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

History of Changes

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

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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
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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

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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.
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

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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 ]

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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 ]

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3. Secondary:

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

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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 ]

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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 ]

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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 ]

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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 ]

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Serious Adverse Events

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Other Adverse Events

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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication

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:

Pineo GF, Gallus AS, Raskob GE, Chen D, Ramirez LM, Ramacciotti E, Lassen MR, Wang L. Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups. J Thromb Haemost. 2013 Mar;11(3):444-51. doi: 10.1111/jth.12109.

Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15. doi: 10.1016/S0140-6736(09)62125-5.

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

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