Atrial Fibrillation
Conditions
Keywords
atrial fibrillation, arrhythmia, pharmacological cardioversion
Brief summary
This was a randomized, placebo-controlled, investigator- and participant-blinded study to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of HSY244 in participants with atrial fibrillation (AF), with and without heart failure (HF).
Detailed description
A screening period of up to 3 days (72 hours) was used to assess eligibility. After eligibility was confirmed, patients were randomized to either HSY244 or placebo. Prior to study drug administration, pre-dose assessments were completed. After the start of study drug administration, the participant was monitored for cardioversion to sinus rhythm. If a participant was still in AF at 90 minutes after the start of study drug administration, direct current cardioversion was planned to be applied at a time deemed appropriate by the investigator.
Interventions
DRUGHSY244
HSY244 concentrate solution for injection via intravenous infusion
OTHERPlacebo
Placebo concentrate solution for injection via intravenous infusion
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * At screening, written informed consent were required to be obtained before any assessment was performed and only participants able to provide written informed consent themselves were included in this study. * Hemodynamically stable men and women (either of non-child-bearing potential or child bearing potential with highly effective contraception) between 18 and 80 years of age (inclusive) at screening with a clinical indication for direct current cardioversion of AF. * At screening, current episode of AF had been ongoing for ≥6 hours and ≤60 days * Successful initiation and achievement of therapeutic levels of national guideline and institution-specific anticoagulation therapy as appropriate for the duration of the AF episode and risk for the participant. * Completion of national guideline and institution-specific imaging evaluation for left atrial thrombi as appropriate for the duration of AF episode and risk for the participant. * At screening, participants were required to weigh at least 60 kg to participate in the study and were required to have a body mass index (BMI) within the range of 18 - 45 kg/m\^2. BMI = Body weight (kg) / \[Height (m)\]\^2 * At screening, vital signs (systolic blood pressure and pulse rate) were assessed in the sitting position. Sitting vital signs were required to be within the following ranges (exclusive): * systolic blood pressure between 100-160 mmHg and diastolic blood pressure 60-100 mmHg * pulse rate (ventricular rate) between 60-120 bpm. Key
Exclusion criteria
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during dosing and for 4 days after stopping of investigational drug. * Sexually active males unwilling to use a condom during intercourse while taking investigational drug and for 96 hours after study drug administration. A condom was required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of the investigational drug via seminal fluid to their partner. In addition, male participants could not donate sperm for the time period specified above. * Use of any anti-arrhythmic class I or III drug (including Ranolazine \[Ranexa\]) within 5 half lives before randomization; including use of amiodarone within 3 months before randomization. * At screening, history of current diagnosis of ECG abnormalities or cardiac rhythm disorders as determined by the Investigator's interpretation of the ECG findings indicating a significant risk for participating in the study, such as: * History of Torsades de Pointes (TdP), any other polymorphic ventricular tachycardia, sustained monomorphic ventricular tachycardia, long QT syndrome, or Brugada syndrome. * Wolfe-Parkinson-White (WPW) syndrome * In the absence of a complete bundle branch block a resting QTcF \>460 msec for men and \>470 msec for women (mean of ≥ 5 consecutive QT intervals) * In the presence of a complete bundle branch block, a prolonged QTcF or JTc that, in the opinion of the investigator, may pose a risk to patient safety * Third-degree (complete) heart block, or second-degree Mobitz type II heart block * Attempted or unsuccessful cardioversion within 2 weeks prior to randomization. * Presence of known severe mitral regurgitation and/or known severely dilated left atrium. * Pre-existing or tachycardia-induced moderate to severe cardiac dysfunction (New York Heart Association Class III and IV). * History within the preceding 3 months prior to randomization of: myocardial infarction, unstable angina, cardiac surgery, or a percutaneous coronary intervention. * History of a confirmed stroke or transient ischemic attack (TIA). * History or current diagnosis of any seizure disorder, epilepsy, significant head trauma, or other disorders increasing the risk for seizures. * History or current diagnosis of a major neurologic or psychiatric disorder that, in the opinion of the investigator, poses a risk to patient safety to participate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Conversion to Sinus Rhythm for at Least 1 Minute Within 90 Minutes From the Start of Study Drug Administration. | 90 minutes from the start of study drug administration | Conversion to sinus rhythm was monitored using a Holter monitoring device through 90 minutes after the start of study drug administration. If a participant had been monitored for at least 45 minutes and did not convert to sinus rhythm for at least one minute, the primary endpoint was defined as 'no'. If a participant converted to sinus rhythm for at least one minute at any time during the post-treatment 90 minutes observation period, regardless of the length of time monitored, the primary endpoint was to be defined as 'yes'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5 | The Cmax is the maximum (peak) observed plasma drug concentration after single-dose administration. Actual recorded sampling times were taken into consideration for PK calculations. |
| Time to Reach the Maximum Concentration After Drug Administration (Tmax) | Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5 | Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). Actual recorded sampling times were taken into consideration for PK calculations. |
| Area Under the Plasma Concentration-time Curve (AUClast) | Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5 | AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast). Actual recorded sampling times were taken into consideration for PK calculations. |
Countries
Germany, United States
Participant flow
Pre-assignment details
A screening period of up to 3 days (72 hours) was used to assess eligibility.
Participants by arm
| Arm | Count |
|---|---|
| HSY244 HSY244 150 mg concentrate solution for injection via intravenous infusion | 7 |
| Placebo Placebo concentrate solution for injection via intravenous infusion | 6 |
| Total | 13 |
Baseline characteristics
| Characteristic | HSY244 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 9.73 | 60.0 years STANDARD_DEVIATION 4.05 | 60.3 years STANDARD_DEVIATION 7.36 |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 6 | 0 / 13 |
| other Total, other adverse events | 6 / 7 | 5 / 6 | 11 / 13 |
| serious Total, serious adverse events | 1 / 7 | 0 / 6 | 1 / 13 |
Outcome results
Primary
Number of Participants With Conversion to Sinus Rhythm for at Least 1 Minute Within 90 Minutes From the Start of Study Drug Administration.
Conversion to sinus rhythm was monitored using a Holter monitoring device through 90 minutes after the start of study drug administration. If a participant had been monitored for at least 45 minutes and did not convert to sinus rhythm for at least one minute, the primary endpoint was defined as 'no'. If a participant converted to sinus rhythm for at least one minute at any time during the post-treatment 90 minutes observation period, regardless of the length of time monitored, the primary endpoint was to be defined as 'yes'.
Time frame: 90 minutes from the start of study drug administration
Population: Pharmacodynamic (PD) analysis set: Participants with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HSY244 | Number of Participants With Conversion to Sinus Rhythm for at Least 1 Minute Within 90 Minutes From the Start of Study Drug Administration. | 0 Participants |
| Placebo | Number of Participants With Conversion to Sinus Rhythm for at Least 1 Minute Within 90 Minutes From the Start of Study Drug Administration. | 0 Participants |
Secondary
Area Under the Plasma Concentration-time Curve (AUClast)
AUClast is the AUC from time zero to the last measurable concentration sampling time (tlast). Actual recorded sampling times were taken into consideration for PK calculations.
Time frame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
Population: Pharmacokinetic (PK) analysis set: Participants with at least one available valid PK concentration measurement, who received the investigational product and with no protocol deviations that impact on PK data. Only participants with available AUClast data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HSY244 | Area Under the Plasma Concentration-time Curve (AUClast) | 2960 h*ng/mL | Standard Deviation 1510 |
Secondary
Maximum Observed Plasma Concentration (Cmax)
The Cmax is the maximum (peak) observed plasma drug concentration after single-dose administration. Actual recorded sampling times were taken into consideration for PK calculations.
Time frame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
Population: Pharmacokinetic (PK) analysis set: Participants with at least one available valid PK concentration measurement, who received the investigational product and with no protocol deviations that impact on PK data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| HSY244 | Maximum Observed Plasma Concentration (Cmax) | 4800 ng/mL | Standard Deviation 3890 |
Secondary
Time to Reach the Maximum Concentration After Drug Administration (Tmax)
Tmax is the time to reach maximum (peak) plasma drug concentration after single dose administration (time). Actual recorded sampling times were taken into consideration for PK calculations.
Time frame: Day 1 (0 min (pre-dose), 15 min (end of infusion), 30 min , 60 min, 90 min and 180 min) and Day 5
Population: Pharmacokinetic (PK) analysis set: Participants with at least one available valid PK concentration measurement, who received the investigational product and with no protocol deviations that impact on PK data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HSY244 | Time to Reach the Maximum Concentration After Drug Administration (Tmax) | 0.28 Hour |