A Blinded Study to Evaluate Effect on Atrial Fibrillation Burden in Patients With Paroxysmal Atrial Fibrillation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of BMS-919373 on atrial fibrillation (AF) through its effect on AF burden (AFB), or the percent of time in AF, in subjects with paroxysmal AF (pAF) when administered orally at a range of doses (2 mg once daily (QD), 5 mg QD, 12 mg QD following a 1-week period of loading doses of 3 mg QD, 8 mg QD and 20 mg QD, respectively) for a total of 4 weeks. It is hypothesized that treatment with BMS-919373 will reduce AF burden as compared to baseline relative to placebo.

Detailed Description
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Primary Purpose: Protocol designed to assess, by the use of long term non-invasive beat-to-beat monitoring with the SEEQ Mobile Cardiac Telemetry (MCT) system, the effect of BMS-919373 on the percent change from baseline relative to placebo of atrial fibrillation burden in subjects with paroxysmal atrial fibrillation.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Parallel Arm Study to Evaluate the Safety, Tolerability, and Effect on Atrial Fibrillation Burden of BMS-919373 in Patients With Paroxysmal Atrial Fibrillation

Conditions
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Paroxysmal Atrial Fibrillation

Intervention / Treatment
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* Drug: BMS-919373
* Drug: Placebo (Matching with BMS-919373)


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Signed informed consent Paroxysmal Atrial Fibrillation (pAF) with available documentation of AF and reporting symptoms within 6 months prior to screening Able to tolerate withdrawal of antiarrhythmic therapy (rhythm control) Echocardiographically measured left ventricular ejection fraction (LVEF) ≥40%,measured within 12 months of enrollment Echocardiographically measured left atrial (LA) diameter ≤ 5.0 cm, measured within 12 months of enrollment Exclusion Criteria: Women of childbearing potential AFB < 3% or > 70%, during both screening periods independently Permanent or persistent Atrial Fibrillation Cardioversion within 3 months of study drug administration Stroke within 12 months of study drug administration TIA within 12 months of study drug administration Heart failure of NYHA class III or greater (symptoms of heart failure at rest or with minimal exertion) Heart failure of NYHA class II (symptoms of heart failure with routine levels of exertion)with ejection fraction <40% as measured by echocardiography at any time within 12 months of study enrollment (i.e. additional ejection fraction measurements ≥ 40% over this period will not counter this exclusion) Valvular heart disease (including any valvular insufficiency or stenosis greater thanmild) Ablation within 3 months of study enrollment
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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm A: Placebo (Matching with BMS-919373)<br>Placebo (Matching with BMS-919373) 0 mg tablets orally once daily for approximately 28 Days | Drug: Placebo (Matching with BMS-919373)<br> <br> |
| Experimental: Arm B: BMS-919373<br>BMS-919373 3 mg tablets orally once daily for approximately 28 days | Drug: BMS-919373<br> <br> |
| Experimental: Arm C: BMS-919373<br>BMS-919373 5 mg tablets orally once daily for approximately 28 days | Drug: BMS-919373<br> <br> |
| Experimental: Arm D: BMS-919373<br>BMS-919373 12 mg tablets orally once daily for approximately 28 days | Drug: BMS-919373<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Atrial Fibrillation Burden (AFB) as Assessed by SEEQ Mobile Cardiac Telemetry (MCT) System | AFB is defined as the percent of time spent in atrial fibrillation (AF). AFB will be assessed by use of long term non- invasive beat-to-beat monitoring with the SEEQ MCT system. This technology consists of a low-profile adhesive patch that has been approved for continuous use for up to 30 days. The patch is able to continuously record electrocardiographic signals and, in conjunction with a wirelessly connected portable cellular communications device, transmit these signals for real-time analysis, including atrial and ventricular arrhythmias and AFB. | Day 8 to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. A SAE is any untoward medical occurrence that at any dose: results in death, is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect. | Up to Day 50 | 
| Maximum Observed Concentarion (Cmax) of BMS-919373 | Cmax is defined as the maximum observed concentration of BMS-919373. | Day 1 and Day 22: Predose 1, 2, and 4 hours postdose | 
| Trough Observed Concentration (Cmin) of BMS-919373 | Ctrough is defined as the minimum estimated plasma concentration at steady state. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Oral Clearance (CL/F) of BMS-919373 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Central Volume of Distribution (Vc/F) of BMS-919373 | Volume of distribution is defined as the theoretical volume in which the total amount of drug is uniformly distributed to produce the desired plasma concentration of a drug. Vc/F is a hypothetical volume into which a drug initially distributes upon administration. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Absorption Rate Constant (Ka) of BMS-919373 | Ka is the absorption rate constant. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Average Concentration (Cavg) of BMS-919373 at Steady State | Cavg is defines as the average concentration at steady state. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Area Under the Concentration-time Curve (AUC) at Steady State of BMS-919373 | AUC is defined as the area under the concentration-time curve at steady state. | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 
| Time to First Atrial Fibrillation Recurrence (TTFR) (Symptomatic or Asymptomatic) | The TTFR is defined as the time to the first MCT-recorded AF episode after the first loading dose on Day 1. MCT will provide both System-triggered and Patient-triggered results and report them separately. System-triggered results will include both symptomatic and asymptomatic findings, while Patient-triggered results will be the symptomatic ones triggered to report by patients. The analysis will be done both for System-triggered and for Patient-triggered results. | Day 8 to Day 29 | 
| Total Number of Atrial Fibrillation Episodes | The total number AF episodes were derived from AF episode histogram data over the monitoring period. | Day 8 to Day 29 | 
| Average Duration of Atrial Fibrillation Per Episode | The average duration of AF per episode was calculated from the total time a participant in AF and the total number of AF episodes over the monitoring period. | Day 8 to Day 29 |