Atrial Fibrillation
Conditions
Keywords
AZD1305, intravenous cardioversion of Atrial Fibrillation
Brief summary
This study is being carried out to see which dose of AZD1305 is safe and effective in cardioverting atrial fibrillation into normal heart rhythm.
Interventions
DRUGAZD1305
Intravenous (iv) single infusion given intravenously until successful conversion of Atrial Fibrillation (AF) to Sinus Rhythm (SR) occur or for a maximum of 30 minutes
DRUGPlacebo
iv single infusion given intravenously until successful conversion of Atrial Fibrillation (AF) to Sinus Rhythm (SR) occur or for a maximum of 30 minutes
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Clinical indication for cardioversion of Atrial Fibrillation, ie a correction of irregular heart rhythm to normal heart rhythm * Current episode of Atrial Fibrillation (ie irregular heart rhythm) lasting up to 3 months at randomisation * Adequate anticoagulation according to international guidelines (ACC/AHA/ESC, 2006) or national guidelines
Exclusion criteria
* Potassium level below 3.8 mmol/L measured in serum or plasma * QTcF interval \>440 ms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-response Relationship for QTcF Interval of AZD1305 | At any time post randomisation until end of Holter recording (18-24 hours post start of drug infusion). | QTcF-QT interval corrected for the RR interval (the time elapsing between two consecutive R waves in the electrocardiogram (ECG)) using the Fridericia formula.For each of 3 consecutive beats (5 consecutive beats if AF) a manual measurement, preferably in lead V2, of QTend intervals was done.The mean QT values of the 3 consecutive beats (5 consecutive beats if AF) were, together with RR intervals, date & time of the ECG, entered into the eCase Report Form (eCRF).The selected beats had to be marked with calipers and noted together with measured values and calculations on the print-out and signed |
| Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | Within 90 minutes from start of infusion | Conversion of AF to SR with maintenance of SR maintained for at least 1 minute |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | During 24 hours following start of study drug infusion | — |
| Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | During 13 to 18 days following study drug infusion | Number of patients in SR at day 13-18 |
| Study the Relationship Between Systemic Exposure and Response, With Special Regards to Conversion of AF to SR and the Effect on the QTcF Interval. | Since this study is no longer intended to be part of any marketing authorisation application, the analyses addressing this objective were not conducted. | — |
| Maximal Observed Plasma Concentration of AZD1305 | Up to 24 hours following start of study drug infusion | Plasma concentration of AZD1305 |
| Wide QRS Tachycardias | From start of study drug infusion until discharge from hospital on study day 2. | Number of patients with wide QRS tachycardias, determined as significant arrhythmias by an Adjudication Committee (AC). The AC analysed and classified the occurrence of significant arrhythmias (other than AF or AFl) and pauses based on the 12-lead Holter reports. All pauses (≥3 sec) and all wide QRS complex tachycardias (≥3 beats, QRS ≥120 ms, and ≥120 bpm). |
| Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | Conversion from AF to SR within 90 minutes from start of infusion | Subgroup analysis for patients with duration of current AF episode 8 days - 30 days. Number of patients converting from AF to SR. |
| Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | Conversion from AF to SR within 90 minutes from start of infusion | Subgroup analysis for patients with duration of current AF episode 31 days - 3 months. Number of patients converting from AF to SR. |
| Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | Six hours following start of study drug infusion | Percentage, with 95% confidence interval, of patients with QTcF≤500 ms six hours following start of study drug infusion |
| Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | Conversion from AF to SR within 90 minutes from start of infusion | — |
| Heart Rhythm. Number of Participants With Early Relapse Into AF. | Within 5 minutes following investigational product (IP) induced conversion, or direct current (DC) cardioversion, of AF to SR | Early relapse into AF within 5 minutes from obtaining the defined criterion for conversion to SR (i.e.1 minute in SR). Patients never converted are not included in the analysis. |
Countries
Czechia, Denmark, Hungary, Netherlands, Norway, Poland, Slovakia, Sweden
Participant flow
Recruitment details
The 1st patient was enrolled in the study on 25 May 2009, and the last patient completed the study on 4 December 2009. In total, 228 patients were enrolled (at 33 centres) and of the 171 patients randomised 170 patients completed the study. There was no discontinuation of the Investigational Product (IP) due to an Adverse Event (AE) in the study.
Pre-assignment details
An enrolment visit (Visit 1) was done within 14 days before scheduled randomisation. Patients who fulfilled criteria and signed the informed consent form, could then be randomised at visit 2. The patients were to have ongoing Atrial Fibrillation with a clinical indication for cardioversion of Atrial Fibrillation (AF).
Participants by arm
| Arm | Count |
|---|---|
| AZD1305 Dose Group 1 AZD1305, intravenous (IV) single infusion given intravenously until successful conversion of Atrial Fibrillation to Sinus Rhythm occur or for a maximum of 30 minutes. Infusion rate 120 ml/h, dose rate 50 mg/h. | 26 |
| AZD1305 Dose Group 2 AZD1305, iv single infusion given intravenously until successful conversion of Atrial Fibrillation to Sinus Rhythm occur or for a maximum of 30 minutes. Infusion rate 120 ml/h, dose rate 101 mg/h. | 45 |
| AZD1305 Dose Group 3 AZD1305, iv single infusion given intravenously until successful conversion of Atrial Fibrillation to Sinus Rhythm occur or for a maximum of 30 minutes. Infusion rate 120 ml/h, dose rate 130 mg/h. | 45 |
| AZD1305 Dose Group 4 AZD1305, iv single infusion given intravenously until successful conversion of Atrial Fibrillation to Sinus Rhythm occur or for a maximum of 30 minutes. Infusion rate 120 ml/h, dose rate 180 mg/h. | 12 |
| Placebo Sodium chloride, iv single infusion given intravenously until successful conversion of Atrial Fibrillation to Sinus Rhythm occur or for a maximum of 30 minutes. Infusion rate 120 ml/h. | 43 |
| Total | 171 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | AZD1305 Dose Group 1 | AZD1305 Dose Group 2 | AZD1305 Dose Group 3 | AZD1305 Dose Group 4 | Placebo | Total |
|---|---|---|---|---|---|---|
| Age Continuous Age (years) | 65 Years STANDARD_DEVIATION 9 | 65 Years STANDARD_DEVIATION 7 | 64 Years STANDARD_DEVIATION 10 | 66 Years STANDARD_DEVIATION 7 | 66 Years STANDARD_DEVIATION 9 | 65 Years STANDARD_DEVIATION 8 |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 14 Participants | 4 Participants | 18 Participants | 62 Participants |
| Sex: Female, Male Male | 17 Participants | 28 Participants | 31 Participants | 8 Participants | 25 Participants | 109 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 | 5 / 26 | 9 / 45 | 8 / 45 | 3 / 12 | 5 / 43 |
| serious Total, serious adverse events | 1 / — | 3 / — | 3 / — | 1 / — | 2 / — |
Outcome results
Primary
Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR)
Conversion of AF to SR with maintenance of SR maintained for at least 1 minute
Time frame: Within 90 minutes from start of infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | 7.7 Percentage of patients converted to SR |
| AZD1305 Dose Group 2 | Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | 17.8 Percentage of patients converted to SR |
| AZD1305 Dose Group 3 | Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | 37.8 Percentage of patients converted to SR |
| AZD1305 Dose Group 4 | Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | 50.0 Percentage of patients converted to SR |
| Placebo | Conversion of Atrial Fibrillation (AF) and Maintenance of Sinus Rhytm (SR) | 0.0 Percentage of patients converted to SR |
Primary
Dose-response Relationship for QTcF Interval of AZD1305
QTcF-QT interval corrected for the RR interval (the time elapsing between two consecutive R waves in the electrocardiogram (ECG)) using the Fridericia formula.For each of 3 consecutive beats (5 consecutive beats if AF) a manual measurement, preferably in lead V2, of QTend intervals was done.The mean QT values of the 3 consecutive beats (5 consecutive beats if AF) were, together with RR intervals, date & time of the ECG, entered into the eCase Report Form (eCRF).The selected beats had to be marked with calipers and noted together with measured values and calculations on the print-out and signed
Time frame: At any time post randomisation until end of Holter recording (18-24 hours post start of drug infusion).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AZD1305 Dose Group 1 | Dose-response Relationship for QTcF Interval of AZD1305 | 461 ms |
| AZD1305 Dose Group 2 | Dose-response Relationship for QTcF Interval of AZD1305 | 486 ms |
| AZD1305 Dose Group 3 | Dose-response Relationship for QTcF Interval of AZD1305 | 490 ms |
| AZD1305 Dose Group 4 | Dose-response Relationship for QTcF Interval of AZD1305 | 482 ms |
| Placebo | Dose-response Relationship for QTcF Interval of AZD1305 | 440 ms |
Secondary
Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days
Time frame: Conversion from AF to SR within 90 minutes from start of infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | 0 Participants |
| AZD1305 Dose Group 2 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | 2 Participants |
| AZD1305 Dose Group 3 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | 5 Participants |
| AZD1305 Dose Group 4 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | 1 Participants |
| Placebo | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 10 Hours to 7 Days | 0 Participants |
Secondary
Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months
Subgroup analysis for patients with duration of current AF episode 31 days - 3 months. Number of patients converting from AF to SR.
Time frame: Conversion from AF to SR within 90 minutes from start of infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | 2 Participants |
| AZD1305 Dose Group 2 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | 2 Participants |
| AZD1305 Dose Group 3 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | 6 Participants |
| AZD1305 Dose Group 4 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | 3 Participants |
| Placebo | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 31 Days - 3 Months | 0 Participants |
Secondary
Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days.
Subgroup analysis for patients with duration of current AF episode 8 days - 30 days. Number of patients converting from AF to SR.
Time frame: Conversion from AF to SR within 90 minutes from start of infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | 0 Participants |
| AZD1305 Dose Group 2 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | 4 Participants |
| AZD1305 Dose Group 3 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | 6 Participants |
| AZD1305 Dose Group 4 | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | 2 Participants |
| Placebo | Conversion From AF to SR Within 90 Minutes From Start of Infusion in the Subgroup of Patients With Duration of Current AF Episode 8 Days - 30 Days. | 0 Participants |
Secondary
Heart Rhythm. Number of Participants With Early Relapse Into AF.
Early relapse into AF within 5 minutes from obtaining the defined criterion for conversion to SR (i.e.1 minute in SR). Patients never converted are not included in the analysis.
Time frame: Within 5 minutes following investigational product (IP) induced conversion, or direct current (DC) cardioversion, of AF to SR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Heart Rhythm. Number of Participants With Early Relapse Into AF. | 1 Participants |
| AZD1305 Dose Group 2 | Heart Rhythm. Number of Participants With Early Relapse Into AF. | 1 Participants |
| AZD1305 Dose Group 3 | Heart Rhythm. Number of Participants With Early Relapse Into AF. | 2 Participants |
| AZD1305 Dose Group 4 | Heart Rhythm. Number of Participants With Early Relapse Into AF. | 0 Participants |
| Placebo | Heart Rhythm. Number of Participants With Early Relapse Into AF. | 1 Participants |
Secondary
Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion.
Number of patients in SR at day 13-18
Time frame: During 13 to 18 days following study drug infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | 14 Participants |
| AZD1305 Dose Group 2 | Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | 23 Participants |
| AZD1305 Dose Group 3 | Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | 25 Participants |
| AZD1305 Dose Group 4 | Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | 7 Participants |
| Placebo | Heart Rhythm. Number of Patients Remaining in SR up to 13 to 18 Days Following Study Drug Infusion. | 22 Participants |
Secondary
Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion
Time frame: During 24 hours following start of study drug infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | 23 Participants |
| AZD1305 Dose Group 2 | Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | 34 Participants |
| AZD1305 Dose Group 3 | Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | 36 Participants |
| AZD1305 Dose Group 4 | Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | 10 Participants |
| Placebo | Heart Rhythm. Number of Patients Remaining in SR up to 24 h Following Start of Study Drug Infusion | 33 Participants |
Secondary
Maximal Observed Plasma Concentration of AZD1305
Plasma concentration of AZD1305
Time frame: Up to 24 hours following start of study drug infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD1305 Dose Group 1 | Maximal Observed Plasma Concentration of AZD1305 | 0.521 mol/L |
| AZD1305 Dose Group 2 | Maximal Observed Plasma Concentration of AZD1305 | 1.28 mol/L |
| AZD1305 Dose Group 3 | Maximal Observed Plasma Concentration of AZD1305 | 1.39 mol/L |
| AZD1305 Dose Group 4 | Maximal Observed Plasma Concentration of AZD1305 | 1.69 mol/L |
Secondary
Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion
Percentage, with 95% confidence interval, of patients with QTcF≤500 ms six hours following start of study drug infusion
Time frame: Six hours following start of study drug infusion
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | 100.0 Percent of participants |
| AZD1305 Dose Group 2 | Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | 95.5 Percent of participants |
| AZD1305 Dose Group 3 | Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | 91.1 Percent of participants |
| AZD1305 Dose Group 4 | Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | 100.0 Percent of participants |
| Placebo | Percentage of Patients, Discharged Within 6 h (QTcF ≤500 ms) After Start of Infusion | 100.0 Percent of participants |
Secondary
Study the Relationship Between Systemic Exposure and Response, With Special Regards to Conversion of AF to SR and the Effect on the QTcF Interval.
Time frame: Since this study is no longer intended to be part of any marketing authorisation application, the analyses addressing this objective were not conducted.
Secondary
Wide QRS Tachycardias
Number of patients with wide QRS tachycardias, determined as significant arrhythmias by an Adjudication Committee (AC). The AC analysed and classified the occurrence of significant arrhythmias (other than AF or AFl) and pauses based on the 12-lead Holter reports. All pauses (≥3 sec) and all wide QRS complex tachycardias (≥3 beats, QRS ≥120 ms, and ≥120 bpm).
Time frame: From start of study drug infusion until discharge from hospital on study day 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD1305 Dose Group 1 | Wide QRS Tachycardias | 4 Participants |
| AZD1305 Dose Group 2 | Wide QRS Tachycardias | 15 Participants |
| AZD1305 Dose Group 3 | Wide QRS Tachycardias | 16 Participants |
| AZD1305 Dose Group 4 | Wide QRS Tachycardias | 2 Participants |
| Placebo | Wide QRS Tachycardias | 7 Participants |