A Phase 2 Study To Evaluate The Safety Of Apixaban In Atrial Fibrillation

A Phase 2b, Randomized, Partially Blind (Open Label Warfarin), Active-Controlled (Warfarin), Multicenter Study, To Evaluate The Safety And Efficacy In 2 Doses Of Apixaban In Comparison To Warfarin, Administered For 12 Weeks In Subjects With NVAF

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00787150

Enrollment

222

Registered

2008-11-07

Start date

2008-06-30

Completion date

2009-09-30

Last updated

2013-05-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Atrial Fibrillation

Brief summary

To assess the effect of two doses of Apixaban (2.5 mg BID and 5 mg BID) versus Warfarin on the composite endpoint of major and clinically relevant non-major bleeding during the treatment period.

Interventions

DRUGApixaban

Apixaban 5 mg tablet BID for 12 weeks

DRUGWarfarin sodium

At each visit, the subject to take appropriate Warfarin tablet (on investigator's order) once a day every morning for 12 weeks

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

20 Years to No maximum

Healthy volunteers

Inclusion criteria

* Age ≥ 20 years outpatient (regardless of sex) * Patients diagnosed as non-valvular atrial fibrillation (NVAF) * One or more following risks of stroke.

Exclusion criteria

* Recent cerebral infarction (includes TIA) within 4 weeks of week 0. * Subjects who have or are suspected to have a serious/hereditary bleeding tendency, such as disseminated intravascular coagulation syndrome (DIC), congenital platelet dysfunction and von Willebrand disease (those suspected from the family history are included). * Subjects who have or are suspected to have a serious/hereditary thrombogenic tendency (those suspected from the family history are included) or those who require continuation of the Warfarin therapy.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Major (Per International Society on Thrombosis and Haemostasis [ISTH] Criteria) or Clinically Relevant Non-major Bleeding Adjudicated by Clinical Event Committee During the Treatment Period	Baseline to Week 12	Major bleeding event was acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occurs in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event. Clinical relevant non-major bleeding was acute or sub-acute clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy.

Secondary

Measure	Time frame	Description
Number of Participants With Total Bleeding Events During the Treatment Period	Baseline to Week 12	Total bleeding events consisted of major (per International Society on Thrombosis and Haemostasis \[ISTH\] Criteria), clinically relevant non-major and minor bleeding events. All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding were classified as minor bleeding.
Number of Participants With Major (Per International Society on Thrombosis and Haemostasis [ISTH] Criteria) Bleeding Events During the Treatment Period	Baseline to Week 12	Major bleeding event is acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occurs in critical site (e.g., intracranial). Fatal bleeding is also major bleeding event.
Number of Participants With Clinically Relevant Non-major Bleeding Events During the Treatment Period	Baseline to Week 12	Clinical relevant non-major bleeding was acute or sub-acute clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy.
Number of Participants With Stroke or Systemic Embolism During the Intended Treatment Period	Baseline to Week 12	The definition of the Intended Treatment Period was the period starting on the day of randomization and ending at the later one of either 2 days after the last dose of the study drug or Day 85/Week 12 after the randomization day.
Number of Participants With Stroke, Systemic Embolism, or All-Cause Death During the Intended Treatment Period	Baseline to Week 12	The definition of the Intended Treatment Period was the period starting on the day of randomization and ending at the later one of either 2 days after the last dose of the study drug or Day 85/Week 12 after the randomization day.
Number of Participants With Myocardial Infarction or All-Cause Death During the Intended Treatment Period	Baseline to Week 12	The definition of the Intended Treatment Period was the period starting on the day of randomization and ending at the later one of either 2 days after the last dose of the study drug or Day 85/Week 12 after the randomization day.

Other

Measure	Time frame	Description
Mean Plasma Apixaban Concentration at Each Time Point in Participants Treated With Apixaban	0, 2, 4 hours postdose at Week 1 and Week 8	Sample at 4 hours postdose was to be taken if possible.
Mean Prothrombin Time (PT) at Each Time Point in Participants Treated With Apixaban	Week 0, 0, 2, 4 hours postdose at Week 1 and Week 8	Sample at 4 hours postdose was to be taken if possible.
Mean Prothrombin Time-International Normalized Ratio (PT-INR) at Each Time Point in Participants Treated With Apixaban	Week 0, 0, 2, 4 hours postdose at Week 1 and Week 8	Blood sample at 4 hours postdose was collected if possible. PT-INR is a standardized measure derived from prothrombin time (PT). The systematic variations in PT assay results are corrected in PT-INR in order to optimize measurements of vitamin K antagonists.
Mean Activated Partial Thromboplastin Time (aPTT) at Each Time Point in Participants Treated With Apixaban	Week 0, 0, 2, 4 hours postdose at Week 1 and Week 8	Blood Sample at 4 hours postdose was collected if possible. The aPTT is a screening test for the intrinsic pathway and is sensitive for deficiencies of Factors I, II, V, VIII, IX, X, XI and XII. Higher values than the baseline indicate anticoagulant effects.
Mean Anti-Xa Activity (Apixaban Units) at Each Time Point in Participants Treated With Apixaban	Week 0, 0, 2, 4 hours postdose at Week 1 and Week 8	Blood sample at 4 hours postdose was collected if possible. Below the limit of quantification (BLQ) was assigned the value 0 for calculation. If 50% or more of the data was BLQ, statistics was not be calculated. Therefore, 0 means not calculated.
Mean Prothrombin Fragment 1+2 (F1+2) at Each Time Point in Participants Treated With Warfarin or Apixaban	Week 0, Week 1, Week 8	Below the limit of quantification (BLQ) was assigned the value 0 for calculation. If 50% or more of the data was BLQ, statistics was not calculated. Therefore, 0 indicates not calculated.
Mean D-Dimer at Each Time Point in Participants Treated With Warfarin or Apixaban	Week 0, Week 1, Week 8	Below the limit of quantification (BLQ) was assigned the value 0 for calculation.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Warfarin The appropriate dose of warfarin sodium, as 2 mg tablet, to achieve the target prothrombin time - international normalization ratio (PT-INR: 2.0-3.0 for under 70 years old; 2.0-2.6 for 70 years or older) was administered once a day every morning after meal for 12 weeks.	74
Apixaban 2.5mg BID One apixaban 2.5 mg tablet and 1 apixaban 5.0 mg placebo tablet were administered twice a day (morning and evening) after a meal for 12 weeks.	74
Apixaban 5.0 mg BID One apixaban 5.0 mg tablet and 1 apixaban 2.5 mg placebo tablet were administered twice a day (morning and evening) after a meal for 12 weeks.	74
Total	222

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	4	4	4
Overall Study	Dosing incorrect study durg	2	0	0
Overall Study	Physician Decision	1	2	1
Overall Study	Withdrawal by Subject	2	1	0

Baseline characteristics

Characteristic	Warfarin	Apixaban 2.5mg BID	Apixaban 5.0 mg BID	Total
Age Continuous	71.7 years STANDARD_DEVIATION 7	69.3 years STANDARD_DEVIATION 8.4	70.0 years STANDARD_DEVIATION 8.1	70.3 years STANDARD_DEVIATION 7.9
Sex: Female, Male Female	14 Participants	11 Participants	13 Participants	38 Participants
Sex: Female, Male Male	60 Participants	63 Participants	61 Participants	184 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	17 / 75	24 / 72	22 / 71
serious Total, serious adverse events	4 / 75	1 / 72	5 / 71

Outcome results

Primary

Number of Participants With Major (Per International Society on Thrombosis and Haemostasis [ISTH] Criteria) or Clinically Relevant Non-major Bleeding Adjudicated by Clinical Event Committee During the Treatment Period

Major bleeding event was acute clinically overt bleeding accompanied by decrease in hemoglobin of 2 g/dL or more over a 24-hour period, transfusion of 2 or more units of packed red blood cells, or bleeding that occurs in critical site (e.g., intracranial). Fatal bleeding was also major bleeding event. Clinical relevant non-major bleeding was acute or sub-acute clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to either hospital admission for bleeding, physician guided medical or surgical treatment for bleeding or a change in antithrombotic therapy.