FENOX Trial (Comparative Effectiveness of Fexuprazan Co-therapy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants) (FENOX)

FENOX Study (Comparative Effectiveness of Fexuprazan Co-therapy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants)

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (AF). Although NOACs substantially reduce intracranial hemorrhage, upper gastrointestinal bleeding (UGIB) remains a frequent and clinically consequential complication. Proton pump inhibitors (PPIs) may reduce UGIB risk; however, concerns regarding long-term safety and pharmacodynamic variability persist. Fexuprazan, a potassium-competitive acid blocker (P-CAB), provides rapid and sustained acid suppression independent of acid activation and CYP2C19 metabolism. No randomized trial has evaluated P-CAB therapy for prevention of UGIB in anticoagulated patients.

Methods FENOX is a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) superiority trial. Approximately 1,000 high-risk patients with non-valvular AF initiating NOAC therapy will be randomized 1:1 to receive fexuprazan plus NOAC therapy or NOAC therapy alone. High-risk enrichment includes advanced age, renal impairment, concomitant antiplatelet therapy, prior ulcer disease, or elevated HAS-BLED score. The primary endpoint is clinically relevant upper gastrointestinal bleeding (CR-UGIB) at 12 months, defined according to ISTH criteria. All events will be adjudicated by an independent blinded Clinical Events Committee. Primary analyses will follow the intention-to-treat principle using time-to-event methods.

Results The planned sample size provides 80% power to detect a 50% relative risk reduction in CR-UGIB, assuming a 12-month incidence of 10% in the control group. Interim safety monitoring will be conducted under independent oversight.

Conclusion FENOX is the first randomized trial designed to evaluate a P-CAB-based gastroprotective strategy for prevention of clinically relevant UGIB in high-risk patients receiving NOAC therapy. By integrating high-risk enrichment, pragmatic design, and blinded endpoint adjudication, the study aims to provide rigorous evidence to inform gastroprotective strategies in anticoagulated populations.

Study Overview

• Status: Not yet recruiting
• Conditions: Drug-Related Side Effects and Adverse Reactions; Atrial Fibrillation (AF); Gastrointestinal Hemorrhage (Clinically Important, Upper); Upper Gastrointestinal Bleeding (UGIB)
• Intervention / Treatment: Drug: Fexuprazan; Drug: NOAC therapy

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yeji Kim MD, PhD; Phone Number: +82-10-8680-9542; Email: lexie6169@gmail.com

Study Locations

• South Korea
  • Seoul, South Korea, 1071
    • Ewha Womans University MokDong Hospital
    • Contact: Junbeom Park, PhD; Phone Number: +82-02-3539-9822; Email: newriser@naver.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Documented non-valvular atrial fibrillation
• Receiving or initiating therapy with a non-vitamin K antagonist oral anticoagulant (NOAC) at guideline-recommended dosing

• At least one high-risk factor for upper gastrointestinal bleeding, including:

  • Age ≥75 years
  • Chronic kidney disease (eGFR <60 mL/min/1.73 m²)
  • Concomitant antiplatelet therapy
  • Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids
  • Prior peptic ulcer disease or upper gastrointestinal bleeding
  • HAS-BLED score ≥3

Exclusion Criteria:

• Active gastrointestinal bleeding at the time of screening
• Requirement for mandatory long-term proton pump inhibitor (PPI) therapy that cannot be discontinued
• Severe hepatic dysfunction
• Life expectancy <1 year
• Known hypersensitivity or contraindication to fexuprazan
• Participation in another interventional clinical trial that may interfere with study outcomes

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fexuprazan plus NOAC therapy; Participants will receive fexuprazan 40 mg orally once daily in addition to standard-of-care non-vitamin K antagonist oral anticoagulant (NOAC) therapy at guideline-recommended dosing.	Drug: Fexuprazan; Fexuprazan 40 mg administered orally once daily for the duration of the study in combination with NOAC therapy.; Drug: NOAC therapy; Non-vitamin K antagonist oral anticoagulant therapy (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban) administered according to approved labeling and guideline-recommended dosing.
Active Comparator: NOAC therapy alone; Participants will receive standard-of-care non-vitamin K antagonist oral anticoagulant (NOAC) therapy at guideline-recommended dosing without additional gastroprotective therapy.	Drug: NOAC therapy; Non-vitamin K antagonist oral anticoagulant therapy (e.g., apixaban, rivaroxaban, dabigatran, or edoxaban) administered according to approved labeling and guideline-recommended dosing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically relevant upper gastrointestinal bleeding (CR-UGIB)	Clinically relevant upper gastrointestinal bleeding (CR-UGIB) defined as either: ISTH-defined major upper gastrointestinal bleeding, or; clinically relevant non-major upper gastrointestinal bleeding requiring emergency department visit, hospitalization, endoscopic intervention, blood transfusion, or temporary interruption of NOAC therapy. All events will be adjudicated by an independent blinded Clinical Events Committee.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ISTH major bleeding	Major bleeding defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria.	12 months
Intracranial hemorrhage	Occurrence of intracranial hemorrhage confirmed by neuroimaging or clinical diagnosis.	12 months
Ischemic stroke or systemic embolism	Composite of ischemic stroke or systemic embolism confirmed by clinical and imaging criteria.	12 months
All-cause mortality	Death from any cause during the follow-up period.	12 months
Net clinical outcome	Composite of clinically relevant upper gastrointestinal bleeding, ischemic stroke/systemic embolism, intracranial hemorrhage, or all-cause death.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Any adverse events reported during the study period.	12 months
Serious adverse events	Serious adverse events defined according to standard regulatory criteria.	12 months
Drug discontinuation due to adverse events	Permanent discontinuation of study medication due to adverse events.	12 months

Collaborators and Investigators

• Sponsor: Ewha Womans University Mokdong Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): November 30, 2029
• Study Completion (Estimated): November 30, 2032

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Non-vitamin K antagonist oral anticoagulants (NOACs), potassium-competitive acid blocker (P-CAB), Upper gastrointestinal bleeding (UGIB)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Digestive System Diseases; Gastrointestinal Diseases; Hemorrhage; Chemically-Induced Disorders; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Hemorrhage; fexuprazan
• Other Study ID Numbers: FENOX Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie the results reported in this study, after de-identification, will be shared.
• IPD Sharing Access Criteria: Data will be made available to qualified researchers who provide a methodologically sound research proposal. Proposals should be directed to the corresponding author. Data access will be granted following review and approval by the study steering committee and execution of a data use agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes