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POTS Adrenergic Ab (CIHR Aims #1&2)

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ClinicalTrials.gov Identifier: NCT02673996
Recruitment Status : Recruiting
First Posted : February 4, 2016
Last Update Posted : March 24, 2020
Sponsor:
Information provided by (Responsible Party):
Dr. Satish Raj, University of Calgary

Tracking Information
First Submitted Date January 28, 2016
First Posted Date February 4, 2016
Last Update Posted Date March 24, 2020
Actual Study Start Date January 2016
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: February 1, 2016)
The proportion of alpha-1 Ab titer positive subjects [ Time Frame: 1 Year (to measure Adrenergic antibody assay) ]
The primary comparison will be the proportion of Ab titers between POTS patients compared to control subjects.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: February 1, 2016)
  • Antibody Positivity by Joint Hypermobility Status [ Time Frame: 1 Year (to measure Adrenergic antibody assay) ]
    These comparisons include proportions of POTS patients with +va adrenergic Ab with a co-diagnosis of joint hypermobility syndrome (EDS III) vs without joint hypermobility syndrome (EDS III).
  • Antibody Positivity by Clinical Autoimmune Syndromes [ Time Frame: 1 Year (to measure Adrenergic antibody assay) ]
    These comparisons include proportions of POTS patients with +ve adrenergic Ab with a co-diagnosis of a clinical autoimmune disorder vs without a clinical autoimmune disorder.
  • Antibody Positivity by Viral Onset of POTS [ Time Frame: 1 Year (to measure Adrenergic Antibody assay) ]
    These comparisons include proportions of POTS patients with +ve adrenergic Ab with a viral onset to their POTS vs without a viral onset to their POTS.
  • Isoproterenol HR Increase (PD25) [ Time Frame: 1 Year (to measure Adrenergic Antibody assay) ]
    A comparison of the dose of isoproterenol required to acutely increase the Heart Rate by 25 bpm from a pre-injection baseline (as a measure of beta-receptor sensitivity) in antibody positive vs. antibody negative subjects.
  • Phenylephrine Systolic BP Increase (PD25) [ Time Frame: 1 Year (to measure Adrenergic Antibody assay) ]
    A comparison of the dose of phenylephrine required to acutely increase the Systolic Blood Pressure by 25 mmHg from a pre-injection baseline (as a measure of alpha-receptor sensitivity) in antibody positive vs. antibody negative subjects.
  • The proportion of beta adrenergic Ab titer positive subjects [ Time Frame: 1 Year (to measure Adrenergic Antibody assay) ]
    The primary comparison will be the proportion of Ab titers between POTS patients
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title POTS Adrenergic Ab (CIHR Aims #1&2)
Official Title The Pathophysiological Role of Adrenergic Antibodies in Postural Tachycardia Syndrome (Aims #1&2)
Brief Summary Objective: In this pilot study, we will test the hypothesis that patients with POTS (age 18-60 years) will have a higher percentage of functional antibodies to adrenergic receptors compared with control subjects without POTS.
Detailed Description

Background & Rationale:

Postural Tachycardia Syndrome (POTS) is a chronic state of orthostatic tachycardia (> 30 bpm increment from lying to standing) and typical symptoms that are worse on standing, and are relieved by lying down. Typical orthostatic symptoms include palpitation, lightheadedness, chest pains, dyspnea, tremulousness, blurred vision and mental clouding. POTS often occurs in younger individuals with a female predominance (4-5 fold). Using the RAND36 quality of life (QOL) tool, we showed that POTS patients had lower quality of life (QOL) scores than healthy subjects for both physical (26±9 vs. 54±6; P<0.0001) and mental health domains (43±11 vs. 52±10; P<0.0001). These QOL scores are similar to scores for chronic obstructive pulmonary disease and congestive heart failure.

In collaboration with the Kem/Yu lab (Oklahoma University), the investigators sought to determine whether POTS patients had functionally significant adrenergic receptor (AR) Abs. Samples from 14 POTS patients (included 7 blinded, well-characterized samples from Vanderbilt) and 10 healthy control subjects. Using the rat cremaster artery assay, the sera/immunoglobulin (IgG) of the POTS patients demonstrated significantly greater arteriolar contractile activity (69±3% of baseline vessel diameter) compared to the control subjects (91±1% of baseline; P<0.001). This contractility was suppressed with prazosin, an α1-AR blocker. With the addition of POTS sera, the phenylephrine dose-response curve was shifted to the right. In other words, a higher dose of phenylephrine was required to achieve the same degree of vasoconstriction, suggests that the α1-AR Ab is actually a partial-agonist/antagonist.

Using a cell-based cyclic AMP (cAMP) reporter assay, all POTS sera had dose-dependent β1-AR activation (max: +30±3% from buffer baseline) compared to control sera (-1±2% from buffer baseline; P<0.001), and 7/14 POTS patients (but no control subjects) had elevated β2-AR activation. The excessive β1-AR activation could be blocked with propranolol. With the addition of POTS sera, the isoproterenol dose-response curve was shifted to the left (a lower isoproterenol dose was required to achieve the same receptor activation in the presence of the POTS sera). These data suggest that the β1-AR Ab is actually a straight agonist.

Big Picture:

While exciting, these data are obtained from only 14 POTS patients. In this protocol (Aim#1; REB15-2434), the investigators will study a larger cohort of POTS patients and control subjects in order to have a better sense of the true prevalence of these antibodies, to determine their association with other autoimmune illnesses, and to see if they relate to the patient-reported onset of illness.

In addition to this, the investigators seek to see whether this is physiologically significant in intact humans in vivo (Aim#2).

The investigators propose to perform dose response studies for phenylephrine and isoproterenol in POTS patients and control subjects with blood pressure (BP) and heart rate (HR) as the output metric and will then determine if these are different between POTS patients and control subjects and, more importantly, based on the auto-antibody in vitro activity.

Specifically, the investigators will give a series of injections of small doses of phenylephrine while monitoring their HR and continuous BP. After each injection, the investigators will note the peak BP increase and will monitor the patient until the BP returns to baseline. The investigators will give incrementally larger doses until the endpoint is achieved. The endpoint is the lowest test dose of phenylephrine that will increase the systolic BP by >25 mmHg (PHE-PD25).

the investigators will then repeat the same process with small doses of isoproterenol with the same monitoring. After each injection, the investigators will note the peak HR increase and will monitor the patient until the HR returns to baseline. The investigators will give incrementally larger doses until the endpoint is achieved. The endpoint is the lowest test dose of isoproterenol that will increase the HR by >25 bpm (ISO-PD25).

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Cross-Sectional
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
Serum for antibody assay; plasma for cytokine assessment; plasma for catecholamines
Sampling Method Non-Probability Sample
Study Population Patients with POstural Tachycardia Syndrome (POTS)
Condition Postural Tachycardia Syndrome
Intervention
  • Drug: Phenylephrine
    incremental small doses of IV phenylephrine to find the dose that transiently raises systolic blood pressure by 25 mmHg
    Other Name: NeoSynephrine
  • Drug: Isoproterenol
    incremental small doses of IV isoproterenol to find the dose that transiently raises heart rate by 25 bpm
    Other Name: Isuprel
Study Groups/Cohorts
  • Postural Tachycardia Syndrome (POTS)
    Patients with postural tachycardia syndrome; patients will receive both IV phenylephrine and IV isoproterenol
    Interventions:
    • Drug: Phenylephrine
    • Drug: Isoproterenol
  • Healthy (control) Subjects
    Healthy volunteers that are gender and age-matched (by groups) to the POTS patients; healthy subjects will receive both IV phenylephrine and IV isoproterenol
    Interventions:
    • Drug: Phenylephrine
    • Drug: Isoproterenol
Publications * Not Provided

*   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: February 1, 2016)
125
Original Estimated Enrollment Same as current
Estimated Study Completion Date December 2023
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Patients who have been previously diagnosed with POTS
  • Control subjects (patients not diagnosed with POTS)
  • Age between 18 - 60 years
  • Males and Females (Give that >80% of POTS patients are female, we will attempt to enroll a similar percentage of female control subjects)
  • Able and willing to provide consent

Exclusion Criteria:

  • Smokers
  • Overt cause for postural tachycardia, i.e., acute dehydration
  • Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or prior testing
  • Highly trained athletes
  • Subjects with somatization or severe anxiety symptoms will be excluded
  • Use of drospirenone (a spironolactone analogue) containing oral contraceptive agent
  • Hypertension defined as supine resting BP>145/95 mmHg off medications or needing antihypertensive medication
  • Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule
  • Unable to give informed consent
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Satish R Raj, MD, MSCI 403-210-6152 autonomic.research@ucalgary.ca
Contact: Robert S Sheldon, MD, PhD 403-220-8191 autonomic.research@ucalgary.ca
Listed Location Countries Canada
Removed Location Countries  
 
Administrative Information
NCT Number NCT02673996
Other Study ID Numbers REB15-2434
MOP142426 ( Other Grant/Funding Number: Canadian Institutes of Health Research )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Dr. Satish Raj, University of Calgary
Study Sponsor University of Calgary
Collaborators Not Provided
Investigators
Principal Investigator: Satish R Raj, MD, MSCI University of Calgary
PRS Account University of Calgary
Verification Date March 2020