Prevention of Syncope Trial 6 - Atomoxetine in Vasovagal Syncope

Study Overview
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Brief Summary
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Objective: To determine if atomoxetine 40 mg bid (bis in die) in patients ≥18 years old with recurrent vasovagal syncope will better prevent syncope during tilt testing than placebo.

Detailed Description
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Background: Syncope affects about 50% of Canadians, is the cause of 1-2% of emergency room visits, and probably is responsible for C$250 million (Canadian dollars) in health care spending each year. It is associated with decreased quality of life, trauma, loss of employment, and limitations in daily activities. The most common cause is vasovagal syncope. This occurs in people of all ages, and is a lifelong predilection. While the median number of faints in the population is 2, those who come to the investigators' care have a median 10-15 lifetime spells, and have an increased frequency in the year before presentation. Vasovagal syncope is due to abrupt hypotension and transient bradycardia, which cause cerebral hypoperfusion. The pathophysiology may be either failure of venous return or progressive vasodilation, both due to inappropriately low sympathetic outflow. There is no known medical treatment for frequent fainting. The investigators performed the pivotal Canadian Institutes of Health Research (CIHR)-funded randomized trials that showed that neither permanent pacing, beta blockers, nor fludrocortisone help the majority of patients. However 2 randomized studies suggest that inhibition of norepinephrine transport (NET) reuptake with sibutramine and reboxetine (NET inhibitors) prevents syncope on tilt testing by about 80%, and the investigators reported that sibutramine markedly reduced the frequency of vasovagal syncope in 7 of our most symptomatic patients. Sibutramine and reboxetine, for different reasons, are not available in Canada. However atomoxetine is available and is used to help patients with attention deficit disorder. There are no data pertaining to its hemodynamic effects in patients with vasovagal syncope. Although a randomized clinical trial of atomoxetine for the prevention of vasovagal syncope would be needed before clinical use, a proof of principle study is needed first. Objective: To determine if atomoxetine 40 mg bid (bis in die) in patients ≥18 years old with recurrent vasovagal syncope will better prevent syncope during tilt testing than placebo. Methods: The investigators will conduct a prospective, randomized, parallel, double-blind, proof-of-concept study to test the hypothesis that norepinephrine transporter inhibition with Atomoxetine prevents tilt-induced vasovagal syncope (VVS)/pre-syncope in patients with clinical vasovagal syncope. Subjects will have had ≥1 faint in the previous year, and a diagnosis of vasovagal syncope based on the Calgary Syncope Symptom Score. The primary outcome measure will be the time to syncope or presyncope with a trough rate-pressure product <7000 mm Hg/min. The primary analysis will be performed on an intention-to-treat basis. Secondary analyses will include modelled estimations of systemic vascular resistance and stroke volume, based on arterial waveform and blood pressure. This will permit us to address whether NET inhibition prevents the vasovagal reflex by maintenance of cardiac preload or maintenance of systemic vascular resistance. The investigators will randomize 64 patients in a double blind acute phase 2 study to either Atomoxetine 40mg PO bid x 2 doses or matching placebo. A sample size of 56 syncope patients would have 85% power to detect a 60% relative risk reduction from a placebo outcome rate of 65%, using an unmatched 2-tailed test with alpha=0.05. To compensate for the report dropout rate we will inflate the sample by 15% to 64 subjects. A formal, blinded mid-way safety and efficacy analysis will be performed with a p<0.01 stopping rule for efficacy. The sample size will be inflated to 74 to account for spending power on the interim analysis. This will provide 85% power to detect an 80% relative risk reduction. Relevance: This will be the first adequately powered study of the ability of atomoxetine to prevent the vasovagal reflex. It will also provide insight as to whether norepinephrine transport inhibition functions here to maintain venous return or increase systemic vascular resistance. If positive, the study will provide a strong biomedical rationale and preliminary clinical results leading to a randomized clinical trial of atomoxetine for the prevention of vasovagal syncope.

Official Title
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A Proof of Principle Study of Atomoxetine for the Prevention of Vasovagal Syncope (VVS): POST6

Conditions
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Vasovagal Syncope

Intervention / Treatment
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* Drug: Atomoxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1 or more syncopal spells in the year preceding enrolment More than -2 points on the Calgary Syncope Symptom Score Age ≥18 years with informed consent Exclusion Criteria: Other causes of syncope, such as ventricular tachycardia, complete heart block, orthostatic hypotension or hypersensitive carotid sinus syndrome Inability to give informed consent important valvular, coronary, myocardial or conduction abnormality or significant arrhythmia. hypertrophic cardiomyopathy a permanent pacemaker a seizure disorder hypertension defined as >150/90 mm Hg pregnancy glaucoma medications with known effects on blood pressure Known hypersensitivity to atomoxetine and derivatives

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo capsule to be given the night before the study tilt, and the morning of the study tilt test. | Drug: Placebo<br>* oral placebo capsule designed to blind the atomoxetine intervention<br>|
| Active Comparator: Atomoxetine<br>Atomoxetine 40mg PO to be given the night before the study tilt, and the morning of the study tilt test. | Drug: Atomoxetine<br>* 40mg PO the night before and the morning of the study tilt table test.<br>* Other names: Strattera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Become Syncopal Associated With Diagnostic Criteria of Hypotension and Bradycardia |  | 1 hour post start of head up tilt | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Become Presyncopal (Isolated) Associated With Diagnostic Criteria of Hypotension and Bradycardia |  | 1 hour post start of head up tilt | 
| Estimated Stroke Volume Index (From the Continuous BP Monitor) During Presyncope |  | From baseline to within 1 hour post start of head up tilt | 
| Cardiac Index (From the Continuous BP Monitor) During Presyncope |  | From baseline to within 1 hour post start of head up tilt | 
| Systematic Vascular Resistance Index (From the Continuous BP Monitor) During Presyncope |  | From baseline to within 1 hour post start of head up tilt |