Ondansetron for the Management of Atrial Fibrillation

Sponsor

Indiana University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05844501

Collaborator

American Heart Association (Other), Purdue University (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

26.7

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

"Afib" is a common irregular heartbeat. Afib can cause stroke, blood clots, dementia and death. Medicines used to treat Afib often do not work well and can cause serious side effects. Clinicians need medicines that work better for Afib. Medicines for Afib work by blocking a current in the heart called a potassium current. There is a newer potassium current called IKas that can contribute to Afib. A medicine called ondansetron is used to keep people with cancer from getting sick to their stomach and throwing up. The investigators have found that ondansetron blocks IKas, and the investigators think that this means that ondansetron may work well to treat Afib. So, in this study the investigators want to find out if ondansetron can: 1) Stop Afib, 2) Reduce the amount of time that people have Afib, and 3) Slow down the heart rate when people have Afib. The investigators will study 80 people who come to the hospital to have a small electric shock to stop their Afib. These patients will be assigned by chance (like flipping a coin) to one of two groups: ondansetron 8 mg by mouth twice daily or a sugar pill (placebo). The people in the study will not know whether they are receiving ondansetron or placebo. The ondansetron or placebo will be started 2 days before the electric shock. The investigators will find out if ondansetron stops the Afib in the 2 days before their electric shock is scheduled. If ondansetron stops the Afib, those people will not need the electric shock. The other people in the study will get the electric shock to stop their Afib, but this does not work in everyone, and the Afib can quickly come back. So, after the first 2 days, all people in the study will stay on ondansetron or placebo for 28 more days. The investigators will find out if ondansetron reduces the percentage of time that people are in Afib. Also, in the 2 days before the electric shock and in the 28 days after, the investigators will find out if ondansetron slows the heart rate while people are having Afib. The investigators will compare the people in the study who take ondansetron with the people in the study who take placebo. This research will help the investigators to find out if ondansetron can be used as a medicine for people who have Afib.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Ondansetron 8mg Drug: Placebo	Phase 4

Detailed Description

Atrial fibrillation (AF) is a common arrhythmia associated with symptoms, stroke, systemic embolism, heart failure, dementia, and mortality. Guideline-recommended strategies for conversion to and maintenance of sinus rhythm (SR) and ventricular rate (VR) control are of limited efficacy and/or are poorly tolerated. There is a critical need for safer, more effective alternatives for AF drug therapy. The apamin-sensitive small-conductance calcium-activated potassium (SK) ion current (IKas) is important for repolarization in the atria and pulmonary vein muscle sleeves. IKas also contributes to sinoatrial and AV node electrophysiology. Therefore, IKas may be a target for rhythm and rate control in AF. Evidence suggests: 1) IKas plays an important role in the mechanism of AF, 2) The antiemetic agent ondansetron at therapeutic concentrations is a potent IKas inhibitor, and 3) Ondansetron is a cardiac-selective IKas inhibitor. Thus, the investigators hypothesize that ondansetron is effective for rhythm and rate control in patients with AF. Specific Aim 1: Determine the efficacy and safety of ondansetron for conversion of AF to SR. This aim will be achieved via a prospective, randomized, double-blind placebo-controlled study in patients with AF (n=80). Patients with persistent AF scheduled to undergo elective direct current cardioversion (DCC) will be randomized to oral ondansetron 8 mg twice daily (n=40) or matching placebo (n=40) for 2 days. ECG recording will be performed using adhesive skin patch ECG monitors, which provide 14-days of continuous recording. The primary outcome measure will be proportion of patients who are in SR prior to scheduled DCC. Successful pharmacological cardioversion will be defined as maintenance of SR for a minimum of 24 hours. Specific Aim 2: Determine the efficacy and safety of ondansetron for reducing AF burden. Patients who did not convert to SR on ondansetron/placebo will undergo DCC. Patients will remain in their originally randomized group for 28 days. Continuous ECG monitoring will be performed using successive 14-day adhesive skin patch ECG monitors. The primary outcome measure will be AF burden (percentage of time in AF). Specific Aim 3: Determine the efficacy and safety of ondansetron for VR control in AF. The effect of ondansetron versus placebo on VR control will be assessed in both phases of the study. Primary outcome measures will be mean daily heart rates on the 2 days prior to and on days 7, 14, 21 and 28 days post-AF conversion.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Inhibition of Small Conductance Calcium-Activated Potassium Current: A New Therapeutic Approach for Atrial Fibrillation

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Dec 1, 2026

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ondansetron Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with ondansetron 8 mg orally twice daily for 31 days (n=40)	Drug: Ondansetron 8mg Ondansetron 8 mg orally twice daily for 31 days
Placebo Comparator: Placebo Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with matching placebo orally twice daily for 31 days (n=40)	Drug: Placebo Matched placebo orally twice daily for 31 days

Arm

Intervention/Treatment

Experimental: Ondansetron

Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with ondansetron 8 mg orally twice daily for 31 days (n=40)

Drug: Ondansetron 8mg

Ondansetron 8 mg orally twice daily for 31 days

Placebo Comparator: Placebo

Patients with atrial fibrillation scheduled for electrical conversion to sinus rhythm will receive treatment with matching placebo orally twice daily for 31 days (n=40)

Drug: Placebo

Matched placebo orally twice daily for 31 days

Outcome Measures

Primary Outcome Measures

Conversion to sinus rhythm [After 2 days of treatment with ondansetron or placebo]
Proportion of patients who are in sinus rhythm prior to scheduled electrical cardioversion. Successful cardioversion will be defined as maintenance of sinus rhythm for a minimum of 24 hours
Atrial fibrillation burden [Total duration of study (31 days)]
Burden of atrial fibrillation, defined as overall percentage of time in atrial fibrillation.
Ventricular rate control prior to day of scheduled electrical cardioversion [One day prior to scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation
Ventricular rate control on day of scheduled electrical cardioversion [On day of scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation
Ventricular rate control after day of scheduled electrical cardioversion [7 days after scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation
Ventricular rate control after day of scheduled electrical cardioversion [14 days after scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation
Ventricular rate control after day of scheduled electrical cardioversion [21 days after scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation
Ventricular rate control after day of scheduled electrical cardioversion [28 days after scheduled electrical cardioversion]
Maximum heart rate while in atrial fibrillation

Secondary Outcome Measures

Time to conversion to sinus rhythm [Within first 2 days of treatment, prior to scheduled electrical cardioversion]
Time to conversion of atrial fibrillation to sinus rhythm
Proportion of patients in sinus rhythm [28 days after scheduled electrical cardioversion]
Proportion of patients in sinus rhythm at 28 days after day of scheduled electrical cardioversion
Time to atrial fibrillation recurrence [28 days after scheduled electrical cardioversion]
Time to atrial fibrillation recurrence after spontaneous or electrical cardioversion
Adverse effects [During the 31 days of treatment with ondansetron or placebo]
Adverse effects associated with ondansetron or placebo

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Men and women 18-85 years of age
Persistent ECG-verified AF requiring elective conversion to SR
Receiving guideline-recommended anticoagulation (if CHA2DS2-VASc score is 0 (men) or 1 (women), anticoagulation can be omitted)

Exclusion Criteria:

Women of childbearing potential
Subject reported syncope of unknown origin within the previous 6 months
Diagnosis of active thyrotoxicosis
Diagnosis AF from reversible noncardiac causes
Diagnosis of acutely decompensated heart failure
Left ventricular ejection fraction less than or equal to 20% New York Heart Association class IV heart failure Diagnosis if severe liver disease (Child-Pugh score greater than or equal to 10)
Cardiac surgery (preceding 2 months)
Not receiving anticoagulation due to contraindications (as determined by treating physician and recorded in the medical record)
Pretreatment QRS > 180 ms, QTc > 450 ms within two weeks of screening visit
Heart rate < 50 beats per minute in SR
Diagnosis of hypotension
Diagnosis of Wolff-Parkinson-White syndrome
Previous ondansetron hypersensitivity or serotonin syndrome
Diagnosis of phenylketonuria
Diagnosis of congenital long QT syndrome
Concomitant therapy with both beta-blockers and a nondihydropyridine CCB
History of drug-induced TdP or QTc prolongation
Concomitant therapy with QTc-prolonging medications (www.crediblemeds.org)
Concomitant therapy with serotonergic drugs (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, lithium, tramadol), apomorphine, phenytoin, carbamazepine, oxcarbazepine, rifampin.
Subjects with pre-existing allergies to adhesives

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana Clinical Research Center	Indianapolis	Indiana	United States	46202
2	Indiana University Health Methodist Hospital	Indianapolis	Indiana	United States	46202
3	Purdue University	Indianapolis	Indiana	United States	46202