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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 
Overall Participants Analyzed 
[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 
[1] Ethnicity was not collected outside of the United States.
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 [1] 
[Units: Participants]
     
Provoked Index VTE   272   272   544 
Unprovoked Index VTE   2416   2429   4845 
Not Reported   3   3   6 
[1] 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.
Index Event Classification [1] 
[Units: Participants]
     
Proximal DVT   1778   1814   3592 
PE   913   890   1803 
Adjudicated Proximal DVT   1749   1783   3532 
Adjudicated PE   930   906   1836 
[1] 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
  Show All Outcome Measures

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


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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