Clinical trial NCT04595942: Midodrine and Fludrocortisone for Vasovagal Syncope
Official title: Comparison of Outcomes With Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS Trial)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Syncope, Vasovagal
Keywords: Syncope, Vasovagal
Syncope
Midodrine
Fludrocortisone
Randomized Controlled Trial
Lead sponsor: Tehran Heart Center
Sponsor class: OTHER
Collaborators: name: Mahidol University
name: Rajaie Cardiovascular Medical and Research Center
name: Tehran Arrhythmia Center
name: Imam Khomeini Hospital
name: AJA University of Medical Sciences
name: Urmia University of Medical Sciences
name: Isfahan University of Medical Sciences
name: Shahid Beheshti University of Medical Sciences
name: Ahvaz Jundishapur University of Medical Sciences
First posted: 2020-10-22
Enrollment: 1375
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to first episode of syncope
timeFrame: The follow-up continues for 12 months after randomization
Secondary outcomes:
measure: Recurrence rate of vasovagal syncope
timeFrame: The follow-up continues for 12 months after randomization
measure: Changes in quality of life
timeFrame: Baseline (It will be evaluated at randomization) and 12 months after randomization.
measure: Major side effects
timeFrame: The follow-up continues for 12 months after randomization
measure: Minor side effects
timeFrame: The follow-up continues for 12 months after randomization
Other outcomes:
Locations:
city: Tehran
country: Iran, Islamic Republic of
facility: Tehran Heart Center
Study officials:
affiliation: Tehran Heart Center, Tehran University of Medical Sciences
name: Arash Jalali, PhD
role: STUDY_DIRECTOR
affiliation: Tehran Heart Center, Tehran University of Medical Sciences
name: Arya Aminorroaya, MD, MPH
role: STUDY_DIRECTOR
affiliation: Tehran Heart Center, Tehran University of Medical Sciences
name: Hamed Tavolinejad, MD
role: STUDY_DIRECTOR
affiliation: Tehran Heart Center, Tehran University of Medical Sciences
name: Saeed Sadeghian, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.