Nonvalvular Atrial Fibrillation
Conditions
Keywords
Anticoagulant Treatment, Risk Factors For Stroke
Brief summary
The main purpose of this study is to provide dose-guiding information by assessing the safety and tolerability of 4 different dosing regimens of an extended-release (ER) formulation of AZD0837 compared with well-controlled, dose-adjusted Vitamin-K antagonists (VKA) (aiming for an international normalized ratio (INR) 2.0 to 3.0) in patients with non-valvular atrial fibrillation (AF) with one or more additional risk factors for stroke.
Interventions
DRUGAZD0837
ER tablet, PO, once daily for a period of 3-9 months.
DRUGVitamin-K antagonist at INR 2-3
Tablet, PO for a period of 3-9 months.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Nonvalvular AF (NVAF) verified by at least two ECGs in the last year separated by at least one week. * Previous cerebral ischemic attack (stroke or TIA, \>30 days prior to randomization) * Previous systemic embolism. * Symptomatic congestive heart failure (CHF) * Impaired left ventricular systolic function * Diabetes mellitus * Hypertension requiring anti-hypertensive treatment.
Exclusion criteria
* AF secondary to reversible disorders, eg hyperthyroidism, drugs and pulmonary embolism * Known contraindication to VKA treatment * Presence of a valvular heart disease, mechanical heart valves, active endocarditis, left ventricular aneurysm or thrombus, atrial myxoma or any condition other than AF requiring chronic anticoagulation treatment * Conditions associated with increased risk of major bleeding for example: history of intracranial bleeding, history of bleeding gastrointestinal disorder or major surgical procedure or trauma two weeks prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Events | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once |
| Creatinine | 12 weeks according to protocol.(baseline to week 12 visit) | Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline) |
| Alanine Aminotransferase (ALAT) | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | Number of patients while on study drug with ALAT\>=3 times upper limit of normal.l |
| Bilirubin | 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit) | Number of patients while on study drug with Bilirubin\>=2 times upper limit of normal |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration of AR-H067637XX (Active Metabolite) | 12 weeks after baseline according to protocol | Assessment made on the week 12 visit |
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | 36 weeks according to protocol | Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T |
| D-Dimer | 14 weeks according to protocol.(enrolment to week 12 visit) | Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment) |
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | 36 weeks according to protocol | Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T |
| Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | 36 weeks according to protocol | Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T |
| Activated Partial Thromboplastin Time (APTT) | 12 weeks according to protocol.(baseline to week 12 visit) | Change in Activated partial thromboplastin time (APTT) from baseline to week 12 visit for VKA naïve patients while on study drug (week 12 visit-baseline) |
| Ecarin Clotting Time (ECT) | 12 weeks according to protocol.(baseline to week 12 visit) | Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline) |
| Plasma Concentration of AZD0837 (Prodrug) | 12 weeks after baseline according to protocol | Assessment made on the week 12 visit |
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 20 February 2007 to 5 June 2008 at medical clinics in Europe.
Pre-assignment details
Participants were enrolled in the study up to two weeks before randomisation and treatment assignment. Participants that were already treated with Vitamin K Antagonists (VKA) at the time of enrollment had their dose adjusted to achive INR \<2.0 at the time of randomisation. If this was not achieved the participant was discontinued from the study.
Participants by arm
| Arm | Count |
|---|---|
| 150 mg od AZD0837 150 mg od | 164 |
| 300 mg od AZD0837 300 mg od | 151 |
| 450 mg od AZD0837 450 mg od | 156 |
| 200 mg bd AZD0837 200 mg bd | 160 |
| VKA INR 2-3 | 318 |
| Total | 949 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 6 | 15 | 16 | 8 |
| Overall Study | Criteria from the CSR | 0 | 0 | 1 | 3 | 3 |
| Overall Study | Development of increasing Liver Function | 0 | 2 | 0 | 1 | 0 |
| Overall Study | Fullfillment of exclusion criteria | 1 | 0 | 0 | 3 | 1 |
| Overall Study | Incorrect enrolment or randomization | 4 | 0 | 0 | 0 | 0 |
| Overall Study | Interupted IP for more than 7 days | 0 | 4 | 1 | 3 | 3 |
| Overall Study | Participant not willing to continue | 7 | 10 | 11 | 5 | 8 |
| Overall Study | Severe non compliance to protocol | 1 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | 150 mg od | 300 mg od | 450 mg od | 200 mg bd | VKA INR 2-3 | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 9.0 Years STANDARD_DEVIATION 69.9 | 9.0 Years STANDARD_DEVIATION 69.8 | 9.4 Years STANDARD_DEVIATION 69.3 | 9.4 Years STANDARD_DEVIATION 67.8 | 9.1 Years STANDARD_DEVIATION 68.3 | 9.18 Years STANDARD_DEVIATION 69.02 |
| Sex: Female, Male Female | 47 Participants | 47 Participants | 49 Participants | 53 Participants | 103 Participants | 299 Participants |
| Sex: Female, Male Male | 117 Participants | 104 Participants | 107 Participants | 107 Participants | 215 Participants | 650 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 | 46 / 166 | 62 / 152 | 46 / 157 | 59 / 161 | 67 / 319 |
| serious Total, serious adverse events | 12 / 166 | 20 / 152 | 31 / 157 | 27 / 161 | 50 / 319 |
Outcome results
Primary
Alanine Aminotransferase (ALAT)
Number of patients while on study drug with ALAT\>=3 times upper limit of normal.l
Time frame: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg od | Alanine Aminotransferase (ALAT) | 6 Participants |
| 300 mg od | Alanine Aminotransferase (ALAT) | 1 Participants |
| 450 mg od | Alanine Aminotransferase (ALAT) | 5 Participants |
| 200 mg bd | Alanine Aminotransferase (ALAT) | 2 Participants |
| VKA INR 2-3 | Alanine Aminotransferase (ALAT) | 5 Participants |
Primary
Bilirubin
Number of patients while on study drug with Bilirubin\>=2 times upper limit of normal
Time frame: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg od | Bilirubin | 1 Participants |
| 300 mg od | Bilirubin | 0 Participants |
| 450 mg od | Bilirubin | 0 Participants |
| 200 mg bd | Bilirubin | 3 Participants |
| VKA INR 2-3 | Bilirubin | 2 Participants |
Primary
Bleeding Events
Number of patients with a bleeding event while on study drug. Patients with multiple events are counted once
Time frame: 36 weeks according to protocol. For patients who discontinued treatment the time frame was <36 weeks. Mean number of weeks was 21 weeks (baseline to end of treatment visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg od | Bleeding Events | 18 Participants |
| 300 mg od | Bleeding Events | 8 Participants |
| 450 mg od | Bleeding Events | 22 Participants |
| 200 mg bd | Bleeding Events | 17 Participants |
| VKA INR 2-3 | Bleeding Events | 46 Participants |
Primary
Creatinine
Change in Creatinine values from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
Time frame: 12 weeks according to protocol.(baseline to week 12 visit)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 150 mg od | Creatinine | 5.95 umol/L | Standard Deviation 11.18 |
| 300 mg od | Creatinine | 4.81 umol/L | Standard Deviation 12.74 |
| 450 mg od | Creatinine | 7.56 umol/L | Standard Deviation 14.95 |
| 200 mg bd | Creatinine | 9.22 umol/L | Standard Deviation 11.24 |
| VKA INR 2-3 | Creatinine | 0.43 umol/L | Standard Deviation 11.79 |
Secondary
Activated Partial Thromboplastin Time (APTT)
Change in Activated partial thromboplastin time (APTT) from baseline to week 12 visit for VKA naïve patients while on study drug (week 12 visit-baseline)
Time frame: 12 weeks according to protocol.(baseline to week 12 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Activated Partial Thromboplastin Time (APTT) | 8.2 sec |
| 300 mg od | Activated Partial Thromboplastin Time (APTT) | 12.3 sec |
| 450 mg od | Activated Partial Thromboplastin Time (APTT) | 17.4 sec |
| 200 mg bd | Activated Partial Thromboplastin Time (APTT) | 16.4 sec |
Secondary
D-Dimer
Change in D-Dimer values from enrolment to week 12 visit for VKA naïve patients while on study drug (week 12 visit-enrolment)
Time frame: 14 weeks according to protocol.(enrolment to week 12 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | D-Dimer | -46.4 ng/mL |
| 300 mg od | D-Dimer | -76.9 ng/mL |
| 450 mg od | D-Dimer | -45.2 ng/mL |
| 200 mg bd | D-Dimer | -68.0 ng/mL |
| VKA INR 2-3 | D-Dimer | -50.3 ng/mL |
Secondary
Ecarin Clotting Time (ECT)
Change in Ecarin clotting time (ECT) from baseline to week 12 visit for patients while on study drug (week 12 visit-baseline)
Time frame: 12 weeks according to protocol.(baseline to week 12 visit)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Ecarin Clotting Time (ECT) | 33.5 sec |
| 300 mg od | Ecarin Clotting Time (ECT) | 53.0 sec |
| 450 mg od | Ecarin Clotting Time (ECT) | 64.0 sec |
| 200 mg bd | Ecarin Clotting Time (ECT) | 73.5 sec |
Secondary
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC
Oral clearance of AR-H067637XX in subgroup of patients with genotype CC for gene polymorphism ABCB1 C3435T
Time frame: 36 weeks according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | 40.9 L/h |
| 300 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | 41.1 L/h |
| 450 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | 43.4 L/h |
| 200 mg bd | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype CC | 39.6 L/h |
Secondary
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC
Oral clearance of AR-H067637XX in subgroup of patients with genotype TC for gene polymorphism ABCB1 C3435T
Time frame: 36 weeks according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | 39.2 L/h |
| 300 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | 39.3 L/h |
| 450 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | 37.7 L/h |
| 200 mg bd | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TC | 40 L/h |
Secondary
Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT
Oral clearance of AR-H067637XX in subgroup of patients with genotype TT for gene polymorphism ABCB1 C3435T
Time frame: 36 weeks according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | 39.7 L/h |
| 300 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | 42.4 L/h |
| 450 mg od | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | 36.3 L/h |
| 200 mg bd | Oral Clearance (CL/F) of AR-H067637XX (Active Metabolite) for C3435T Genotype TT | 35.6 L/h |
Secondary
Plasma Concentration of AR-H067637XX (Active Metabolite)
Assessment made on the week 12 visit
Time frame: 12 weeks after baseline according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Plasma Concentration of AR-H067637XX (Active Metabolite) | 223.8 nmol/L |
| 300 mg od | Plasma Concentration of AR-H067637XX (Active Metabolite) | 373.6 nmol/L |
| 450 mg od | Plasma Concentration of AR-H067637XX (Active Metabolite) | 454.8 nmol/L |
| 200 mg bd | Plasma Concentration of AR-H067637XX (Active Metabolite) | 600.8 nmol/L |
Secondary
Plasma Concentration of AZD0837 (Prodrug)
Assessment made on the week 12 visit
Time frame: 12 weeks after baseline according to protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 150 mg od | Plasma Concentration of AZD0837 (Prodrug) | 199.8 nmol/L |
| 300 mg od | Plasma Concentration of AZD0837 (Prodrug) | 617.5 nmol/L |
| 450 mg od | Plasma Concentration of AZD0837 (Prodrug) | 564.5 nmol/L |
| 200 mg bd | Plasma Concentration of AZD0837 (Prodrug) | 1143.5 nmol/L |