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 ]

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
  Hide Serious Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Reporting Groups
  Description
Apixiban, 2.5 mg BID Plus 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 Plus Placebo Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID

Serious Adverse Events
    Apixiban, 2.5 mg BID Plus Placebo     Enoxaparin, 40 mg QD Plus Placebo  
Total, serious adverse events      
# participants affected / at risk     72/1501 (4.80%)     88/1508 (5.84%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     2/1501 (0.13%)     1/1508 (0.07%)  
Thrombocytopenia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Coagulopathy † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Cardiac disorders      
Ventricular extrasystoles † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Atrial flutter † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Myocardial ischaemia † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Cardiac failure congestive † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Angina pectoris † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Bradycardia † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Supraventricular tachycardia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Acute left ventricular failure † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Palpitations † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Atrial fibrillation † 1    
# participants affected / at risk     1/1501 (0.07%)     5/1508 (0.33%)  
Ventricular tachycardia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Ear and labyrinth disorders      
Vertigo † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Gastrointestinal disorders      
Duodenal ulcer † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Gastrointestinal haemorrhage † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Ileus paralytic † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Duodenal ulcer haemorrhage † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Gastritis † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Intra-abdominal haematoma † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Rectal haemorrhage † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Small intestinal obstruction † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Faecaloma † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
General disorders      
Oedema peripheral † 1    
# participants affected / at risk     2/1501 (0.13%)     2/1508 (0.13%)  
Injection site extravasation † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Pyrexia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Death † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Catheter related complication † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Multi-organ failure † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Hepatobiliary disorders      
Hepatitis † 1    
# participants affected / at risk     2/1501 (0.13%)     0/1508 (0.00%)  
Cholecystitis acute † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Cholelithiasis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Hepatic ischaemia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Immune system disorders      
Anaphylactic reaction † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Infections and infestations      
Subcutaneous abscess † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Erysipelas † 1    
# participants affected / at risk     2/1501 (0.13%)     1/1508 (0.07%)  
Gastroenteritis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Lower respiratory tract infection † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Respiratory tract infection viral † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Arthritis bacterial † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Bronchitis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Bronchopneumonia † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Post procedural infection † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Wound sepsis † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Device related infection † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Postoperative wound infection † 1    
# participants affected / at risk     3/1501 (0.20%)     1/1508 (0.07%)  
Tuberculosis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Localised infection † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Staphylococcal infection † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Wound infection † 1    
# participants affected / at risk     2/1501 (0.13%)     4/1508 (0.27%)  
Injury, poisoning and procedural complications      
Overdose † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Suture related complication † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Device dislocation † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Foreign body trauma † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Post procedural haematoma † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Post procedural haemorrhage † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Procedural pain † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Wound † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Hip fracture † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Fall † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Operative haemorrhage † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Post procedural complication † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Femur fracture † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Incision site haemorrhage † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Tendon rupture † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Wound dehiscence † 1    
# participants affected / at risk     2/1501 (0.13%)     0/1508 (0.00%)  
Tibia fracture † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Investigations      
Creatinine renal clearance decreased † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Platelet count increased † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Body temperature increased † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Oxygen saturation decreased † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Haemoglobin decreased † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Hepatic enzyme increased † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Metabolism and nutrition disorders      
Malnutrition † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Metabolic acidosis † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Hyponatraemia † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Musculoskeletal and connective tissue disorders      
Fistula † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Joint stiffness † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Joint swelling † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Myalgia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Osteoarthritis † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Arthralgia † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Haemarthrosis † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Joint range of motion decreased † 1    
# participants affected / at risk     1/1501 (0.07%)     1/1508 (0.07%)  
Nervous system disorders      
Hypokinesia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Cerebrovascular accident † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Cerebral infarction † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Senile dementia † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Cerebrovascular insufficiency † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Renal and urinary disorders      
Renal failure acute † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Renal failure † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Reproductive system and breast disorders      
Benign prostatic hyperplasia † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Respiratory, thoracic and mediastinal disorders      
Epistaxis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Respiratory acidosis † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Dyspnoea † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Pulmonary embolism † 1    
# participants affected / at risk     5/1501 (0.33%)     1/1508 (0.07%)  
Atelectasis † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Skin and subcutaneous tissue disorders      
Angioedema † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Vascular disorders      
Hypertensive crisis † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Wound haemorrhage † 1    
# participants affected / at risk     2/1501 (0.13%)     0/1508 (0.00%)  
Hypertension † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Varicose vein † 1    
# participants affected / at risk     1/1501 (0.07%)     0/1508 (0.00%)  
Haemorrhage † 1    
# participants affected / at risk     4/1501 (0.27%)     3/1508 (0.20%)  
Hypotension † 1    
# participants affected / at risk     0/1501 (0.00%)     1/1508 (0.07%)  
Haematoma † 1    
# participants affected / at risk     0/1501 (0.00%)     2/1508 (0.13%)  
Deep vein thrombosis † 1    
# participants affected / at risk     11/1501 (0.73%)     22/1508 (1.46%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 11.1




  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