Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery (ADVANCE-2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00452530
First received: March 23, 2007
Last updated: July 8, 2014
Last verified: July 2014
Results First Received: April 14, 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
Conditions: Deep Vein Thrombosis
Pulmonary Embolism
Interventions: Drug: Enoxaparin
Drug: Apixaban
Drug: Enoxaparin-matching placebo
Drug: Apixaban-matching placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 3221 patients enrolled, 3057 were randomized. Primary participants=those who were randomized and had an adjudicated evaluable bilateral venogram or an adjudicated venous thromboembolic event or died. Evaluable participants=those with significant protocol deviations expected to affect the primary endpoint.

Reporting Groups
  Description
Apixaban, 2.5 mg BID + Placebo Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD)
Enoxaparin, 40 mg QD + Placebo Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID

Participant Flow:   Overall Study
    Apixaban, 2.5 mg BID + Placebo     Enoxaparin, 40 mg QD + Placebo  
STARTED     1528 [1]   1529 [1]
Received Treatment     1501     1508  
Evaluable Participants     907     921  
Primary Participants     976     997  
COMPLETED     1392     1393  
NOT COMPLETED     136     136  
Death                 1                 0  
Adverse Event                 40                 44  
Withdrawal by Subject                 68                 57  
Lost to Follow-up                 1                 0  
Poor compliance/noncompliance                 1                 2  
No longer met study criteria                 18                 22  
Not specified                 7                 11  
[1] Randomized



  Baseline Characteristics
  Hide Baseline Characteristics

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.
All participants randomized to treatment

Reporting Groups
  Description
Apixaban, 2.5 mg BID + Placebo Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD)
Enoxaparin, 40 mg QD + Placebo Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID
Total Total of all reporting groups

Baseline Measures
    Apixaban, 2.5 mg BID + Placebo     Enoxaparin, 40 mg QD + Placebo     Total  
Number of Participants  
[units: participants]
  1528     1529     3057  
Age  
[units: Years]
Median ± Standard Deviation
  67  ± 9.85     67  ± 9.82     67  ± 9.84  
Age, Customized  
[units: Participants]
     
Younger than 65 years     632     636     1268  
65 years to younger than 75 years     608     576     1184  
75 years and older     288     317     605  
Gender  
[units: Participants]
     
Female     1089     1127     2216  
Male     439     402     841  
Race/Ethnicity, Customized  
[units: Participants]
     
White     1216     1211     2427  
Black/African American     14     17     31  
Asian     252     254     506  
Native Hawaiian/Other Pacific Islander     1     1     2  
Other [Not specified]     45     46     91  
Hispanic/Latino     0     1     1  
Not Hispanic/Latino     53     57     110  
Ethnicity not reported     1475     1471     2946  
Region of Enrollment  
[units: Participants]
     
Philippines     12     14     26  
Spain     61     60     121  
Ukraine     181     182     363  
Russian Federation     150     156     306  
Israel     43     43     86  
Chile     1     5     6  
Colombia     36     35     71  
Italy     69     69     138  
India     92     92     184  
France     72     68     140  
Malaysia     4     4     8  
Denmark     26     23     49  
South Africa     56     56     112  
China     90     90     180  
Korea, Republic of     40     38     78  
Austria     156     151     307  
United Kingdom     63     61     124  
Czech Republic     48     50     98  
Hungary     17     19     36  
Mexico     60     59     119  
Belgium     27     25     52  
Brazil     17     17     34  
Poland     41     45     86  
Singapore     8     9     17  
Norway     35     36     71  
Germany     122     122     244  
Sweden     1     0     1  
Type of Risk Factor  
[units: Participants]
     
Knee replacement     257     286     543  
Hip replacement     90     80     170  
Hip or knee fracture surgery     55     49     104  
Deep vein thrombosis     36     32     68  
Pulmonary embolism     10     10     20  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period   [ Time Frame: Day of randomization to later of 2 days after last dose or 14 days after first dose; 14 days after randomization for those who did not receive study drug ]
  Hide Outcome Measure 1

Measure Type Primary
Measure Title Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period
Measure Description Event rate=Number of events divided by the number of patients evaluated. Intended treatment period starts on the day of randomization, and for those who received study drug, ends at the later of 2 days after last dose or 14 days after the first dose of study drug; for randomized patients who did not receive study drug, the period ends 14 days after randomization.Venous thromboembolic event (VTE)=nonfatal pulmonary embolism (PE), symptomatic deep vein thrombosis (DVT), or asymptomatic proximal DVT detected by ultrasound. VTE-related death=fatal PE or sudden death for which VTE could not be excluded as a cause.
Time Frame Day of randomization to later of 2 days after last dose or 14 days after first dose; 14 days after randomization for those who did not receive study drug  
Safety Issue No  

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.
The primary efficacy data set (all randomized participants who, during the Intended Treatment Period, had an adjudicated and evaluable bilateral venogram, an adjudicated venous thrombolytic event; or died due to any cause.)

Reporting Groups
  Description
Apixaban, 2.5 mg BID Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD)
Enoxaparin, 40 mg QD Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID

Measured Values
    Apixaban, 2.5 mg BID     Enoxaparin, 40 mg QD  
Number of Participants Analyzed  
[units: participants]
  976     997  
Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period  
[units: Percentage of events/patients evaluated]
Number ( 95% Confidence Interval )
  15.06  
  ( 12.95 to 17.46 )  
  24.37  
  ( 21.81 to 27.14 )  


Statistical Analysis 1 for Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period
Groups [1] All groups
Method [2] Yanagawa, Tango, and Hiejima test
P Value [3] <0.0001
Risk Ratio (RR) [4] 0.62
95% Confidence Interval ( 0.51 to 0.74 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Sequential testing was used to control for overall type-I error and to compare the effect of apixaban with that of enoxaparin. Noninferiority (NI) of apixaban compared with enoxaparin for primary endpoint was tested first at 1-sided α=0.025 level. If NI on primary endpoint was demonstrated, superiority for the endpoint was then tested at 1-sided α=0.025 level. If superiority was demonstrated on the primary endpoint, NI was then tested on the key secondary endpoint at 1-sided α=0.025 level.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value was statistically significant at the 1-sided 0.025 level
[4] Other relevant estimation information:
  Apixaban-enoxaparin

Statistical Analysis 2 for Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period
Groups [1] All groups
Method [2] Yanagawa, Tango, and Hiejima test
P Value [3] <0.0001
Risk Difference (RD) [4] -9.27
95% Confidence Interval ( -12.74 to -5.79 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Sequential testing was used to control for overall type-I error and to compare the effect of apixaban with that of enoxaparin. Noninferiority (NI) of apixaban compared with enoxaparin for primary endpoint was tested first at 1-sided α=0.025 level. If NI on primary endpoint was demonstrated, superiority for the endpoint was then tested at 1-sided α=0.025 level. If superiority was demonstrated on the primary endpoint, NI was then tested on the key secondary endpoint at 1-sided α=0.025 level.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  P-value is statistically significant at the 1-sided 0.025 level
[4] Other relevant estimation information:
  Apixaban-enoxaparin



2.  Secondary:   Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period   [ Time Frame: Day of randomization to later of 2 days after last dose or 14 days after first dose; 14 days after randomization for those who did not receive study ]

3.  Secondary:   Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), and Major Bleeding or CRNM   [ Time Frame: Days 1 to 12 ]

4.  Secondary:   Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome   [ Time Frame: Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug ]

5.  Other Pre-specified:   Summary of Laboratory Marked Abnormalities on Hematology and Liver and Kidney Function Test Results During the Treatment Period (Patients With Available Measurements)   [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up ]

6.  Other Pre-specified:   Summary of Laboratory Marked Abnormalities in Electrolyte and Other Clinical Test Results During the Treatment Period (Patients With Available Measurements)   [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (±5 days) of follow-up ]

7.  Other Pre-specified:   Summary of Laboratory Marked Abnormalities in Urinalysis Results During the Treatment Period-Treated Subjects With Available Measurements (Urinalysis)   [ Time Frame: Randomization to Days 2, 3, 4, and 12 (±2 days) and at Days 42 and 72 (± 5 days) of follow-up ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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
No text entered.


  More Information
  Hide More Information

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: NCT00452530     History of Changes
Other Study ID Numbers: CV185-047, EUdraCT: 2006-006896-19
Study First Received: March 23, 2007
Results First Received: April 14, 2014
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration