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A Proof of Principal Study of Atomoxetine for the Prevention of Vasovagal Syncope (POST6)

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ClinicalTrials.gov Identifier: NCT02874937
Recruitment Status : Completed
First Posted : August 22, 2016
Last Update Posted : May 16, 2019
Sponsor:
Information provided by (Responsible Party):
Dr. Bob Sheldon, University of Calgary

Brief Summary:
Syncope affects about 50% of Canadians, is the cause of 1-2% of emergency room visits, and probably is responsible for CDN $250 million in health care spending each year.There is no known medical treatment for frequent fainting. Two 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, the investigators first need a proof of principle study. The objective is to determine in a prospective, randomized, parallel, double-blind study if atomoxetine 40 mg bid in patients at least 18 years old with recurrent vasovagal syncope will better prevent syncope during tilt testing than placebo.

Condition or disease Intervention/treatment Phase
Syncope, Vasovagal Drug: Atomoxetine Drug: Matching Placebo Phase 2

Detailed Description:

Study Design: This will be a randomized, double-blind, parallel-arm study in which the subjects will undergo a tilt table test following 2 doses of atomoxetine 40mg PO (evening before and morning of study) or after 2 doses of matching placebo (on separate days). On the morning of the study, the fasting subject (except for medications) will be instrumented, on an empty bladder. ECG electrodes will be applied to monitor continuous heart rhythm. Blood pressure will be monitored continuously using a finger volume clamp method using one or more of several extant devices, and calibrated with intermittent brachial cuff measurements. One intravenous cannula will be placed in the contralateral arm (to the blood pressure cuff) for blood sampling.

Tilt Table Protocol: Following the insertion of the venous cannulae, a period of at least 20 minutes will be allowed to elapse before a 10-minute basal control (baseline) period. Baseline data will be digitally recorded in this time. In the last 5 minutes of this period, blood will be drawn for fractionated plasma catecholamines. The table will be rapidly raised to 80 degrees for up to 60 minutes. The investigators are deliberately avoiding tilt test methods with provocative medications to avoid the issue of multiple causal factors. At 10 minutes and 30 minutes following onset of tilt (or at the onset of severe presyncope or hypotension [systolic blood pressure <70 mmHg]), venous fractionated catecholamines will be sampled. The study will be terminated if the subject develops hypotension with severe presyncopal symptoms associated with a systolic blood pressure ≤70 mmHg or at the completion of the protocol.

A sample size of 56 syncope patients will 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 the investigators will inflate the sample by 15% to 64 subjects. A formal, blinded mid-way safety and efficacy analysis will be performed with a p<0.05 stopping rule for efficacy. This also will provide 85% power to detect an 80% relative risk reduction.

Randomization will be carried out using a computerized algorithm. Patients will be randomized in a double blind fashion to receive atomoxetine 40mg PO x2 or matching placebo with a 1:1 randomization ratio. Medication containers will be centrally filled and labeled with the randomization code number.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Proof of Principal Study of Atomoxetine for the Prevention of Vasovagal Syncope (POST 6)
Study Start Date : February 2015
Actual Primary Completion Date : November 28, 2017
Actual Study Completion Date : January 8, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fainting

Arm Intervention/treatment
Active Comparator: Atomoxetine
2 doses of atomoxetine 40mg PO (evening before and morning of study)
Drug: Atomoxetine
norepinephrine transporter inhibitor
Other Name: Apo-atomoxetine

Placebo Comparator: Placebo
2 doses of matching placebo 40 mg PO (evening before and morning of study)
Drug: Matching Placebo
matching placebo identical in appearance.
Other Name: Placebo




Primary Outcome Measures :
  1. Time to syncope or presyncope [ Time Frame: 1 hour ]

Secondary Outcome Measures :
  1. systemic vascular resistance [ Time Frame: 1 hour ]
  2. stroke volume [ Time Frame: 1 hour ]
  3. cardiac output [ Time Frame: 1 hour ]
  4. catecholamine levels [ Time Frame: 1 hour ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥1 syncopal spells in the year preceding enrolment
  • ≥-2 points on the Calgary Syncope Symptom Score
  • Age ≥18 years with informed consent
  • The Calgary Syncope Symptom Score is used to diagnose VVS in patients with structurally normal hearts

Exclusion Criteria:

  • Other causes of syncope, such as ventricular tachycardia, complete heart block, orthostatic hypotension or hypersensitive carotid sinus syndrome
  • An inability to give informed consent
  • Important valvular, coronary, myocardial or conduction abnormality or significant arrhythmia
  • Hypertrophic cardiomyopathy
  • Permanent pacemaker
  • Seizure disorder
  • Hypertension defined as >150/90 mm Hg
  • Pregnancy
  • Glaucoma
  • Medications with known effects on blood pressure
  • Known hypersensitivity to atomoxetine and derivatives
  • Other factors which, in the investigator's opinion, would prevent the subject from completing the protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02874937


Locations
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Canada, Alberta
University of Calgary, Faculty of Medicine
Calgary, Alberta, Canada, T2N 4N1
Sponsors and Collaborators
University of Calgary
Investigators
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Principal Investigator: Robert S Sheldon, MD, PhD University of Calgary

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Responsible Party: Dr. Bob Sheldon, Professor, University of Calgary
ClinicalTrials.gov Identifier: NCT02874937     History of Changes
Other Study ID Numbers: ucalgary
First Posted: August 22, 2016    Key Record Dates
Last Update Posted: May 16, 2019
Last Verified: May 2019

Keywords provided by Dr. Bob Sheldon, University of Calgary:
Syncope
Vasovagal
Atomoxetine

Additional relevant MeSH terms:
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Syncope
Syncope, Vasovagal
Unconsciousness
Consciousness Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Atomoxetine Hydrochloride
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs