subject to place hands and feet on SUDOSCAN metal plates. Reverse iontophoresis and chronoamperometry are used to assess chloride ion concentration of the skin which represents a measure of sudomotor output. This test is painless and non-invasive and requires the subject to stand still for 3 minutes while the SUDOSCAN assesses function. 5 minutes

5. Orthostatic challenge requires the subject to lay supine while ‘beat to beat’ non-invasive BP and HR recordings are taken. The subject then stands still for 10 minutes and changes in BP and HR are monitored. 12 minutes

6. Blood Draw: Subjects will undergo blood draw of 15 ml (3 teaspoons). Blood specimens will be collected by trained phlebotomist and/or clinicians in a manner that is consistent with University and clinical safety protocols.

Blood tests:
• Complete Blood Panel and Electrolytes, CRP, ESR,
• # TNF-a, IL-6, IL-1ß, IL-10, IL-21, INFy, INF a/ß, CD30,
• # a1 adrenergic, Beta-1/2 adrenergic, M1 and M4 muscarinic cholinergic receptor Ab;
• # Aldosterone, Potassium, Renin activity, copeptin level;
• # Plasma Histamine, heparin, chromogranin A

7. CANTAB cognitive testing requires the participant to complete a series of neurocognitive tests (CANTAB: Cambridge Neuropsychological Test Automated Battery, Cambridge Cognition Ltd.) to assess executive function, reaction time, memory, and attention. This testing is undertaken in the seated position, using an IPAD. The assessment time is approximately 30 minutes and includes the following tests:

• Memory:
o Delayed Matching to Sample which assesses visual matching ability and short-term visual recognition memory.
• Executive Function:
o Multi-tasking Test which assesses the subject’s ability to manage conflicting information and to ignore task-irrelevant information.
• Attention and Psychomotor Speed:
o Reaction Time: which assesses motor and mental response speeds, as well as measures of movement time, response accuracy, reaction time, and impulsivity.
o Rapid Visual Information Processing which is a measure of sustained attention

8. 24 hr Urinary volume, sodium and osmolarity: At the end of their testing subjects will be given a container and a measuring pot to undertake a 24hr urine sodium, volume and osmolality study. This urine sample will be returned to a dedicated pathology collection centre the following day.




Intervention code [1] 320295 0
Not applicable
Comparator / control treatment
This study will include age matched, healthy controls as a comparison group for observation.
Control group
Active

Outcomes
Primary outcome [1] 327209 0
The primary objective of this study is to:

[1] Assess the prevalence of POTS in those with LCS, using a standardised and detailed autonomic testing protocol (this is a composite primary outcome).

Autonomic Nervous System testing entails a battery of tests which evaluate cardiovagal function and vasomotor adrenergic function. There is no standard battery of tests for ANS testing, but there a recommended inclusions as per the below:

As per the American Academy of Neurology (AAN), we will measure heart rate and blood pressure variability during deep breathing and valsalva manoeuvre. In addition Sudomotor function will be assessed using SUDOSCAN. Below references were used to develop the autonomic testing protocols for this study and are consistent with practices at 'centres of excellence' in POTS diagnosis.

American Academy of Neurology. (2009; reaffirmed 2016). Practice parameter: Evaluation of distal symmetric polyneuropathy: Role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Retrieved December 28, 2017 from http://www.neurology.org.

American Academy of Neurology. (2014, September). Autonomic testing – model coverage policy. Retrieved February 18, 2015 from www.aan.com.

American Association of Neuromuscular & Electrodiagnostic Medicine. (2017, May). Proper performance of autonomic function testing. Retrieved December 28, 2017 from www.aanem.com.

BlueCross BlueShield Association. Evidence Positioning System. (7:2019). Autonomic nervous system testing (2.01.96). Retrieved June 16, 2020 from https://www.evidencepositioningsytem.com/. (18 articles and/or guidelines reviewed)
Timepoint [1] 327209 0
Cross-sectional. One timepoint
Secondary outcome [1] 394218 0
Determining the impact of LCS with and without POTS and POTS on quality of life using EQ5D-5L score and SF-36 Score, compare to matched, healthy controls.
Timepoint [1] 394218 0
Cross-sectional, one time point
Secondary outcome [2] 394286 0
Determining the impact of LCS with and without POTS and POTS on symptom scores compare to matched, healthy controls. As determined by a composite of COMPASS-31, Fatigue Severity Scale, Orthostatic Hypotension Score, 5 point hypermobility score
Timepoint [2] 394286 0
Cross-sectional, one timepoint
Secondary outcome [3] 394287 0
Determining the impact of LCS with and without POTS and POTS on cognitive function compare to matched, healthy controls. Using CANTAB neuropsychological battery testing.
Timepoint [3] 394287 0
Cross-Sectional, one point in time
Secondary outcome [4] 394288 0
Determining the impact of LCS with and without POTS and POTS on psychological wellbeing compare to matched, healthy controls. Using hospital anxiety/depression scale.
Timepoint [4] 394288 0
Cross-sectional, one point in time
Secondary outcome [5] 394371 0
Characterising the neuroendocrine biomarker profile of those with LCS(+)POTS/LCS(-)POTS and POTS and compare to matched, healthy controls. These are exploratory outcomes as there is currently little understanding of the roles of these biomarkers in POTS and LCS.
Morning blood test with a 8 hr food fast (drink to thirst). Plasma will be collected in EDTA tubes, centrifuged and kept in -80 degrees freezer before batch analysis using the Thermo Scientific B·R·A·H·M·S Copeptin proAVP KRYPTOR assay using B·R·A·H·M·S KRYPTOR compact PLUS, Hennigsdorf, Germany).

Timepoint [5] 394371 0
Cross-sectional, one timepoint
Secondary outcome [6] 394372 0
Characterising the inflammatory biomarker profile of those with LCS(+)POTS/LCS(-)POTS and POTS and compare to matched, healthy controls. These are exploratory outcomes as there is currently little understanding of the roles of these biomarkers in POTS and LCS.
Inflammatory biomarkers will be processed using ProcartaPlex™ Multiplex Immunoassay as per manufacturer’s instructions.

Timepoint [6] 394372 0
One Timepoint, Cross sectional
Secondary outcome [7] 394373 0
Characterising the immune biomarker profile of those with LCS(+)POTS/LCS(-)POTS and POTS and compare to matched, healthy controls. These are exploratory outcomes as there is currently little understanding of the roles of these biomarkers in POTS and LCS. ELISA kits will be purchased form CellTrend GmbH (Luckenwalde, Germany). Samples will be processed as per the manufacturer’s instructions. to detect autoantibodies

Timepoint [7] 394373 0
One timepoint, cross-secitonal

Eligibility
Key inclusion criteria
Cohort 1 (LCS): Adults aged 18 years old or greater (male or female); Able to provide written informed consent; previous SARS-CoV-2 infection (As some Australians contracted SARS-CoV-2 in countries that did not undertake testing in the early stages of the pandemic, some participants will not have a diagnosis by PCR. Inclusion with physician confirmed Long Covid is consistent with worldwide research practices for Long Covid studies); continuing chronic symptoms persisting for greater than 3 months post-acute COVID-19 infection and not attributable to an alternative disease state.

Cohort 2 (POTS): Adults aged 18 years old and older (male or female); POTS diagnosis; Able to provide written informed consent; Diagnostic criteria for POTS met as per the following: 1. sustained heart rate elevation of 30 beats/min or greater within 10 minutes. 2. No other secondary cause of these symptoms. 3. Absence of orthostatic hypotension 4. Symptomatology present for greater than 3 months

Cohort 3 (Healthy Control): Otherwise, healthy adults aged 18 years old or greater (male or female); Able to provide written informed consent; absence of POTS diagnosis or previous SARS-CoV-2 infection.

Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Non-consent for participation in study; pregnancy or lactation; other known causes of autonomic dysfunction; co-morbidities such as Type 1 Diabetes, Parkinson’s disease, multiple sclerosis, alcoholism, drug addiction, malignant neoplasm, recent cerebrovascular accident or transient ischaemic attack, acquired brain injury; significant surgery within the last 3 months; unavailability for completion of all assessments as per the study protocol; non-English speaker; terminally ill with life expectancy <12 months.

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
A base sample size calculation can be made using the formula: n = (t2 x p(1-p))m2, where t=confidence level at 95%, p=estimated prevalence of POTS within an LCS sample and m is the relative precision. Using this formula, a sample size of 139 provides sufficient statistical power to estimate a proportion (10% POTS amongst LCS) with a precision of 5% at the 95% confidence level. The number is increased to 150 to allow for withdrawal from the study.

From Walker et al. 2013 paper, the following information was obtained: at 30 minutes of orthostatic time, Stand healthy group (N=15) had mean orthostatic change in heart rate 26 bpm + SE=4 (SD=SE*SQRT(N) = 15.5) and the Stand POTS group (N=15) had mean orthostatic change in heart rate 45 bpm + SE=5 (SD=SE*SQRT(N) = 19.4).24 Using a two-sample Satterthwaite t Test assuming unequal variance, with alpha=0.05, two-sided test and SD=15.5 and 19.4, if was found that there was 80% power to detect a mean difference of 45-26=19 when using a sample size of N=15 per group. If there is expected to be 20% loss to follow up, then a total of (20/9)*30=66.66 so N=34 is required in each group (N=68 in total) The statistical software used was SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
Continuous variables will be reported as mean and standard deviation, or median and interquartile range, as appropriate to distribution. Count variables will be reported as numbers and percentages. Categorical variables will be evaluated using a chi-square or Fisher exact test as appropriate. All statistical tests will be two-sided, and a p value of <0.05 will be considered significant. All analyses will be undertaken using Stata 13.0 (Stata Corporation).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
23/04/2021
Actual
13/05/2021
Date of last participant enrolment
Anticipated
20/12/2023
Actual
Date of last data collection
Anticipated
31/01/2024
Actual
Sample size
Target
218
Accrual to date
200
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment postcode(s) [1] 37113 0
5068 - Kensington Park
Recruitment postcode(s) [2] 37114 0
5068 - Kensington Park
Recruitment postcode(s) [3] 37115 0
3150 - Glen Waverley

Funding & Sponsors
Funding source category [1] 308373 0
University
Name [1] 308373 0
The University of Adelaide
Country [1] 308373 0
Australia
Funding source category [2] 308374 0
Charities/Societies/Foundations
Name [2] 308374 0
Standing up to POTS
Country [2] 308374 0
United States of America
Primary sponsor type
University
Name
The University of Adelaide
Address
Royal Adelaide Hospital
Cardiology 4G751-769
The University of Adelaide
Port Rd, SA 5000
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 309192 0
Other Collaborative groups
Name [1] 309192 0
South Australian Health and Medical Research Institute
Address [1] 309192 0
North Terrace Adelaide, South Australia 5000
Country [1] 309192 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308339 0
University of Adelaide , Ethics Committee
Ethics committee address [1] 308339 0
Ethics committee country [1] 308339 0
Australia
Date submitted for ethics approval [1] 308339 0
17/03/2021
Approval date [1] 308339 0
16/04/2021
Ethics approval number [1] 308339 0
HREC-2021-053

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110362 0
Prof Dennis Lau
Address 110362 0
Royal Adelaide Hospital
Cardiology 4G751-769
The University of Adelaide
Port Rd, SA 5000
AUSTRALIA
Country 110362 0
Australia
Phone 110362 0
+61 452 646 375
Fax 110362 0
Email 110362 0
[email protected]
Contact person for public queries
Name 110363 0
Marie-Claire Seeley
Address 110363 0
Royal Adelaide Hospital
Cardiology 4G751-769
The University of Adelaide
Port Rd, SA 5000
AUSTRALIA
Country 110363 0
Australia
Phone 110363 0
+61 8 8313 9000
Fax 110363 0
Email 110363 0
[email protected]
Contact person for scientific queries
Name 110364 0
Dennis Lau
Address 110364 0
Royal Adelaide Hospital
Cardiology 4G751-769
The University of Adelaide
Port Rd, SA 5000
AUSTRALIA
Country 110364 0
Australia
Phone 110364 0
+61 8 8313 9000
Fax 110364 0
Email 110364 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
AFter de-identification, individual participant data underlying published results
When will data be available (start and end dates)?
Data will be available immediately following publication - no end date.
Available to whom?
Case by case basis at the discretion of the primary sponsor
Available for what types of analyses?
Data will be available for any purpose as per the unspecified consent obtained from participants
How or where can data be obtained?
Access will be via approval by Principal Investigator Assoc/Prof Dennis Lau [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11407Ethical approval    See attached document 381826-(Uploaded-18-04-2021-19-08-42)-Study-related document.pdf



Results publications and other study-related documents

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