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Deep Vein ThrombosisPhase 3ADVANCE-2NCT00452530

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

A Phase 3 study testing Enoxaparin and Apixaban in people with Deep Vein Thrombosis and Pulmonary Embolism, run by Bristol-Myers Squibb at 122 sites in 27 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The purpose of this study is to learn whether apixaban prevents the development of blood clots in the leg (deep vein thrombosis) and lung (pulmonary embolism), which sometimes occur after knee replacement surgery, and to compare the efficacy of apixaban with that of enoxaparin (Lovenox®) in the prevention of these… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Deep Vein Thrombosis, Pulmonary Embolism
What is being tested?
Enoxaparin and Apixaban
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
3,221 participants
Where
122 sitesin 27 countries
Study dates
Jun 2007to Jan 2009
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients scheduled for either elective unilateral or same-day bilateral total knee replacement surgery (TKR) or a revision of at least 1 component of a TKR
  • Patients willing and able to undergo bilateral ascending contrast venography

Who cannot join

  • Known or suspected hereditary or acquired bleeding or coagulation disorders in the participant or his or her first-degree relative
  • Known or suspected history of heparin-induced thrombocytopenia
  • Known coagulopathy
  • Active bleeding or at high risk for bleeding
  • Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days
  • Active hepatobiliary disease
Show all 14Show fewer
  • Alcohol and/or substance abuse within the past year
  • Any condition for which, in the opinion of the investigator, surgery or administration of an anticoagulant was contraindicated
  • Two consecutive blood pressure readings within 15 to 30 minutes with supine systolic blood pressure >180 mm Hg or supine diastolic blood pressure >105 mm Hg
  • Clinically significant laboratory abnormalities at the enrollment visit:
  • Hemoglobin <10 g/dL
  • Platelet count <100,000/mm^3
  • Creatinine clearance <30 mL/min, as estimated by the method of Cockcroft and Gault
  • Alanine aminotransferase or aspartate aminotransferase level >2*upper limit of normal (ULN) or a total bilirubin ≥1.5*ULN (unless an alternative causative factor such as Gilbert's syndrome was identified)

Trial locations and contacts

122 sites in 27 countries.

122 sites in 27 countries

Germany10 sites

  • Local Institution

    Bad Mergentheim, 97980

  • Local Institution

    Bochum, 44791

  • Local Institution

    Brandenburg, 14770

  • Local Institution

    Dresden, 01307

  • Local Institution

    Frankfurt, 65929

  • Local Institution

    Frankfurt am Main, 60528

  • Local Institution

    Halle/S, 06112

  • Local Institution

    Kremmen Ot Sommerfeld, 16766

  • Local Institution

    Rheinfelden, 79618

  • Local Institution

    Witten, 58455

Other trials in Germany

Russia10 sites

  • Local Institution

    Chelyabinsk, 454021

  • Local Institution

    Kazan', 420029

  • Local Institution

    Lipetsk, 398035

  • Local Institution

    Moscow, 115522

  • Local Institution

    Rostov-on-Don, 344010

  • Local Institution

    Saint Petersburg, 193312

  • Local Institution

    Saint Petersburg, 194354

  • Local Institution

    Saint Petersburg, 195427

  • Local Institution

    Saint Petersburg, 199106

  • Local Institution

    Samara, 443095

Other trials in Russia

Austria7 sites

  • Local Institution

    Graz, 8036

  • Local Institution

    Innsbruck, 6020

  • Local Institution

    Linz, 4010

  • Local Institution

    Vienna, 1090

  • Local Institution

    Vienna, 1130

  • Local Institution

    Wels, 4600

  • Local Institution

    Wiener Neustadt, 2700

Other trials in Austria

South Africa7 sites

  • Local Institution

    Johannesburg, Gauteng, 2031

  • Local Institution

    Johannesburg, Gauteng, 2193

  • Local Institution

    Pretoria, Gauteng, 0083

  • Local Institution

    Randburg, Free State, 2194

  • Local Institution

    Somerset West, Western Cape, 7130

  • Local Institution

    Tygerberg, Western Cape, 7505

  • Local Institution

    Worcester, Western Cape, 6850

Other trials in South Africa

Spain7 sites

  • Local Institution

    Badalona-Barcelona, 08916

  • Local Institution

    Barcelona, 08006

  • Local Institution

    Barcelona, 08024

  • Local Institution

    Barcelona, 08035

  • Local Institution

    Madrid, 28034

  • Local Institution

    Santiago de Compostela, 15706

  • Local Institution

    Valencia, 46010

Other trials in Spain

Ukraine7 sites

  • Local Institution

    Cherkassy, 18009

  • Local Institution

    Chernivtsy, 58013

  • Local Institution

    Dnipropetrovsk, 49005

  • Local Institution

    Ivano-Frankivsk, 76008

  • Local Institution

    Kyiv, 01601

  • Local Institution

    Kyiv, 04107

  • Local Institution

    Sevastopol, 99018

Other trials in Ukraine

China6 sites

  • Local Institution

    Beijing, Beijing Municipality, 100035

  • Local Institution

    Beijing, Beijing Municipality, 100835

  • Local Institution

    Qingdao, Shandong, 266003

  • Local Institution

    Shanghai, Shanghai Municipality, 200011

  • Local Institution

    Shanghai, Shanghai Municipality, 200025

  • Local Institution

    Shanghai, Shanghai Municipality, 200233

Other trials in China

France6 sites

  • Local Institution

    Monaco, 98000

  • Local Institution

    Nice, 06200

  • Local Institution

    Paris, 75014

  • Local Institution

    Paris, 75019

  • Local Institution

    Paris, 75679

  • Local Institution

    Saint-Saulve, 59880

Other trials in France

Czechia5 sites

  • Local Institution

    Brno, 662 50

  • Local Institution

    Chomutov, 430 12

  • Local Institution

    Pardubice, 532 03

  • Local Institution

    Prague, 180 81

  • Local Institution

    Uherské Hradiště, 686 68

Other trials in Czechia

India5 sites

  • Local Institution

    Ahmedabad, Gujarat, 380054

  • Local Institution

    Bangalore, 560034

  • Local Institution

    Baroda, 390007

  • Local Institution

    Ludhiana, Punjab, 141001

  • Local Institution

    Mangalore, 575001

Other trials in India

Israel5 sites

  • Local Institution

    Jeruselem, 91031

  • Local Institution

    Petah Tikva, 49372

  • Local Institution

    Safed, 13110

  • Local Institution

    Tel Aviv, 64239

  • Local Institution

    Tel HaShomer, 52621

Other trials in Israel

Italy5 sites

  • Local Institution

    Abano Terme (Pd), 35031

  • Local Institution

    Bologna, 40136

  • Local Institution

    Pordenone, 33170

  • Local Institution

    Roma, 00168

  • Local Institution

    San Donato Milanese (Mi), 20097

Other trials in Italy

Mexico5 sites

  • Local Institution

    Aguascalientes, Aguascalientes, 20010

  • Local Institution

    Hermosillo, Sonora, 83190

  • Local Institution

    San Luis Potosí City, San Luis Potosí, 78340

  • Local Institution

    Veracruz, Veracruz, 91700

  • Local Institution

    Zapopan, Jalisco, 45200

Other trials in Mexico

Colombia4 sites

  • Local Institution

    Bogotá, XXXXX

  • Local Institution

    Bogotá

  • Local Institution

    Cali

  • Local Institution

    Medellín

Other trials in Colombia

Denmark4 sites

  • Local Institution

    Hellerup, 2900

  • Local Institution

    Hvidovre, 2650

  • Local Institution

    Kolding, 6000

  • Local Institution

    Viborg, 8800

Other trials in Denmark

Poland4 sites

  • Local Institution

    Bytom, 41-902

  • Local Institution

    Gdansk, 80-803

  • Local Institution

    Warsaw, 03-242

  • Local Institution

    Wroclaw, 50-556

Other trials in Poland

South Korea4 sites

  • Local Institution

    Jeonnam, 519-809

  • Local Institution

    Seoul, 110-744

  • Local Institution

    Seoul, 136-705

  • Local Institution

    Seoul, 138-736

Other trials in South Korea

Norway3 sites

  • Local Institution

    Ålesund, 6026

  • Local Institution

    Gjettum, 1346

  • Local Institution

    Kongsvinger, 2212

Other trials in Norway

Philippines3 sites

  • Local Institution

    Manila, 1000

  • Local Institution

    Quezon City, 1102

  • Local Institution

    Quezon City, 1114

Other trials in Philippines

Belgium2 sites

  • Local Institution

    Antwerp, 2020

  • Local Institution

    Hasselt, 3500

Other trials in Belgium

Brazil2 sites

  • Local Institution

    Belo Horizonte - Mg, Minas Gerais, 30130

  • Local Institution

    São Paulo, São Paulo, 04023

Other trials in Brazil

Chile2 sites

  • Local Institution

    Santiago, Santiago Metropolitan, 7500922

  • Local Institution

    Santiago, Santiago Metropolitan, 8330033

Other trials in Chile

Hungary2 sites

  • Local Institution

    Szeged, 6725

  • Local Institution

    Szekszárd, 7100

Other trials in Hungary

Malaysia2 sites

  • Local Institution

    Kuala Lumpur, Kuala Lumpur, 50586

  • Local Institution

    Kuala Lumpur, Kuala Lumpur, 56000

Other trials in Malaysia

Singapore2 sites

  • Local Institution

    Singapore, 169608

  • Local Institution

    Singapore, 529889

Other trials in Singapore

United Kingdom2 sites

  • Local Institution

    Epsom, Surrey, KT18 7EG

  • Local Institution

    London, Greater London, SE5 9PJ

Other trials in United Kingdom

Sweden1 site

  • Local Institution

    Borås, 501 82

Other trials in Sweden

About this study

Official title: A Phase 3, Randomized, Double-blind, Active-controlled (Enoxaparin 40 mg QD), Parallel-group, Multi-center Study to Evaluate the Safety and Efficacy of Apixaban in Subjects Undergoing Elective Total Knee Replacement Surgery (The ADVANCE - 2 Study)

The purpose of this study is to learn whether apixaban prevents the development of blood clots in the leg (deep vein thrombosis) and lung (pulmonary embolism), which sometimes occur after knee replacement surgery, and to compare the efficacy of apixaban with that of enoxaparin (Lovenox®) in the prevention of these clots. The safety of apixaban will also be studied.

Being tested
Enoxaparin, Apixaban, Enoxaparin-matching placebo, Apixaban-matching placebo
Keywords
Prevention of deep vein thrombosis and pulmonary embolism after total knee replacement surgery
Medical subject headings
Venous Thrombosis, Pulmonary Embolism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EnoxaparinDrug

    Also called Lovenox®

    40 mg, administered once daily by subcutaneous injection, for 12 days

  • ApixabanDrug

    Also called BMS-562247

    2.5 mg, administered twice daily as tablets, for 12 days

  • Enoxaparin-matching placeboDrug

    Administered once daily by subcutaneous injection

  • Apixaban-matching placeboDrug

    Oral tablet administered twice daily

Study groups in NCT00452530
Study groupRoleWhat they receive
Apixaban, 2.5 mg BID + PlaceboExperimentalParticipants received apixaban, 2.5-mg tablets twice daily (BID), plus a matching enoxaparin-placebo injection 12 (±3) hours prior to hip-replacement surgery through 11 (±2) days after the day of surgery.
Receives: Drug: Apixaban; Drug: Enoxaparin-matching placebo
Enoxaparin, 40 mg QD + PlaceboActive comparatorParticipants received enoxaparin, 40-mg subcutaneous injection once daily (QD), plus a matching apixaban-placebo tablet 12 (±3) hours prior to hip-replacement surgery through 11 (±2) days after the day of surgery.
Receives: Drug: Enoxaparin; Drug: Apixaban-matching placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Rate of Adjudicated Venous Thromboembolic Event-related and All-cause Deaths With Onset During the Intended-treatment Period

    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.

    Measured: 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

Secondary outcomes (3)

  1. Rate of Adjudicated Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism, and Venous Thromboembolic Event-related Death With Onset During the Intended Treatment Period

    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; 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 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.

    Measured: 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

  2. Rate of Major Bleeding, Clinically Relevant Nonmajor Bleeding (CRNM), and Major Bleeding or CRNM

    Event rate=Number of events divided by number of patients evaluated. Adjusted difference of event rates takes into consideration type of surgery as a stratification factor. Bleeding Criteria: Major bleeding=an event consisting of clinically overt bleeding accompanied by a decrease in hemoglobin of 2 g/dL or more and/or a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least 1 of the following critical sites: intracranial, intraspinal, intraocular (within the corpus of the eye; a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, and retroperitoneal; bleeding that was fatal. CRNM bleeding= clinically overt bleeding; that satisfies none of the additional criteria required for the event to be adjudicated as a major bleeding event; that led to either hospital admission for bleeding, physician-guided medical or surgical treatment for bleeding; or a change in antithrombic treatment.

    Measured: Days 1 to 12

  3. Number of Participants With Serious Adverse Events (SAE), Bleeding Adverse Events (AEs), Discontinuations Due to AEs, and Death as Outcome

    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Bleeding AEs=all serious or nonserious bleeding-related AEs.

    Measured: Days 1 through 12 + 2 days (nonserious AEs, bleeding AES) or 30 days (SAES, deaths) after last dose of study drug

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Mar 2007 (estimated)
  2. Study startJun 2007
  3. Primary completionJan 2009
  4. Study completionJan 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
3,221 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00452530
Sponsor's protocol ID
CV185-047
Other IDs
EUdraCT: 2006-006896-19
Acronym
ADVANCE-2
Status last verified
Jul 2014
First submitted
23 Mar 2007
Last updated
9 Jul 2014
Data monitoring committee
Yes

Publications

  • Jamieson MJ, Byon W, Dettloff RW, Crawford M, Gargalovic PS, Merali SJ, Onorato J, Quintero AJ, Russ C. Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data. Am J Cardiovasc Drugs. 2022 Nov;22(6):615-631. doi: 10.1007/s40256-022-00524-x. Epub 2022 May 16.

    PubMed 35570249

  • 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.

    PubMed 23279103

  • 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.

    PubMed 20206776

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Enoxaparin and Apixaban in people with Deep Vein Thrombosis and Pulmonary Embolism, run by Bristol-Myers Squibb at 122 sites in 27 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Jul 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 122 sites in Germany, Russia, Austria, South Africa, Spain and 22 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 May 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00452530, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2014.

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