Paroxysmal Atrial Fibrillation
Conditions
Brief summary
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
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.
Interventions
DRUGBMS-919373
DRUGPlacebo (Matching with BMS-919373)
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Atrial Fibrillation Burden (AFB) as Assessed by SEEQ Mobile Cardiac Telemetry (MCT) System | Day 8 to Day 29 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentarion (Cmax) of BMS-919373 | Day 1 and Day 22: Predose 1, 2, and 4 hours postdose | Cmax is defined as the maximum observed concentration of BMS-919373. |
| Trough Observed Concentration (Cmin) of BMS-919373 | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | Ctrough is defined as the minimum estimated plasma concentration at steady state. |
| Oral Clearance (CL/F) of BMS-919373 | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 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. |
| Central Volume of Distribution (Vc/F) of BMS-919373 | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | 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. |
| Absorption Rate Constant (Ka) of BMS-919373 | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | Ka is the absorption rate constant. |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Up to Day 50 | 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. |
| Area Under the Concentration-time Curve (AUC) at Steady State of BMS-919373 | Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28) | AUC is defined as the area under the concentration-time curve at steady state. |
| Time to First Atrial Fibrillation Recurrence (TTFR) (Symptomatic or Asymptomatic) | Day 8 to Day 29 | 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. |
| Total Number of Atrial Fibrillation Episodes | Day 8 to Day 29 | The total number AF episodes were derived from AF episode histogram data over the monitoring period. |
| Average Duration of Atrial Fibrillation Per Episode | Day 8 to Day 29 | 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. |
| Average Concentration (Cavg) of BMS-919373 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) | Cavg is defines as the average concentration at steady state. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Total 158 participants were enrolled out of which 26 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| BMS-919373 3/2 mg Participants received loading dose of BMS-919373 3 milligram (mg) as oral tablets (each tablet of 1 mg\*3) once daily (QD) for one week followed by maintenance dose of BMS-919373 2 mg as oral tablets (each tablet of 1 mg\*2) QD for 3 weeks. | 7 |
| BMS-919373 8/5 mg Participants received loading dose of BMS-919373 8 mg as oral tablets (each tablet of 1 mg\*3 + 5 mg\*1) QD for one week followed by maintenance dose of BMS-919373 5 mg as oral tablets (each tablet of 5 mg\*1) QD for 3 weeks. | 7 |
| BMS-919373 20/12 mg Participants received loading dose of BMS-919373 20 mg as oral tablets (each tablet of 5 mg\*4) QD for one week followed by maintenance dose of BMS-919373 12 mg as oral tablets (each tablet of 5 mg\*2 + 1 mg\*2) QD for 3 weeks. | 6 |
| Placebo Participants received placebo matching with BMS-919373 0 mg tablets (4 tablets) orally QD for 28 Days. | 6 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Follow-up Period | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 0 | 0 | 1 |
| Treatment Period | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Treatment Period | no longer meets study criteria | 0 | 0 | 1 | 0 |
| Treatment Period | Poor/non-compliance | 0 | 1 | 0 | 0 |
| Treatment Period | Subject request to discontinue treatment | 0 | 1 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BMS-919373 3/2 mg | BMS-919373 8/5 mg | BMS-919373 20/12 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 70.0 Years STANDARD_DEVIATION 5.83 | 61.0 Years STANDARD_DEVIATION 8.23 | 65.7 Years STANDARD_DEVIATION 10.05 | 65.0 Years STANDARD_DEVIATION 10.77 | 65.4 Years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 5 Participants | 3 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 7 Participants | 4 Participants | 5 Participants | 23 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 4 Participants | 5 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 4 / 6 | 4 / 7 | 4 / 7 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 7 | 0 / 7 | 0 / 6 |
Outcome results
Primary
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.
Time frame: Day 8 to Day 29
Population: Data was not collected for any participants due to termination of the study
Secondary
Absorption Rate Constant (Ka) of BMS-919373
Ka is the absorption rate constant.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study
Secondary
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.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study
Secondary
Average Concentration (Cavg) of BMS-919373 at Steady State
Cavg is defines as the average concentration at steady state.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study
Secondary
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.
Time frame: Day 8 to Day 29
Population: Data was not collected for any participants due to termination of the study
Secondary
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.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study
Secondary
Maximum Observed Concentarion (Cmax) of BMS-919373
Cmax is defined as the maximum observed concentration of BMS-919373.
Time frame: Day 1 and Day 22: Predose 1, 2, and 4 hours postdose
Population: Data was not collected for any participants due to termination of the study
Secondary
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.
Time frame: Up to Day 50
Population: All treated participants included all the participants who have received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMS-919373 3/2 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | SAEs | 0 Participants |
| BMS-919373 3/2 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Death | 0 Participants |
| BMS-919373 3/2 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | AEs | 4 Participants |
| BMS-919373 3/2 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Treatment-related AEs | 0 Participants |
| BMS-919373 8/5 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | SAEs | 0 Participants |
| BMS-919373 8/5 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | AEs | 4 Participants |
| BMS-919373 8/5 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Death | 0 Participants |
| BMS-919373 8/5 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Treatment-related AEs | 3 Participants |
| BMS-919373 20/12 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Treatment-related AEs | 0 Participants |
| BMS-919373 20/12 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | AEs | 3 Participants |
| BMS-919373 20/12 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | SAEs | 0 Participants |
| BMS-919373 20/12 mg | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | Treatment-related AEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | SAEs | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment-related AEs and Death | AEs | 4 Participants |
Secondary
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.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study
Secondary
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.
Time frame: Day 8 to Day 29
Population: Data was not collected for any participants due to termination of the study
Secondary
Total Number of Atrial Fibrillation Episodes
The total number AF episodes were derived from AF episode histogram data over the monitoring period.
Time frame: Day 8 to Day 29
Population: Data was not collected for any participants due to termination of the study
Secondary
Trough Observed Concentration (Cmin) of BMS-919373
Ctrough is defined as the minimum estimated plasma concentration at steady state.
Time frame: Day 8 (predose), Day 22 (predose, 1, 2, and 4 hours postdose), and Day 29 (24 hours after last dose of Day 28)
Population: Data was not collected for any participants due to termination of the study