Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study (The APEX Study) (APEX)

• ClinicalTrials.gov Identifier: NCT01583218
• Recruitment Status: Completed
• First Posted: April 23, 2012
• Results First Posted: September 20, 2017
• Last Update Posted: September 26, 2018
• Sponsor: Portola Pharmaceuticals
• Information provided by (Responsible Party): Portola Pharmaceuticals

Tracking Information

• First Submitted Date: April 16, 2012
• First Posted Date: April 23, 2012
• Results First Submitted Date: July 19, 2017
• Results First Posted Date: September 20, 2017
• Last Update Posted Date: September 26, 2018
• Study Start Date: March 2012
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2017)

• Modified Intent-to-Treat (mITT) Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic Deep Vein Thrombosis (DVT), Non-fatal Pulmonary Emboli (PE), VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 [ Time Frame: mITT Cohort 1: Between randomization and Day 47 (max) ]
  mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, venous thromboembolism (VTE) related death adjudicated by a blinded independent Clinical Events Committee (CEC) between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
• mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 [ Time Frame: mITT Cohort 2: Between randomization and Day 47 (max) ]
  mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
• mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, VTE-related Death, or Asymptomatic Proximal DVT, Through Visit 3 [ Time Frame: mITT: Between randomization and Day 47 (max) ]
  mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3, or a blinded ultrasound core laboratory measuring of asymptomatic proximal DVT between randomization and Day 47. Visit 3 is between day 35-42 after randomization (day 1).
• Percentage of Participants Experiencing Major Bleeding Through Seven Days After Discontinuation of All Study Medication [ Time Frame: Between randomization and Day 49 (max) ]
  Percentage of participants experiencing at least one major bleeding adjudicated by a blinded independent CEC between randomization (day 1) and up to seven days after discontinuation of all study medication.

• Original Primary Outcome Measures (submitted: April 19, 2012): Composite of VTE (DVT and/or PE) and VTE Death [ Time Frame: Occurrence of any of the events through the Day 35 visit ]

Current Secondary Outcome Measures (submitted: September 18, 2017)

• mITT Cohort 1: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 [ Time Frame: mITT Cohort 1: Between randomization and Day 42 (max) ]
  mITT Cohort 1: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
• mITT Cohort 2: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 [ Time Frame: mITT Cohort 2: Between randomization and Day 42 (max) ]
  mITT Cohort 2: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).
• mITT: Percentage of Participants Experiencing the Composite Event of Symptomatic DVT, Non-fatal PE, or VTE-related Death, Through Visit 3 [ Time Frame: mITT: Between randomization and Day 42 (max) ]
  mITT: Percentage of participants experiencing either symptomatic DVT, non-fatal PE, or VTE related death adjudicated by a blinded independent CEC between randomization and on or before Visit 3 or Day 42 if patient did not have a Visit 3. Visit 3 is between day 35-42 after randomization (day 1).

• Original Secondary Outcome Measures (submitted: April 19, 2012): Number of patients with symptomatic VTE [ Time Frame: The occurrence through the Day 35 visit ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study (The APEX Study)
• Official Title: (Apex) Multicenter, Randomized, Active-Controlled Efficacy And Safety Study Comparing Extended Duration Betrixaban With Standard Of Care Enoxaparin For The Prevention Of Venous Thromboembolism In Acute Medically Ill Patients
• Brief Summary: The purpose of this study is to evaluate whether extended prophylaxis with oral betrixaban can prevent blood clots in the leg and lung that sometime occur in patients hospitalized for an acute medical illness and to compare these results with standard of care enoxaparin. The safety of betrixaban will also be studied.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Venous Thromboembolism (VTE)

Intervention

• Drug: Betrixaban

  Betrixaban 80 mg PO once daily (QD) for 35 day + 7 days.

  Enoxaparin Placebo: Once daily, 6-14 days

• Drug: Enoxaparin

  Enoxaparin 40 mg subcutaneous (SC) QD for 10 ± 4 days.

  Betrixaban Placebo: once daily, 35 days

Study Arms

• Experimental: Betrixaban
  Daily oral (PO) betrixaban capsules for 35 to 42 days and subcutaneous (SQ) injections of enoxaparin placebo for 10 ± 4 days
  Intervention: Drug: Betrixaban
• Active Comparator: Enoxaparin
  Daily subcutaneous (SQ) injections of enoxaparin for 10 ± 4 days and oral (PO) betrixaban placebo capsules for 35 to 42 days
  Intervention: Drug: Enoxaparin

Publications *

• Jamil A, Jamil U, Singh K, Khan F, Chi G. Extended Thromboprophylaxis With Betrixaban or Rivaroxaban for Acutely Ill Hospitalized Medical Patients: Meta-Analysis of Prespecified Subgroups. Crit Pathw Cardiol. 2021 Mar 1;20(1):16-24. doi: 10.1097/HPC.0000000000000232.
• Yee MK, Gibson CM, Nafee T, Kerneis M, Daaboul Y, Korjian S, Chi G, AlKhalfan F, Hernandez AF, Hull RD, Cohen AT, Goldhaber SZ. Characterization of Major and Clinically Relevant Non-Major Bleeds in the APEX Trial. TH Open. 2019 Apr 17;3(2):e103-e108. doi: 10.1055/s-0039-1685496. eCollection 2019 Apr.
• Guy H, Laskier V, Fisher M, Bucior I, Deitelzweig S, Cohen AT. Budget impact analysis of betrixaban for venous thromboembolism prophylaxis in nonsurgical patients with acute medical illness in the United Kingdom. Expert Rev Pharmacoecon Outcomes Res. 2020 Jun;20(3):259-267. doi: 10.1080/14737167.2019.1629905. Epub 2019 Jun 19.
• Chi G, Gibson CM, Kalayci A, Cohen AT, Hernandez AF, Hull RD, Kahe F, Jafarizade M, Sharfaei S, Liu Y, Harrington RA, Goldhaber SZ. Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy. Intensive Care Med. 2019 Apr;45(4):477-487. doi: 10.1007/s00134-019-05565-6. Epub 2019 Feb 18.
• Kalayci A, Gibson CM, Chi G, Yee MK, Korjian S, Datta S, Nafee T, Gurin M, Haroian N, Qamar I, Hull RD, Hernandez AF, Cohen AT, Harrington RA, Goldhaber SZ. Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. Thromb Haemost. 2018 Dec;118(12):2046-2052. doi: 10.1055/s-0038-1675606. Epub 2018 Nov 12.
• Chi G, Gibson CM, Liu Y, Hernandez AF, Hull RD, Cohen AT, Harrington RA, Goldhaber SZ. Inverse relationship of serum albumin to the risk of venous thromboembolism among acutely ill hospitalized patients: Analysis from the APEX trial. Am J Hematol. 2019 Jan;94(1):21-28. doi: 10.1002/ajh.25296. Epub 2018 Oct 17.
• Chi G, Goldhaber SZ, Hull RD, Hernandez AF, Kerneis M, Al Khalfan F, Cohen AT, Harrington RA, Gibson CM. Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial. Thromb Haemost. 2017 Dec;117(12):2389-2395. doi: 10.1160/TH17-08-0538. Epub 2017 Dec 6.
• Yee MK, Nafee T, Daaboul Y, Korjian S, AlKhalfan F, Kerneis M, Wiest C, Goldhaber SZ, Hernandez AF, Hull RD, Cohen AT, Harrington RA, Gibson CM. Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial. J Thromb Thrombolysis. 2018 Jan;45(1):1-8. doi: 10.1007/s11239-017-1583-0.
• Chi G, Januzzi JL, Korjian S, Daaboul Y, Goldhaber SZ, Hernandez AF, Hull RD, Gold A, Cohen AT, Harrington RA, Gibson CM. N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy. J Thromb Thrombolysis. 2017 Nov;44(4):457-465. doi: 10.1007/s11239-017-1552-7.
• Arbetter DF, Jain P, Yee MK, Michalak N, Hernandez AF, Hull RD, Goldhaber SZ, Harrington RA, Gold A, Cohen AT, Gibson CM. Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy. Pharm Stat. 2017 Nov;16(6):445-450. doi: 10.1002/pst.1823. Epub 2017 Aug 24.
• Chi G, Goldhaber SZ, Kittelson JM, Turpie AGG, Hernandez AF, Hull RD, Gold A, Curnutte JT, Cohen AT, Harrington RA, Gibson CM. Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. J Thromb Haemost. 2017 Oct;15(10):1913-1922. doi: 10.1111/jth.13783. Epub 2017 Sep 4.
• Gibson CM, Korjian S, Chi G, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Lopes RD, Gold A, Cohen AT, Harrington RA; APEX Investigators. Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy. J Am Heart Assoc. 2017 Jul 11;6(7):e006015. doi: 10.1161/JAHA.117.006015.
• Gibson CM, Goldhaber SZ, Cohen AT, Nafee T, Hernandez AF, Hull R, Korjian S, Daaboul Y, Chi G, Yee M, Harrington RA. When academic research organizations and clinical research organizations disagree: Processes to minimize discrepancies prior to unblinding of randomized trials. Am Heart J. 2017 Jul;189:1-8. doi: 10.1016/j.ahj.2017.03.018. Epub 2017 Mar 31. No abstract available.
• Marszalek J, Mehrsefat S, Chi G. The risk of stroke among acutely ill hospitalized medical patients: lessons from recent trials on extended-duration thromboprophylaxis. Expert Rev Hematol. 2017 Aug;10(8):679-684. doi: 10.1080/17474086.2017.1343662. Epub 2017 Jun 21.
• Gibson CM, Chi G, Halaby R, Korjian S, Daaboul Y, Jain P, Arbetter D, Goldhaber SZ, Hull R, Hernandez AF, Gold A, Bandman O, Harrington RA, Cohen AT; APEX Investigators. Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation. 2017 Feb 14;135(7):648-655. doi: 10.1161/CIRCULATIONAHA.116.025427. Epub 2016 Nov 14.
• Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016 Aug 11;375(6):534-44. doi: 10.1056/NEJMoa1601747. Epub 2016 May 27.
• Cohen AT, Harrington R, Goldhaber SZ, Hull R, Gibson CM, Hernandez AF, Kitt MM, Lorenz TJ. The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. Am Heart J. 2014 Mar;167(3):335-41. doi: 10.1016/j.ahj.2013.11.006. Epub 2013 Dec 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 18, 2017): 7513
• Original Estimated Enrollment (submitted: April 19, 2012): 6850
• Actual Study Completion Date: January 2016
• Actual Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• men and non-pregnant, non-breastfeeding women
• anticipated to be severely immobilized for at least 24 hours after randomization

• hospitalized with one of the following

  • congestive heart failure
  • acute respiratory failure,
  • acute infection without septic shock,
  • acute rheumatic disorders
  • acute ischemic stroke with lower extremity hemiparesis or hemi paralysis

Exclusion Criteria:

• a condition requiring prolonged anticoagulation or anti-platelets
• active bleeding or at high risk of bleeding
• contraindication to anticoagulant therapy
• general conditions in which subjects are not suitable to participate in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Croatia, Czechia, Denmark, Estonia, Finland, France, Georgia, Germany, Hungary, Israel, Italy, Latvia, Lithuania, Montserrat, Peru, Poland, Romania, Russian Federation, Serbia, Singapore, Slovakia, South Africa, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01583218
• Other Study ID Numbers: 11-019
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Portola Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Portola Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Portola Pharmaceuticals
• Verification Date: June 2016