Milvexian vs Apixaban for Atrial Fibrillation

(LIBREXIA-AF Trial)

Not currently recruiting at 1633 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Janssen Research & Development, LLC

Must be taking: Anticoagulants

Disqualifiers: Valve disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 4 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a new drug, milvexian, matches the effectiveness of the current treatment, apixaban (Eliquis), in preventing strokes and blood clots in people with atrial fibrillation (an irregular heartbeat). Participants will be divided into two groups: one will take milvexian, and the other will take apixaban. The trial seeks individuals with atrial fibrillation who have experienced a stroke or have risk factors like high blood pressure or diabetes. For those concerned about strokes or blood clots due to atrial fibrillation, this trial might be suitable. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on anticoagulation for a condition other than atrial fibrillation, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that milvexian was safe in earlier studies. Participants tolerated milvexian well, with manageable side effects. Due to these findings, the FDA granted it Fast Track status to expedite the review of promising drugs, indicating confidence in its safety.

Apixaban, already approved by the FDA for conditions like atrial fibrillation, has a well-established safety record from past use.

Both treatments have evidence supporting their safety, but discussing potential risks with a healthcare provider remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about milvexian for atrial fibrillation because it offers a new approach to preventing blood clots. Unlike standard treatments like apixaban, which is a Factor Xa inhibitor, milvexian is a novel oral small molecule that directly inhibits Factor XIa. This unique mechanism could potentially reduce the risk of bleeding, a common side effect associated with current anticoagulants. By targeting a different part of the clotting process, milvexian may provide a safer alternative for patients needing long-term blood clot prevention.

What evidence suggests that this trial's treatments could be effective for atrial fibrillation?

This trial will compare milvexian with apixaban for preventing strokes in people with atrial fibrillation. Studies have shown that milvexian, a new type of medication, may help prevent strokes similarly to apixaban. Research suggests that milvexian could effectively prevent blood clots while possibly causing less bleeding than other treatments. While apixaban is already known to reduce stroke risk in atrial fibrillation patients, this trial tests milvexian to determine if it can match or surpass apixaban's effectiveness. Early results are promising, indicating that milvexian might be a strong alternative for stroke prevention. ^{1 2 3 4 6}

Who Is on the Research Team?

Janssen Research & Development, LLC Clinical Trial

Principal Investigator

Janssen Research & Development, LLC

Are You a Good Fit for This Trial?

This trial is for adults with atrial fibrillation who need long-term anticoagulation. It's suitable for those over 18, especially if they're 65 or older with additional risk factors like high blood pressure, diabetes, heart disease, or a history of stroke.

Inclusion Criteria

I am 75 or older, or have had a stroke, or I am 65-74 with two of the following: high blood pressure, diabetes, heart disease, or heart failure.

I have atrial fibrillation and can take blood thinners.

I am medically stable and can undergo long-term treatment to prevent blood clots.

Exclusion Criteria

I have serious heart valve problems that might need surgery during the study.

I need long-term blood thinners for a condition other than atrial fibrillation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either milvexian or apixaban orally, twice daily, from Day 1 through the end of treatment

Up to 4 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may opt into receiving open-label apixaban for 30 days after the end of treatment

What Are the Treatments Tested in This Trial?

Interventions

• Apixaban
• Milvexian

Trial Overview The study compares Milvexian and Apixaban to see which one is better at preventing strokes and systemic embolism in people with atrial fibrillation. Participants will receive either the test drug Milvexian or the standard treatment Apixaban.

How Is the Trial Designed?

Group I: Milvexian Experimental Treatment 2 Interventions

Participants will receive milvexian 100 milligrams (mg) orally, twice daily and placebo that matches apixaban beginning on Day 1 through end of treatment (EOT). Participants after the EOT visit may have an option to receive open-label apixaban at the appropriate dose (5 mg or 2.5 mg, twice daily), for which the sponsor provides a 30-day supply.

Group II: Apixaban Active Control 2 Interventions

Participants will receive a placebo that matches milvexian and a capsule containing apixaban 5 mg or 2.5 mg orally, twice daily. Participants after the EOT visit may have an option to receive open-label apixaban (5 mg or 2.5 mg, twice daily) at the appropriate dose, for which the sponsor provides a 30-day supply.

Apixaban is already approved in European Union, United States for the following indications:

Approved in European Union as Eliquis for:

• Deep vein thrombosis
• Pulmonary embolism
• Nonvalvular atrial fibrillation

Approved in United States as Eliquis for:

• Deep vein thrombosis
• Pulmonary embolism
• Nonvalvular atrial fibrillation
• Stroke prevention

Who Is Running the Clinical Trial?

Janssen Research & Development, LLC

Lead Sponsor

Trials

1,022

Recruited

6,408,000+

Joaquin Duato

Janssen Research & Development, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Research & Development, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In a study of 20 patients with pulmonary arterial hypertension (PAH), transitioning from ambrisentan to bosentan was found to be safe, with no significant deterioration in hemodynamics or hematology over a 2-year follow-up period.

Although the 6-minute walking distance (6MWD) was shorter in the bosentan group at baseline, there were no significant differences in 6MWD between the two groups after 1 and 2 years, indicating comparable efficacy in the long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transition from Ambrisentan to Bosentan in Pulmonary Arterial Hypertension: A Single-Center Prospective Study. Gong, SG., Wang, L., Pudasaini, B., et al.[2019]

Dabigatran etexilate is shown to be an effective and safe anticoagulation therapy for patients undergoing atrial fibrillation (AF) ablation, with no embolic complications reported in the study.

The safety outcomes, including the incidence of pericardial tamponade and other complications, were similar between dabigatran etexilate and warfarin groups, suggesting that dabigatran can be a viable alternative to warfarin for this procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Usefulness of dabigatran etexilate as periprocedural anticoagulation therapy for atrial fibrillation ablation. Yamaji, H., Murakami, T., Hina, K., et al.[2021]

In a study involving 14 healthy male subjects, macitentan did not alter the pharmacokinetics or pharmacodynamics of warfarin, indicating that the two medications can be safely used together without requiring dose adjustments.

The study found that plasma concentrations of warfarin remained consistent whether macitentan was administered or not, suggesting no significant drug interactions between these two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the effect of macitentan on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Sidharta, PN., Dietrich, H., Dingemanse, J.[2021]

In a 12-month study involving 157 patients with pulmonary arterial hypertension (PAH), transitioning from ambrisentan to macitentan was successful, with 92.4% of patients meeting the criteria for continuous treatment.

Patients experienced improvements in exercise capacity, cardiac function, and hemodynamics after the transition, and the overall incidence of adverse events remained similar before and after switching treatments, indicating that macitentan is a well-tolerated option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Transition From Ambrisentan to Macitentan in Patients With Pulmonary Arterial Hypertension: A Real-word Prospective Study. Chen, Y., Luo, J., Chen, J., et al.[2022]

In a study of 15 newly diagnosed pulmonary arterial hypertension (PAH) patients, the combination therapy of macitentan and riociguat significantly improved exercise capacity, as shown by an increase in the 6-minute walk distance from 281.6 m at baseline to 315.7 m at 4 months and 313.9 m at 12 months (P < 0.05).

The therapy also led to significant improvements in hemodynamic parameters, including a decrease in pulmonary vascular resistance and mean pulmonary artery pressure, with a transplant-free survival rate of 85% over 36 months, indicating the treatment's potential efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension. Sulica, R., Sangli, S., Chakravarti, A., et al.[2020]

A reliable and sensitive method was developed to measure apixaban and its major metabolite in human plasma, which is crucial for clinical testing and monitoring of this anticoagulant drug.

The method showed excellent precision and accuracy, with low limits of quantification, making it effective for supporting clinical studies involving apixaban.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LC-MS/MS determination of apixaban (BMS-562247) and its major metabolite in human plasma: an application of polarity switching and monolithic HPLC column. Pursley, J., Shen, JX., Schuster, A., et al.[2022]

In the open-label extension of the AVERROES trial, 3,275 out of 5,599 participants received apixaban for a median follow-up of 3 years, showing an annual stroke or systemic embolism rate of just 1.0%.

The safety profile of apixaban remained consistent, with low annual rates of hemorrhagic stroke (0.3%) and major bleeding (1.2%), supporting its long-term efficacy and safety in patients with atrial fibrillation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Treatment with Apixaban in Patients with Atrial Fibrillation: Outcomes during the Open-Label Extension following AVERROES. Benz, AP., Eikelboom, JW., Yusuf, S., et al.[2021]

Apixaban is an effective direct oral anticoagulant for treating venous thromboembolism (VTE), showing safety and efficacy in large phase III trials, making it a convenient alternative to warfarin.

However, there is limited research on its use in certain populations, such as patients over 75, those with cancer, and pediatric patients, indicating a need for further studies in these groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comprehensive evaluation of apixaban in the treatment of venous thromboembolism. Koehl, JL., Hayes, BD., Al-Samkari, H., et al.[2021]

Apixaban is as effective as warfarin for preventing stroke in patients with atrial fibrillation (AF) and is associated with a significantly lower risk of major bleeding compared to warfarin, making it a safer option.

In comparison to other oral anticoagulants like rivaroxaban, dabigatran, and edoxaban, apixaban shows similar effectiveness in preventing stroke or thromboembolism, but has a notably lower risk of major bleeding compared to rivaroxaban.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-Analysis of Effectiveness and Safety of Oral Anticoagulants in Atrial Fibrillation With Focus on Apixaban. Bai, Y., Shi, XB., Ma, CS., et al.[2017]

Apixaban is an effective oral medication for preventing venous thromboembolism (VTE) after knee or hip replacement surgery, showing better efficacy than subcutaneous enoxaparin sodium in phase III trials ADVANCE-2 and -3 without significantly increasing bleeding risk.

While apixaban did not meet noninferiority criteria compared to a specific enoxaparin regimen in the ADVANCE-1 trial, it was associated with fewer bleeding complications, suggesting it may be a safer option for thromboprophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: a review of its use in the prevention of venous thromboembolism after knee or hip replacement surgery. Deeks, ED.[2021]

Apixaban is an effective oral anticoagulant for treating and preventing venous thromboembolism (VTE), showing noninferiority to the traditional enoxaparin/warfarin treatment in large phase III trials over 6 months.

It has a lower risk of major bleeding compared to enoxaparin/warfarin and is well tolerated, making it a safer alternative for patients with VTE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: A Review in Venous Thromboembolism. Greig, SL., Garnock-Jones, KP.[2020]

Apixaban, an oral direct factor Xa inhibitor, has been approved in the EU for preventing venous thromboembolism (VTE) after hip or knee replacement surgeries, demonstrating its efficacy in reducing the risk of blood clots in these patients.

The drug is also undergoing phase III trials for preventing strokes in patients with atrial fibrillation, indicating its potential for broader applications in thrombotic disorders, although development for acute coronary syndromes has been halted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apixaban: first global approval. Watson, J., Whiteside, G., Perry, C.[2021]

Healthcare professionals (HCPs) and patients demonstrated satisfactory knowledge of bleeding risks associated with apixaban, with 96.1% of HCPs recognizing symptoms that require immediate attention and 71.2% of patients identifying abnormal bleeding as a significant side effect.

The study found that a significant majority of HCPs (97.8%) who received the Prescriber Guide utilized it in patient discussions, and 90.9% of patients who received the Patient Alert Card read it at least once, indicating effective distribution and utilization of these educational materials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the Effectiveness of Apixaban Additional Risk Minimisation Measures Using Surveys in Europe. Mayall, S., Kahlon, R., Al-Dakkak, I., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39214801/

Milvexian vs apixaban for stroke prevention in atrial ... The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05757869

NCT05757869 | A Study of Milvexian Versus Apixaban in ... The purpose of this study is to evaluate if milvexian is at least as effective as apixaban for reducing the risk of the composite stroke and non-central ...

3. news.bms.com news.bms.com/news/details/2023/Milvexian-Granted-U.S.-FDA-Fast-Track-Designation-for-All-Three-Indications-Under-Evaluation-in-Phase-3-Librexia-Program-Ischemic-Stroke-Acute-Coronary-Syndrome-and-Atrial-Fibrillation/default.aspx

Milvexian Granted U.S. FDA Fast Track Designation for All ... These data also suggest a positive efficacy and bleeding profile in stroke patients where FXa inhibitors are not indicated. About Milvexian*.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0002870324002060

Trial Designs Milvexian vs apixaban for stroke prevention ... The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either ...

5. jdc.jefferson.edu jdc.jefferson.edu/cgi/viewcontent.cgi?article=1486&context=medfp

Milvexian vs Apixaban for Stroke Prevention in Atrial Fibrillation Milvexian is an oral Factor. XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. Methods LIBREXIA AF ( ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8841437/

First‐in‐human study of milvexian, an oral, direct, small ... These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development. Study Highlights. WHAT IS ...