Midodrine and Fludrocortisone for Vasovagal Syncope

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Syncope, Vasovagal

Intervention / Treatment
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* Drug: Midodrine Hydrochloride Tablets
* Drug: Fludrocortisone Acetate Tablets
* Behavioral: Lifestyle modification


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Midodrine<br>10 mg midodrine three times a day | Drug: Midodrine Hydrochloride Tablets<br>* 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).<br>* Other names: Gutron;Behavioral: Lifestyle modification<br>* 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.<br>|
| Active Comparator: Fludrocortisone<br>0.1 mg fludrocortisone two times a day | Drug: Fludrocortisone Acetate Tablets<br>* 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.<br>* Other names: Florinef;Behavioral: Lifestyle modification<br>* 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.<br>|
| Other: Lifestyle modification<br>Education, salt and water intake, counter-pressure maneuvers | Behavioral: Lifestyle modification<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Syncope, Vasovagal, Syncope, Midodrine, Fludrocortisone, Randomized Controlled Trial