Midodrine and Fludrocortisone for Vasovagal Syncope (COMFORTS)

Comparison of Outcomes With Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS Trial)

Syncope is a common condition which can disturb daily functions of the patients and impair their quality of lives. It contributes to 0.8 to 2.4% of the visits of emergency rooms. Noticeably, studies demonstrated that the lifetime prevalence of syncope is as high as 41% with a 13.5% recurrence rate.

The cornerstone of the treatment of vasovagal syncope (VVS), the most common type of syncope, is lifestyle modifications and patient education to avoid potential triggers of syncope. These recommendations alleviate vasovagal spells in many patients; however, some patients experience life-disturbing vasovagal attacks despite compliance with these modifications. This fact underscores the importance of efficient pharmacological interventions as well.

Currently, there is an ongoing controversy about the efficacy of midodrine and fludrocortisone as adjunct pharmacological interventions for the prevention of VVS. In the COMFORTS trial, we are going to evaluate the efficacy of midodrine, fludrocortisone, and lifestyle modifications for prevention of vasovagal attacks in patients with VVS.

Study Overview

• Status: Recruiting
• Conditions: Syncope, Vasovagal
• Intervention / Treatment: Drug: Midodrine Hydrochloride Tablets; Behavioral: Lifestyle modification; Drug: Fludrocortisone Acetate Tablets

Detailed Description

Background: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions.

Methods: In the COMFORTS trial, a multi-center randomized controlled trial, 1375 patients with VVS will be randomized into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or just lifestyle modifications. All patients will receive recommendations for lifestyle modifications. In the pharmacological intervention arms, patients will receive 5 mg of midodrine three times a day or 0.1 mg of fludrocortisone twice daily. In case of intolerance, the dosage will be cut by half. If the patient does not tolerate even the reduced dosage, the medication will be discontinued and the patient will be advised to use compression garments, practice tilt training exercises, or switch to the other medication. The patients will be followed on 3, 6, and 12 months after dose stabilization. Primary efficacy outcomes of the study is the time to the first syncopal episode. The secondary efficacy outcome are the recurrence rate of syncope, number of syncopal episodes and the quality of life of the patients which will be assessed by the 36-Item Short Form Survey questionnaire at the enrollment and 12 months after dose stabilization.

• Study Type: Interventional
• Enrollment (Anticipated): 1375
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Masih Tajdini, MD; Phone Number: +982188029640; Email: mtajdini@sina.tums.ac.ir

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of, 1411713138
    • Recruiting
    • Tehran Heart Center
    • Contact: Masih Tajdini, MD; Phone Number: +982188029640; Email: mtajdini@sina.tums.ac.ir

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Vasovagal syncope as the cause of transient loss of consciousness (Clinical diagnosis AND Calgary Syncope Symptom Score ≥ -2; Head-up tilt test is not mandatory for diagnosis)
• ≥2 episodes of syncope during the last year
• Medication-naïve or have at least a 2-week washout period prior to randomization
• The capability of giving informed consent
• Signed written informed consent

Exclusion Criteria:

• Other causes of transient loss of consciousness including orthostatic hypotension, postural tachycardia, carotid sinus hypersensitivity, or seizure
• Cardiac rhythm disorders including ventricular tachycardia, long QT syndrome, Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, complete heart block, and any conduction abnormality on electrocardiogram
• Severe valvular heart disease
• Hypertrophic cardiomyopathy
• Cardiac systolic dysfunction (ejection fraction≤40%)
• Obstructive coronary artery disease
• Hypertension
• Diabetes mellitus
• Cirrhosis
• Renal failure stage≥3
• Known intolerance or hypersensitivity to midodrine or fludrocortisone
• Urinary retention
• Pheochromocytoma
• Thyrotoxicosis
• Glaucoma
• Previous use of midodrine or fludrocortisone for treatment of VVS or another condition
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Midodrine; 10 mg midodrine three times a day	Drug: Midodrine Hydrochloride Tablets; Patients will be started on 5 mg Midodrine three times a day and after one week the dosage will be up-titrated to 10 mg three times a day and continued for 12 months. They will receive the medication at four-hour intervals upon rising in the morning (the last dose should not be taken later than 6 PM). In case of intolerance, the dosage will be reduced to 2.5 mg three times a day. Patients will also receive recommendations for lifestyle modifications including drinking 2 to 3 liters of fluid per day, daily consumption of 10 grams of salt, and practicing counter-pressure maneuvers (handgrip, arm-tensing, leg crossing and squatting).; Other Names: Gutron; Behavioral: Lifestyle modification; Patients will be recommended to drink 2 to 3 liters of fluid per day, consume 10 grams of salt per day, and practice counter-pressure maneuvers (handgrip, arm-tensing, leg crossing and squatting) for 12 months.
Active Comparator: Fludrocortisone; 0.1 mg fludrocortisone two times a day	Behavioral: Lifestyle modification; Patients will be recommended to drink 2 to 3 liters of fluid per day, consume 10 grams of salt per day, and practice counter-pressure maneuvers (handgrip, arm-tensing, leg crossing and squatting) for 12 months.; Drug: Fludrocortisone Acetate Tablets; Patients will be started on 0.05 mg of fludrocortisone twice daily and after one week the dosage will be up-titrated to 0.1 mg fludrocortisone twice daily taken for 12 months. Patients will also receive recommendations for lifestyle modifications including drinking 2 to 3 liters of fluid per day, daily consumption of 10 grams of salt, and practicing counter-pressure maneuvers (handgrip, arm-tensing, leg crossing and squatting). In this arm, potassium levels will be checked 7-14 days after dose stabilization.; Other Names: Florinef
Other: Lifestyle modification; Education, salt and water intake, counter-pressure maneuvers	Behavioral: Lifestyle modification; Patients will be recommended to drink 2 to 3 liters of fluid per day, consume 10 grams of salt per day, and practice counter-pressure maneuvers (handgrip, arm-tensing, leg crossing and squatting) for 12 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first episode of syncope	Time from randomization to occurrence of the first episode of vasovagal syncope during the follow-up.	The follow-up continues for 12 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence rate of vasovagal syncope	The proportion of patients who incurred at least one episode of vasovagal syncope during the follow-up.	The follow-up continues for 12 months after randomization
Changes in quality of life	It is measured by the 36-item short form (SF-36) questionnaire.	Baseline (It will be evaluated at randomization) and 12 months after randomization.
Major side effects	The proportion of patients who do not tolerate the initial dosage of medications which leads to either a reduced dosage or discontinuation.	The follow-up continues for 12 months after randomization
Minor side effects	The proportion of patients who experience minor side effects without dosage changes.	The follow-up continues for 12 months after randomization

Collaborators and Investigators

• Sponsor: Tehran Heart Center
• Collaborators: Mahidol University; Shahid Beheshti University of Medical Sciences; Isfahan University of Medical Sciences; Urmia University of Medical Sciences; Tehran Arrhythmia Center; Rajaie Cardiovascular Medical and Research Center; Imam Khomeini Hospital; Ahvaz Jundishapur University of Medical Sciences; AJA University of Medical Sciences
• Investigators: Study Director: Hamed Tavolinejad, MD, Tehran heart center, Tehran university of medical sciences; Study Director: Arash Jalali, PhD, Tehran heart center, Tehran university of medical sciences; Study Director: Arya Aminorroaya, MD, MPH, Tehran heart center, Tehran university of medical sciences; Study Chair: Saeed Sadeghian, MD, Tehran heart center, Tehran university of medical sciences

Publications and helpful links

General Publications

• Sadeghian S, Aminorroaya A, Tajdini M. The Syncope Unit of Tehran Heart Center. Eur Heart J. 2021 Jan 7;42(2):148-150. doi: 10.1093/eurheartj/ehaa532. No abstract available.
• Aminorroaya A, Tavolinejad H, Sadeghian S, Jalali A, Alaeddini F, Emkanjoo Z, Mollazadeh R, Bozorgi A, Oraii S, Kiarsi M, Shahabi J, Akbarzadeh MA, Rahimi B, Joharimoghadam A, Mohsenizade A, Mohammadi R, Oraii A, Ariannejad H, Apakuppakul S, Ngarmukos T, Tajdini M. Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial. Am Heart J. 2021 Jul;237:5-12. doi: 10.1016/j.ahj.2021.03.002. Epub 2021 Mar 6.

Helpful Links

• The COMFORTS Trial website

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2020
• Primary Completion (Anticipated): October 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: October 15, 2020
• First Submitted That Met QC Criteria: October 20, 2020
• First Posted (Actual): October 22, 2020

Study Record Updates

• Last Update Posted (Actual): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 14, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Syncope; Syncope, Vasovagal; Midodrine; Fludrocortisone
• 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; Anti-Inflammatory Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Midodrine; Fludrocortisone
• Other Study ID Numbers: 99-2-408-49493

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The data is not publicly available due to privacy/ethical restrictions. The data can be shared upon reasonable request to the trial committee,

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No