Assessment of Midodrine in the Prevention of Vasovagal Syncope: The Prevention of Syncope Trial IV (POST 4)

Assessment of Midodrine in the Prevention of Vasovagal Syncope: The Prevention of Syncope Trial IV (Post 4)

About 20% of adults faint recurrently. These patients are often highly symptomatic, have problems with employment and driving and have reduced quality of life. There are no therapies that have withstood the test of adequately designed and conducted randomized clinical trials. Midodrine is a prodrug whose metabolite is an alpha-1 adrenergic agonist that increases venous return to the heart and raises blood pressure. There is considerable lower level evidence that it might prevent vasovagal syncope.

The investigators will test the hypothesis that Midodrine prevents recurrences of syncope in patients with moderate to severe vasovagal syncope.

Study Overview

• Status: Active, not recruiting
• Conditions: Vasovagal Syncope
• Intervention / Treatment: Drug: midodrine hydrochloride; Drug: matching placebo

• Study Type: Interventional
• Enrollment (Actual): 134
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
    • Edmonton, Alberta, Canada, T5H 3V9
      • Alberta Health Services - Royal Alexandra Hospital
    • Red Deer, Alberta, Canada, T4N 4E7
      • Red Deer Regional Hospital
  • British Columbia
    • Victoria, British Columbia, Canada, V8R 4R2
      • Victoria Cardiac Arrythmia trials
  • Manitoba
    • St. Boniface, Manitoba, Canada, R2H 2A6
      • St. Boniface General Hospital
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • New Brunswick Heart Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A6
      • Queen E II Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton Health Sciences
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
      • Hopital Sacre Coeur de Montreal
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4P 0W5
      • Prairie Vascular Research Network/Regina General Hospital
    • Saskatoon, Saskatchewan, Canada, S7K 3H1
      • Saskatoon Cardiology Consultants/Royal University Hospital
• Poland
  • Lodz, Poland, 93-005
    • Medical University of Lodz
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients will be eligible if they have:

  • ≥2 syncopal spells in the year preceding enrolment, and
  • ≥ -2 points on the Syncope Symptom Score for Structurally Normal hearts, and
  • Age ≥ 18 years with informed consent.

Exclusion Criteria:

• Patients will be excluded if they have:

  • other causes of syncope, such as ventricular tachycardia, complete heart block, postural hypotension or hypersensitive carotid sinus syndrome,
  • an inability to give informed consent,
  • important valvular, coronary, myocardial or conduction abnormality or significant arrhythmia,
  • hypertrophic cardiomyopathy,
  • a permanent pacemaker,
  • a seizure disorder,
  • urinary retention,
  • hypertension defined as >140/90 mm Hg,
  • hepatic disease,
  • glaucoma or
  • a 5-minute stand test resulting in diagnoses of Postural Orthostatic Tachycardia Syndrome or Orthostatic Hypotension.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: midodrine hydrochloride pills	Drug: midodrine hydrochloride; Target dose is midodrine hydrochloride or placebo pills 10 mg three times a day for 12 months. The starting dose is 5mg q4h x3, and if tolerated a forced titration up to 10mg/dose. If there is an intolerance, then the dose can be reduced to 2.5mg/dose.; Other Names: Brand name for the drug is midodrine.
PLACEBO_COMPARATOR: oral placebo or sugar pill	Drug: midodrine hydrochloride; Target dose is midodrine hydrochloride or placebo pills 10 mg three times a day for 12 months. The starting dose is 5mg q4h x3, and if tolerated a forced titration up to 10mg/dose. If there is an intolerance, then the dose can be reduced to 2.5mg/dose.; Other Names: Brand name for the drug is midodrine.; Drug: matching placebo; The target dose in this study is 10mg q4h x3 for 12 months. The starting dose is 5mg q4h x3, and if tolerated a forced titration up to 10mg/dose. If there is an intolerance, then the dose can be reduced to 2.5mg/dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome measure will be the proportion of patients having at least one syncope recurrence.	1 year.

Secondary Outcome Measures

Outcome Measure	Time Frame
A secondary outcome will be the time between the first and second syncope recurrences.	1 year
A secondary outcome will be the frequency of syncopal spells.	1 year
A secondary outcomes will be quality of life as measured by the EQ-5D and the ISQL.	1 year
A secondary outcome is the number, duration, and severity of presyncopal spells (as measured with the Calgary Presyncope Scale(19)).	1 year.

Collaborators and Investigators

• Sponsor: Dr. Bob Sheldon
• Collaborators: Vanderbilt University

Publications and helpful links

General Publications

• Sheldon R, Faris P, Tang A, Ayala-Paredes F, Guzman J, Marquez M, Morillo CA, Krahn AD, Kus T, Ritchie D, Safdar S, Maxey C, Raj SR; POST 4 investigators. Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial. Ann Intern Med. 2021 Oct;174(10):1349-1356. doi: 10.7326/M20-5415. Epub 2021 Aug 3.
• Raj SR, Faris PD, McRae M, Sheldon RS. Rationale for the prevention of syncope trial IV: assessment of midodrine. Clin Auton Res. 2012 Dec;22(6):275-80. doi: 10.1007/s10286-012-0167-5. Epub 2012 May 19.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): December 20, 2018
• Study Completion (ANTICIPATED): December 31, 2023

Study Registration Dates

• First Submitted: October 14, 2011
• First Submitted That Met QC Criteria: October 19, 2011
• First Posted (ESTIMATE): October 20, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: midodrine; vasovagal syncope; reflex fainting
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Autonomic Nervous System Diseases; Unconsciousness; Consciousness Disorders; Primary Dysautonomias; Orthostatic Intolerance; Syncope; Syncope, Vasovagal; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Midodrine
• Other Study ID Numbers: CIHR#243314