Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack (PACIFIC-AMI)

• ClinicalTrials.gov Identifier: NCT04304534
• Recruitment Status: Completed
• First Posted: March 11, 2020
• Results First Posted: April 5, 2023
• Last Update Posted: April 5, 2023
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 8, 2020
• First Posted Date: March 11, 2020
• Results First Submitted Date: February 19, 2023
• Results First Posted Date: April 5, 2023
• Last Update Posted Date: April 5, 2023
• Actual Study Start Date: June 17, 2020
• Actual Primary Completion Date: February 21, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 19, 2023)

• Efficacy - Number of Participants With Composite of CV Death, MI, Stroke and Stent Thrombosis (ST) [ Time Frame: From baseline up to 52 weeks ]
  CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. ST was defined incorporating diagnostic certainty as well as timing: "Definite" ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. "Probable" ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
• Safety - Number of Participants With BARC Bleeding Definition Type 2, 3 and 5 [ Time Frame: From baseline up to 52 weeks ]
  Type 2: any overt, actionable sign of hemorrhage that doesn't fit the criteria for type 3 or 5 but meets at least one of the following criteria: 1) requires nonsurgical, med intervention by a HCP, 2) leads to hospital or rise in level of care, or 3) prompt eval. Type 3a: 1) overt bleed + Hg drop of 3 to <5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation.

Original Primary Outcome Measures (submitted: March 8, 2020)

• Time from randomization to first occurrence of any of the components of the composite outcome including Cardiovascular (CV) death, Myocardial infarction (MI), stroke and stent thrombosis [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of Bleeding Academic Research Consortium (BARC) bleeding definition type 2, 3 and 5 [ Time Frame: From baseline up to 12 months ]

Current Secondary Outcome Measures (submitted: February 19, 2023)

• Efficacy - Number of Participants With CV Death [ Time Frame: From baseline up to 52 weeks ]
  CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included.
• Efficacy - Number of Participants With MI [ Time Frame: From baseline up to 52 weeks ]
  Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. According to MI Universal Definition from 2018 the diagnosis of MI requires combination of: 1. Presence of acute myocardial injury. 2. Evidence of acute myocardial ischemia derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging, or in case of post-mortem pathological findings irrespective of biomarker values.
• Efficacy - Number of Participants With Stroke [ Time Frame: From baseline up to 52 weeks ]
  Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction.
• Efficacy - Number of Participants With Stent Thrombosis [ Time Frame: From baseline up to 52 weeks ]
  ST was defined incorporating diagnostic certainty as well as timing: "Definite" ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. "Probable" ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
• Efficacy - Number of Participants With All Cause Mortality [ Time Frame: From baseline up to 52 weeks ]
• Safety - Number of Participants With All Bleeding [ Time Frame: From baseline up to 52 weeks ]
  All bleeding events occurred from first intake of study intervention until 2 days after the last intake of study intervention
• Safety - Number of Participants With BARC Bleeding Definition Type 3, 5 [ Time Frame: From baseline up to 52 weeks ]
  Type 3a: 1) overt bleed + Hg drop of 3 to <5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn't include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation.
• Safety - Number of Participants With BARC Bleeding Definition Type 1,2,3,5 [ Time Frame: From baseline up to 52 weeks ]
  Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional. For BARC bleeding definition 2,3 and 5, please refer to second primary endpoint.

Original Secondary Outcome Measures (submitted: March 8, 2020)

• Time from randomization to death (all cause mortality) [ Time Frame: From baseline up to 12 months ]
• Time from randomization to CV death [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of MI [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of stroke (ischemic and hemorrhagic) [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of stent thrombosis [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of all bleeding [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of BARC bleeding definition Type 3, 5 [ Time Frame: From baseline up to 12 months ]
• Time from randomization to first occurrence of BARC bleeding definition Type 1, 2, 3, 5 [ Time Frame: From baseline up to 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack
• Official Title: Multicenter, Randomized, Placebo Controlled, Double-blind, Parallel Group, Dose-finding Phase 2 Study to Evaluate the Efficacy and Safety of BAY 2433334 in Patients Following an Acute Myocardial Infarction
• Brief Summary: The purpose of this study is to try to find the best dose of the new drug BAY 2433334 to give to participants and to look at how well BAY 2433334 works on top of a dual antiplatelet therapy (acetylsalicylic acid +/- clopidogrel) in patients following a recent heart attack (myocardial infarction) that happens when a blood vessel in the heart suddenly becomes blocked. BAY 2433334, works by blocking a step of the blood clotting process in our body and thins the blood and is a so called oral FXIa inhibitor.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Myocardial Infarction

Intervention

• Drug: BAY2433334
  Tablet, taken orally once a day.
• Other: BAY2433334 matching placebo
  Tablet, taken orally once a day.

Study Arms

• Experimental: BAY 2433334 high dose
  Intervention: Drug: BAY2433334
• Experimental: BAY 2433334 medium dose
  Intervention: Drug: BAY2433334
• Experimental: BAY 2433334 low dose
  Intervention: Drug: BAY2433334
• Placebo Comparator: BAY2433334 matching placebo
  Intervention: Other: BAY2433334 matching placebo

• Publications *: Rao SV, Kirsch B, Bhatt DL, Budaj A, Coppolecchia R, Eikelboom J, James SK, Jones WS, Merkely B, Keller L, Hermanides RS, Campo G, Ferreiro JL, Shibasaki T, Mundl H, Alexander JH; PACIFIC AMI Investigators. A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction. Circulation. 2022 Oct 18;146(16):1196-1206. doi: 10.1161/CIRCULATIONAHA.122.061612. Epub 2022 Aug 27. Erratum In: Circulation. 2022 Dec 6;146(23):e330.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 19, 2023): 1601
• Original Estimated Enrollment (submitted: March 8, 2020): 1600
• Actual Study Completion Date: February 21, 2022
• Actual Primary Completion Date: February 21, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must be 45 years of age or older, at the time of signing the informed consent

• Acute myocardial infarction (excluding MI associated with PCI or CABG revascularization procedures) with:

  • clinical symptoms of acute myocardial infarction AND
  • elevated biomarkers of myocardial necrosis (creatine kinase-muscle and brain isoenzyme [CK-MB] or cardiac troponins) AND

  • at least one of the following risk factors need to be fulfilled:

    • Age ≥ 65 years
    • Prior MI (before the index AMI event)
    • Prior peripheral arterial disease
    • Diabetes Mellitus
    • Prior coronary artery bypass grafting (CABG) AND
  • initial angiography and revascularization procedures, either PCI or CABG, as treatment for the index event performed before randomization. (Note: a planned, staged PCI procedure can be performed after randomization)
• Plan for dual antiplatelet therapy (ASA + P2Y12 inhibitor) after hospital discharge for the index AMI
• Randomization during hospitalization for the index AMI event and latest within 5 days of hospital admission
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent has to be signed before any study-specific procedure.

Exclusion Criteria:

• Hemodynamically significant ventricular arrhythmias or cardiogenic shock at time of randomization
• Active bleeding; known bleeding disorder, history of major bleeding (intracranial, retroperitoneal, intraocular) or clinically significant gastrointestinal bleeding within last 6 months of randomization
• Planned use or requirement of full dose and long term anticoagulation therapy during study conduct.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 45 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: Austria, Belgium, Czechia, Germany, Hungary, Italy, Japan, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT04304534
• Other Study ID Numbers: 20603; 2019-003244-79 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: April 2023