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Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism

This study has been completed.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00643201
First received: March 20, 2008
Last updated: April 17, 2014
Last verified: April 2014
Results First Received: March 4, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Venous Thrombosis
Interventions: Drug: Enoxaparin
Drug: warfarin
Drug: Placebo for apixaban
Drug: Placebo for enoxaparin
Drug: Placebo for warfarin
Drug: apixaban

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First participant, first visit: 27 August 2008; Last participant, last visit: 12 March 2013.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
5614 enrolled, 5395 randomized; Reasons for non-randomization: 173 did not meet inclusion/exclusion criteria; 12 withdrew consent; 5 had clinical reason to continue current treatment; 3 administrative reason by sponsor; 1 death; 1 adverse event (AE); 24 other reasons. 1 site (5 patients) excluded from analysis due to unconfirmed accuracy of data.

Reporting Groups
  Description
Apixaban

apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months.

Placebo for enoxaparin: solution, subcutaneous, 1milligram per kilogram (mg/kg) every 12 hours until sham international normalized ratio (INR) greater than, equal to ( ≥) 2.

Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months

Enoxaparin + Warfarin

Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2.

Warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months

Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months


Participant Flow for 2 periods

Period 1:   Randomized, Completed 6 Months of Study
    Apixaban     Enoxaparin + Warfarin  
STARTED     2691 [1]   2704 [1]
COMPLETED     2314     2291  
NOT COMPLETED     377     413  
Death                 20                 26  
Adverse Event                 150                 182  
Withdrawal by Subject                 49                 49  
Lost to Follow-up                 14                 14  
Poor or non-compliance                 20                 23  
Pregnancy                 3                 2  
Fails to meet inclusion/exclusion                 13                 9  
Administrative reason                 1                 1  
not specified                 107                 107  
[1] 15 participants were randomized to treatment but not treated.

Period 2:   Completed Study Follow Up
    Apixaban     Enoxaparin + Warfarin  
STARTED     2617     2639  
COMPLETED     2547 [1]   2560 [2]
NOT COMPLETED     70     79  
Death                 28                 34  
Withdrawal by Subject                 23                 29  
Lost to Follow-up                 18                 16  
non-specified                 1                 0  
[1] Of 70 who did not complete follow up: 7 completed treatment; 63 discontinued treatment
[2] Of 79 who did not complete follow up: 3 completed treatment, 76 discontinued treatment



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized Participants

Reporting Groups
  Description
Apixaban

apixaban: tablets, oral, 10 milligram (mg) tablets, twice daily, for 7 days followed by apixaban 5 mg, twice daily, 6 months.

Placebo for enoxaparin: solution, subcutaneous, 1milligram per kilogram (mg/kg) every 12 hours until sham International normalized ratio (INR) greater than, equal to ( ≥) 2.

Placebo for warfarin: tablets, oral, dosing to target sham INR range between 2.0 - 3.0, once daily, 6 months

Enoxaparin + Warfarin

Enoxaparin: solution, subcutaneous, 1 mg/kg Q12h until INR ≥2.

warfarin: tablets, oral, dosing to target INR range between 2.0 - 3.0, once daily, 6 months

Placebo for apixaban: tablets, oral, 10 mg tablets, twice daily, for 7 days followed by placebo for apixaban 5 mg tablets, twice daily, 6 months

Total Total of all reporting groups

Baseline Measures
    Apixaban     Enoxaparin + Warfarin     Total  
Number of Participants  
[units: participants]
  2691     2704     5395  
Age  
[units: years]
Mean ± Standard Deviation
  57.2  ± 15.98     56.7  ± 16.01     56.9  ± 16.00  
Age, Customized  
[units: participants]
     
Less than (<) 65     1729     1762     3491  
65 to < 75     560     570     1130  
Greater than, equal to (>=) 75     402     372     774  
Gender  
[units: participants]
     
Female     1122     1106     2228  
Male     1569     1598     3167  
Race/Ethnicity, Customized [1]
[units: participants]
     
White     2218     2243     4461  
Black or African American     106     98     204  
American Indian or Alaska Native     6     2     8  
Asian     227     226     453  
Other Race     89     85     174  
Race Not Reported     45     50     95  
Hispanic or Latino     20     18     38  
Not Hispanic or Latino     367     380     747  
Ethnicity Not Reported     2304     2306     4610  
Region of Enrollment  
[units: participants]
     
Portugal     10     9     19  
United States     387     398     785  
Hong Kong     2     1     3  
Spain     56     51     107  
Ukraine     213     211     424  
Israel     162     163     325  
Russian Federation     178     174     352  
Italy     167     169     336  
India     101     99     200  
France     140     149     289  
Malaysia     0     2     2  
Australia     56     64     120  
Denmark     69     72     141  
South Africa     70     77     147  
China     113     114     227  
Korea, Republic of     2     2     4  
Austria     40     39     79  
Czech Republic     140     134     274  
Hungary     145     128     273  
Mexico     59     57     116  
Canada     147     152     299  
Argentina     17     16     33  
Poland     60     59     119  
Brazil     77     81     158  
Singapore     5     5     10  
Romania     33     41     74  
Norway     40     32     72  
Germany     202     205     407  
Qualifying index Venous Thromboembolic Embolism [2]
[units: participants]
     
Provoked Index VTE     272     272     544  
Unprovoked Index VTE     2416     2429     4845  
Not Reported     3     3     6  
Index Event Classification [3]
[units: participants]
     
Proximal DVT     1778     1814     3592  
PE     913     890     1803  
Adjudicated Proximal DVT     1749     1783     3532  
Adjudicated PE     930     906     1836  
[1] Ethnicity was not collected outside of the United States.
[2] Both the 2004 and 2008 American College of Chest Physicians (ACCP) recommendations for treatment of venous thromboembolic events (VTE) were used during this study and recommendations were consistent. Participants with provoked and unprovoked index events were summarized. For unprovoked events in participants with certain risk factors and medical conditions, such as cancer, an idiopathic event, presence of pro-thrombotic genotype, or presence of a marker indicative of an increased risk of recurrent thromboembolism treatment for 6 months or longer is supported by the ACCP guidelines.
[3] Participants with events of either deep vein thrombosis (DVT) or pulmonary embolism (PE) were enrolled. If a participant had both DVT and PE, the participant was classified to PE. Each participant was counted once in a category but could be counted in more than one category. An Independent Central Adjudication Committee (ICAC) reviewed participants in a blinded manner. The ICAC included a chairman and independent reviewers who were physicians with experience in vascular medicine and thrombosis. The ICAC adjudicated all index events (proximal DVT and/or PE).



  Outcome Measures
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1.  Primary:   Incidence of Adjudicated Composite of Symptomatic, Recurrent Venous Thromboembolism (VTE) or VTE-Related Death During 6 Months of Treatment   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 days (Discontinued Early) ]

2.  Secondary:   Incidence of Adjudicated Composite of Recurrent Symptomatic Venous Thromboembolism (VTE) or All-Cause Death   [ Time Frame: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) ]

3.  Secondary:   Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or Cardiovascular (CV)-Related Death   [ Time Frame: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) ]

4.  Secondary:   Incidence of Adjudicated Composite of Recurrent Symptomatic VTE or VTE-related Death or Major Bleeding   [ Time Frame: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) ]

5.  Secondary:   Incidence of Adjudicated Composite of Recurrent Symptomatic VTE, Myocardial Infarction, Stroke, CV-related Death, Clinically Relevant Non-major (CRNM) Bleeding or Major Bleeding   [ Time Frame: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) ]

6.  Secondary:   Incidence of Adjudicated Symptomatic Nonfatal Deep Vein Thrombosis (DVT) During the Intended Treatment Period   [ Time Frame: Day 1 up to 24 Weeks + 2 Days or 355 Days (Discontinued Early) ]

7.  Secondary:   Incidence of Adjudicated Symptomatic Nonfatal Pulmonary Embolism (PE) During the Intended Treatment Period   [ Time Frame: Day 1 to Week 24 + + 2 Days or 355 Days (Discontinued Early) ]

8.  Secondary:   Incidence of Adjudicated Venous Thromboembolism (VTE)-Related Death During the Intended Treatment Period   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

9.  Secondary:   Incidence of Cardiovascular (CV)-Related Death Including VTE-related Death During the Intended Treatment Period   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

10.  Secondary:   Incidence of All-Cause Death During the Intended Treatment Period   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

11.  Secondary:   Incidence of Adjudicated Major Bleeding During the Treatment Period in Treated Participants   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

12.  Secondary:   Incidence of Adjudicated Major/CRNM Bleeding During the Treatment Period in Treated Participants   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

13.  Secondary:   Incidence of Adjudicated Clinically Relevant Non Major (CRNM) Bleeding During the Treatment Period in Treated Participants   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

14.  Secondary:   Incidence of Adjudicated Minor Bleeding During the Treatment Period in Treated Participants   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

15.  Secondary:   Incidence of Adjudicated Total Bleeding During the Treatment Period in Treated Participants   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

16.  Secondary:   Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Bleeding AEs, Discontinuations Due to AEs and Death During the Treatment Period in Treated Participants   [ Time Frame: First dose to last dose of 24 Weeks + 2 days (AEs) or + 30 days (SAEs) or until drug discontinued ]

17.  Secondary:   Number of Treated Participants With Marked Abnormalities in Hematology Laboratory Tests   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

18.  Secondary:   Number of Treated Participants With Marked Abnormalities in Electrolyte Laboratory Tests   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

19.  Secondary:   Number of Treated Participants With Marked Abnormalities in Kidney and Liver Function Laboratory Tests   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

20.  Secondary:   Number of Treated Participants With Marked Abnormalities in Creatine Kinase, Uric Acid, and Total Protein Laboratory Tests   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]

21.  Secondary:   Number of Treated Participants With Marked Abnormalities in Urinalysis Laboratory Tests   [ Time Frame: Day 1 to Week 24 + 2 Days or 355 Days (Discontinued Early) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided by Bristol-Myers Squibb

Publications automatically indexed to this study:

Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00643201     History of Changes
Other Study ID Numbers: CV185-056, EUDRACT: 2007-007867-25
Study First Received: March 20, 2008
Results First Received: March 4, 2014
Last Updated: April 17, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration
Canada: Health Canada
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Brazil: National Health Surveillance Agency
Chile: Instituto de Salud Pública de Chile
Mexico: Federal Commission for Sanitary Risks Protection
Austria: Secretariat of Health
Denmark: Danish Medicines Agency
France: Ministry of Health
Germany: Ministry of Health
Israel: Ministry of Health
Italy: Ministry of Health
Norway: Directorate of Health
Spain: Spanish Agency of Medicines
South Africa: Department of Health
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Czech Republic: Ministry of Health
Hungary: Ministry of Health, Social and Family Affairs
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Ukraine: Ministry of Health
Australia: Department of Health and Ageing Therapeutic Goods Administration
Hong Kong: Department of Health
India: Central Drugs Standard Control Organization
Korea: Food and Drug Administration
Malaysia: National Pharmaceutical Control Bureau
Taiwan: Department of Health
Romania: National Medicines Agency
Portugal: National Pharmacy and Medicines Institute
Singapore: Ministry of Health
China: Food and Drug Administration