Midodrine and Fludrocortisone for Vasovagal Syncope (COMFORTS)

Tehran Heart Center

Status and phase: Unknown; Phase 3

Conditions: Syncope, Vasovagal

Treatments: Behavioral: Lifestyle modification; Drug: Fludrocortisone Acetate Tablets; Drug: Midodrine Hydrochloride Tablets

Study type: Interventional

Funder types: Other

Identifiers

NCT04595942

99-2-408-49493

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1,375 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,375 participants in 3 patient groups

Midodrine

Active Comparator group

Description:

10 mg midodrine three times a day

Treatment:

Drug: Midodrine Hydrochloride Tablets

Behavioral: Lifestyle modification

Fludrocortisone

Active Comparator group

Description:

0.1 mg fludrocortisone two times a day

Treatment:

Drug: Fludrocortisone Acetate Tablets

Behavioral: Lifestyle modification

Lifestyle modification

Other group

Description:

Education, salt and water intake, counter-pressure maneuvers

Treatment:

Behavioral: Lifestyle modification