Persistent or Permanent Non-valvular Atrial Fibrillation
Conditions
Brief summary
The purpose of this study is to assess the safety and tolerability of AZD0837 in patients with atrial fibrillation who are unable or unwilling to take vitamin K antagonist therapy for up to 3 months.
Interventions
DRUGAZD0837
ER formulation
DRUGAspirin
Oral form
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Either one of the following risk factors is sufficient for inclusion (high risk patient) * Previous cerebral ischaemic attack (stroke or transient ischaemic attack (TIA), \>30 days prior to randomization) * Previous systemic embolism or at least one of the following risk factors are needed for inclusion: Age ≥75 years * Symptomatic congestive heart failure * Impaired left ventricular systolic function * Diabetes mellitus; Hypertension requiring anti-hypertensive treatment * In addition to AF the patient must be appropriate for but unable or unwilling to take VKA therapy
Exclusion criteria
* Presence of a clinically significant valvular heart disease;; Stroke or TIA and/or systemic embolism within the previous 30 days prior to randomization * Conditions associated with increased risk of major bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Premature Discontinuation of Study or Study Drug Due to Any Reason | 28 week (randomisation visit to last follow up visit in study) according to protocols | The premature discontinuation of study or study drug due to any reason |
| Premature Discontinuation of Study Drug Due to Any Reason | 24 weeks (randomisation visit to last treatment visit) | The premature discontinuation of study drug due to any reason |
| Premature Discontinuation of Study Due to Any Reason | 28 weeks (randomisation visit to last follow up visit) | \|The premature discontinuation of study due to any reason |
| Compliance With Study Drug | 24 weeks (randomisation visit to last treatment visit) according to protocol | \[(number of doses dispensed-number of doses returned)/number of days between visits\]\*100 |
| Compliance With Study Visits/Assessments | 28 weeks (randomisation visit to last follow up visit) according to protocol | (number of visits attended acroos the time of study divided by the number of expected visits according to the time of entry into study)\*100 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of AR-H067637XX (Active Metabolite) | 4 weeks after baseline according to protocol | Assessment of plasma concentration of AR-H067637XX (active metabolite) made on the week 4 visit |
| Change in D-Dimer Level | 4 weeks according to protocol.(baseline to week 4 visit) | Individual change in D-Dimer level (ng/ml) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline) |
| Bleeding Events | 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit) | Number of patients with a bleeding event while on study drug. Patients with multiple bleeding events are counted once |
| Ecarin Clotting Time (ECT) | 4 weeks according to protocol.(baseline to week 4 visit) | Individual change in Ecarin clotting time (ECT) (sec) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline) |
| Activated Partial Thromboplastin Time (APTT) | 4 weeks according to protocol.(baseline to week 4 visit) | Individual change in Activated partial thromboplastin time (APTT) (sec) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline) |
| Change in Creatinine Level | 4 weeks according to protocol (randomisation visit to week 4 visit) | Individual change in Creatinine level (umil/L) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline) |
| Alanine Aminotransferase (ALAT) | 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit) | Number of patients while on study drug with Alanine aminotransferase (ALAT)\>=3 times upper limit of normal. |
| Bilirubin | 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit) | Number of patients while on study drug with Bilirubin\>=2 times upper limit of normal. |
| Plasma Concentration of AZD0837 (Prodrug) | 4 weeks after baseline according to protocol | Assessment of plasma concentration of AZD0837 (prodrug) made on the week 4 visit |
Countries
Denmark, Norway, Poland, Russia, Sweden, United Kingdom
Participant flow
Recruitment details
The study population included male and female participants \>18 years of age with chronic non-valvular Atrial Fibrillation. The participants were recruited during the time period from 22 October 2007 to 21 October 2008 at medical clinics in Europe.
Pre-assignment details
For participants treated with Vitamin K Antagonists (VKA) at the time of enrollment, VKA treatment was to be adjusted (and stopped before randomisation) to ensure that INR was below 2.0 at randomisation. If this was not achieved the participant was discontinued from the study.
Participants by arm
| Arm | Count |
|---|---|
| AZD0837 150 mg AZD0837 150 mg | 41 |
| AZD0837 300 mg AZD0837 300 mg | 42 |
| Standard Therapy Standard Therapy | 45 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 0 |
| Overall Study | Criteria from CSR | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | AZD0837 150 mg | AZD0837 300 mg | Standard Therapy | Total |
|---|---|---|---|---|
| Age Continuous | 72.5 Years STANDARD_DEVIATION 8 | 71.6 Years STANDARD_DEVIATION 8.51 | 68.8 Years STANDARD_DEVIATION 9.36 | 70 Years STANDARD_DEVIATION 8.68 |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 17 Participants | 49 Participants |
| Sex: Female, Male Male | 25 Participants | 26 Participants | 28 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 41 | 1 / 41 | 1 / 46 |
| serious Total, serious adverse events | 2 / 41 | 3 / 41 | 2 / 46 |
Outcome results
Primary
Compliance With Study Drug
\[(number of doses dispensed-number of doses returned)/number of days between visits\]\*100
Time frame: 24 weeks (randomisation visit to last treatment visit) according to protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD0837 150 mg | Compliance With Study Drug | 96.95 Percentage | Standard Deviation 16.503 |
| AZD0837 300 mg | Compliance With Study Drug | 99.82 Percentage | Standard Deviation 11.383 |
Primary
Compliance With Study Visits/Assessments
(number of visits attended acroos the time of study divided by the number of expected visits according to the time of entry into study)\*100
Time frame: 28 weeks (randomisation visit to last follow up visit) according to protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD0837 150 mg | Compliance With Study Visits/Assessments | 93.3 Percentage | Standard Deviation 15.01 |
| AZD0837 300 mg | Compliance With Study Visits/Assessments | 95.6 Percentage | Standard Deviation 10.45 |
| Standard Therapy | Compliance With Study Visits/Assessments | 97.5 Percentage | Standard Deviation 6.8 |
Primary
Premature Discontinuation of Study Drug Due to Any Reason
The premature discontinuation of study drug due to any reason
Time frame: 24 weeks (randomisation visit to last treatment visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Premature Discontinuation of Study Drug Due to Any Reason | 3 Participants |
| AZD0837 300 mg | Premature Discontinuation of Study Drug Due to Any Reason | 3 Participants |
| Standard Therapy | Premature Discontinuation of Study Drug Due to Any Reason | 1 Participants |
Primary
Premature Discontinuation of Study Due to Any Reason
\|The premature discontinuation of study due to any reason
Time frame: 28 weeks (randomisation visit to last follow up visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Premature Discontinuation of Study Due to Any Reason | 4 Participants |
| AZD0837 300 mg | Premature Discontinuation of Study Due to Any Reason | 4 Participants |
| Standard Therapy | Premature Discontinuation of Study Due to Any Reason | 2 Participants |
Primary
Premature Discontinuation of Study or Study Drug Due to Any Reason
The premature discontinuation of study or study drug due to any reason
Time frame: 28 week (randomisation visit to last follow up visit in study) according to protocols
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Premature Discontinuation of Study or Study Drug Due to Any Reason | 4 Participants |
| AZD0837 300 mg | Premature Discontinuation of Study or Study Drug Due to Any Reason | 6 Participants |
| Standard Therapy | Premature Discontinuation of Study or Study Drug Due to Any Reason | 3 Participants |
Secondary
Activated Partial Thromboplastin Time (APTT)
Individual change in Activated partial thromboplastin time (APTT) (sec) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline)
Time frame: 4 weeks according to protocol.(baseline to week 4 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0837 150 mg | Activated Partial Thromboplastin Time (APTT) | 31.74 sec |
| AZD0837 300 mg | Activated Partial Thromboplastin Time (APTT) | 51.51 sec |
Secondary
Alanine Aminotransferase (ALAT)
Number of patients while on study drug with Alanine aminotransferase (ALAT)\>=3 times upper limit of normal.
Time frame: 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit)
Population: 41 + 42 + 45 participants were randomized into the study to treatment arm 1, arm 2 and arm 3 respectively. However, one of the participants randomized to arm 2 was treated according to treatment arm 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Alanine Aminotransferase (ALAT) | 0 Participants |
| AZD0837 300 mg | Alanine Aminotransferase (ALAT) | 0 Participants |
| Standard Therapy | Alanine Aminotransferase (ALAT) | 1 Participants |
Secondary
Bilirubin
Number of patients while on study drug with Bilirubin\>=2 times upper limit of normal.
Time frame: 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit)
Population: 41 + 42 + 45 participants were randomized into the study to treatment arm 1, arm 2 and arm 3 respectively. However, one of the participants randomized to arm 2 was treated according to treatment arm 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Bilirubin | 1 Participants |
| AZD0837 300 mg | Bilirubin | 0 Participants |
| Standard Therapy | Bilirubin | 0 Participants |
Secondary
Bleeding Events
Number of patients with a bleeding event while on study drug. Patients with multiple bleeding events are counted once
Time frame: 24 weeks (randomisation visit to last treatment visit) according to protocol. For patients who discontinued treatment the time frame was <24 weeks. Mean number of weeks was 7 weeks (baseline to end of treatment visit)
Population: 41 + 42 + 45 participants were randomized into the study to treatment arm 1, arm 2 and arm 3 respectively. However, one of the participants randomized to arm 2 was treated according to treatment arm 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD0837 150 mg | Bleeding Events | 0 Participants |
| AZD0837 300 mg | Bleeding Events | 5 Participants |
| Standard Therapy | Bleeding Events | 2 Participants |
Secondary
Change in Creatinine Level
Individual change in Creatinine level (umil/L) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline)
Time frame: 4 weeks according to protocol (randomisation visit to week 4 visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD0837 150 mg | Change in Creatinine Level | 6.2 umol/L | Standard Deviation 8.64 |
| AZD0837 300 mg | Change in Creatinine Level | 3.6 umol/L | Standard Deviation 13.21 |
| Standard Therapy | Change in Creatinine Level | 2.6 umol/L | Standard Deviation 12.9 |
Secondary
Change in D-Dimer Level
Individual change in D-Dimer level (ng/ml) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline)
Time frame: 4 weeks according to protocol.(baseline to week 4 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0837 150 mg | Change in D-Dimer Level | -33.484 ng/ml |
| AZD0837 300 mg | Change in D-Dimer Level | -41.445 ng/ml |
| Standard Therapy | Change in D-Dimer Level | 4.853 ng/ml |
Secondary
Ecarin Clotting Time (ECT)
Individual change in Ecarin clotting time (ECT) (sec) from baseline to week 4 visit for patients while on study drug (week 4 visit-baseline)
Time frame: 4 weeks according to protocol.(baseline to week 4 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0837 150 mg | Ecarin Clotting Time (ECT) | 125.6 sec |
| AZD0837 300 mg | Ecarin Clotting Time (ECT) | 179.1 sec |
Secondary
Plasma Concentration of AR-H067637XX (Active Metabolite)
Assessment of plasma concentration of AR-H067637XX (active metabolite) made on the week 4 visit
Time frame: 4 weeks after baseline according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0837 150 mg | Plasma Concentration of AR-H067637XX (Active Metabolite) | 258.5 nmol/L |
| AZD0837 300 mg | Plasma Concentration of AR-H067637XX (Active Metabolite) | 368.5 nmol/L |
Secondary
Plasma Concentration of AZD0837 (Prodrug)
Assessment of plasma concentration of AZD0837 (prodrug) made on the week 4 visit
Time frame: 4 weeks after baseline according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD0837 150 mg | Plasma Concentration of AZD0837 (Prodrug) | 596.0 nmol/L |
| AZD0837 300 mg | Plasma Concentration of AZD0837 (Prodrug) | 636.0 nmol/L |