Atrial Flutter
Conditions
Brief summary
The purpose of the study is to measure the effects of AZD1305 on cardiac electrophysiological properties and intracardiac pressures
Interventions
DRUGAZD1305
Intravenous infusion
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with atrial flutter (with a ventricular rate of \<100 beats/minute at enrolment), scheduled for curative catheter ablation * Sinus rhythm at randomisation
Exclusion criteria
* QTc (Fridericia, QTcF ) \>450 ms measured in sinus rhythm at randomisation, * Serum potassium below 3.8 or above 5.0 mmol/L or plasma potassium below 3.6 or above 5.0 mmol/L * QRS duration \>120 ms at randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product | Absolute change, after - before infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product | Absolute change, after - before infusion |
| QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product. ECG measurements, including QTcF, are available from several additiona | Absolute change, after - before infusion |
| RAERP (Right Atrial Effective Refractory Period) | Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product | Absolute change, after - before infusion |
| AUC Total of AZD1305 (Umol*h/L) | Based on PK samples during and after infusion | A total of 13 scheduled PK samples for each patient during and after infusion |
| Number of Patients Who Had at Least One AE | During active treatment period | Number of patients |
| Cmax Observed for AZD1305 | During and after infusion | A total of 13 scheduled PK samples for each patient during and after infusion |
Countries
Denmark, Finland, Norway, Sweden
Participant flow
Recruitment details
A total of 68 patients were enrolled into the study. The study randomised 55 patients and 50 of those patients received study drug. All patients who received study drug completed the study.
Pre-assignment details
At the pre-entry visit, which took place within 14 days before the planned catheter ablation (Study Day), patients underwent a full clinical assessment including a physical examination, ECG recording, Bood pressure(BP)/heart rate measurement, routine laboratory tests, and transthoracic echocardiography (TTE, if not done within the prior 6 months).
Participants by arm
| Arm | Count |
|---|---|
| AZD1305 Dose Group 1 Loading dose 15 min at 43.5 mg/h, Maintenance dose maximum 60 additional min at 19.6 mg/h | 11 |
| AZD1305 Dose Group 2 Loading dose 15 min at 130.4 mg/h, Maintenance dose maximum 60 additional min at 58.7 mg/h | 12 |
| AZD1305 Dose Group 3 Loading dose 15 min at 325.9 mg/h, Maintenance dose maximum 60 additional min at 146.6 mg/h | 13 |
| AZD1305 Dose Group 4 Loading dose 15 min at 488.8 mg/h, Maintenance dose maximum 60 additional min at 220.0 mg/h | 2 |
| Placebo Corresponding placebo | 12 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | AV-block | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | AZD1305 Dose Group 1 | AZD1305 Dose Group 2 | AZD1305 Dose Group 3 | AZD1305 Dose Group 4 | Placebo |
|---|---|---|---|---|---|---|
| Age Continuous Age (years) | 56 Years STANDARD_DEVIATION 14.5 | 60 Years STANDARD_DEVIATION 14 | 62 Years STANDARD_DEVIATION 6 | 60 Years STANDARD_DEVIATION 8 | 50 Years STANDARD_DEVIATION 23 | 62 Years STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 44 Participants | 9 Participants | 10 Participants | 11 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / — | 1 / — | 1 / — | 1 / — | 0 / — |
| serious Total, serious adverse events | 0 / 11 | 1 / 12 | 1 / 13 | 0 / 2 | 1 / 12 |
Outcome results
Primary
LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation))
Absolute change, after - before infusion
Time frame: Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | 11 ms | Full Range -15 |
| AZD1305 Dose Group 2 | LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | 43 ms | Full Range 0 |
| AZD1305 Dose Group 3 | LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | 55 ms | Full Range -5 |
| AZD1305 Dose Group 4 | LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | 50 ms | Full Range 40 |
| Placebo | LAERP (Left Atrial Effective Refractory Period (ie, the Longest S1-S2 Interval That Fails to Result in Atrial Depolarisation)) | -10 ms | Full Range -90 |
Secondary
AUC Total of AZD1305 (Umol*h/L)
A total of 13 scheduled PK samples for each patient during and after infusion
Time frame: Based on PK samples during and after infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | AUC Total of AZD1305 (Umol*h/L) | 1.54 umol*h/L | Full Range 0.97 |
| AZD1305 Dose Group 2 | AUC Total of AZD1305 (Umol*h/L) | 4.97 umol*h/L | Full Range 2.7 |
| AZD1305 Dose Group 3 | AUC Total of AZD1305 (Umol*h/L) | 10.3 umol*h/L | Full Range 5.71 |
| AZD1305 Dose Group 4 | AUC Total of AZD1305 (Umol*h/L) | 17.3 umol*h/L | Full Range 16.5 |
Secondary
Cmax Observed for AZD1305
A total of 13 scheduled PK samples for each patient during and after infusion
Time frame: During and after infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | Cmax Observed for AZD1305 | 0.178 umol/L | Full Range 0.104 |
| AZD1305 Dose Group 2 | Cmax Observed for AZD1305 | 0.692 umol/L | Full Range 0.368 |
| AZD1305 Dose Group 3 | Cmax Observed for AZD1305 | 1.46 umol/L | Full Range 0.931 |
| AZD1305 Dose Group 4 | Cmax Observed for AZD1305 | 2.41 umol/L | Full Range 2.24 |
Secondary
Number of Patients Who Had at Least One AE
Number of patients
Time frame: During active treatment period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Number of Patients Who Had at Least One AE | 2 Participants |
| AZD1305 Dose Group 2 | Number of Patients Who Had at Least One AE | 2 Participants |
| AZD1305 Dose Group 3 | Number of Patients Who Had at Least One AE | 2 Participants |
| AZD1305 Dose Group 4 | Number of Patients Who Had at Least One AE | 1 Participants |
| Placebo | Number of Patients Who Had at Least One AE | 1 Participants |
Secondary
QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds)
Absolute change, after - before infusion
Time frame: Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product. ECG measurements, including QTcF, are available from several additiona
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | 20 ms | Full Range -2 |
| AZD1305 Dose Group 2 | QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | 65 ms | Full Range 13 |
| AZD1305 Dose Group 3 | QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | 79 ms | Full Range 31 |
| AZD1305 Dose Group 4 | QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | 65 ms | Full Range 59 |
| Placebo | QTcF (Interval From the Beginning of the Q or R Wave to the End of the T Wave in the Surface ECG, Corrected for Changes in RR Interval Using Fridericia' Formula =QT/RR1/3 Interval in Seconds) | 4 ms | Full Range -51 |
Secondary
RAERP (Right Atrial Effective Refractory Period)
Absolute change, after - before infusion
Time frame: Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | RAERP (Right Atrial Effective Refractory Period) | 19 ms | Full Range -5 |
| AZD1305 Dose Group 2 | RAERP (Right Atrial Effective Refractory Period) | 42 ms | Full Range 0 |
| AZD1305 Dose Group 3 | RAERP (Right Atrial Effective Refractory Period) | 84 ms | Full Range -30 |
| AZD1305 Dose Group 4 | RAERP (Right Atrial Effective Refractory Period) | 135 ms | Full Range 100 |
| Placebo | RAERP (Right Atrial Effective Refractory Period) | -12 ms | Full Range -90 |
Secondary
VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop)
Absolute change, after - before infusion
Time frame: Measurements were obtained twice, from the invasive electrophysiological measurements made before and 20 min (or more) after the start of administration of the investigational product
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD1305 Dose Group 1 | VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | 11 ms | Full Range -25 |
| AZD1305 Dose Group 2 | VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | 41 ms | Full Range 5 |
| AZD1305 Dose Group 3 | VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | 59 ms | Full Range 25 |
| AZD1305 Dose Group 4 | VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | 65 ms | Full Range 45 |
| Placebo | VERP (Ventricular Effective Refractory Period)) and Other Electrophysiological and Electrocardiographic Variables; RR, P Wave Duration, PR, QRS, QTend, QTcF, QTtop, QTend - QTtop) | 3 ms | Full Range -25 |