Zastaprazan for the prEvention of Upper GI Bleeding in Ischemic Stroke

• Zastaprazan (Drug): Zastaprazan citrate 20 mg, a potassium-competitive acid blocker (P-CAB), administered orally once daily at a fixed dose, in addition to standard antiplatelet or anticoagulant therapy.
• Placebo (Drug): Matching placebo for zastaprazan citrate 20 mg, administered orally once daily at a fixed dose, in addition to standard antiplatelet or anticoagulant therapy.

Primary outcomes

• Time to First Composite Clinical Event of Upper Gastrointestinal Bleeding as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years, including a 24-month enrollment period and 12-month follow-up)]: Time from randomization to the first occurrence of a composite clinical event of upper gastrointestinal (GI) bleeding, as adjudicated by the Clinical Event Committee (CEC). The composite event includes: (1) upper GI bleeding confirmed by endoscopy or imaging, with hematemesis and/or melena; (2) upper GI bleeding of unclear origin, judged by the investigator to originate from the upper GI tract; (3) occult GI bleeding, defined as a decrease in hemoglobin ≥2 g/dL or hematocrit ≥10%; (4) symptomatic uncomplicated gastroduodenal ulcer, confirmed by endoscopy or imaging with persistent pain (≥3 days) and no evidence of bleeding; (5) symptomatic gastroduodenal erosive lesions, with persistent pain (≥3 days) and ≥5 gastroduodenal erosions confirmed by endoscopy, excluding mucosal bleeding; (6) upper GI obstruction; and (7) upper GI perforation.

Secondary outcomes

• Time to First Composite Clinical Event of Upper Gastrointestinal Bleeding as Judged by the Investigator [From randomization up to end of study (up to approximately 3 years)]
• Time to First Upper Gastrointestinal Bleeding Event Confirmed by Endoscopy or Imaging, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Upper Gastrointestinal Bleeding Event of Unclear Origin, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Occult Gastrointestinal Bleeding Event, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Symptomatic Uncomplicated Gastroduodenal Ulcer Event, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Symptomatic Gastrointestinal Erosive Lesion Event, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Upper Gastrointestinal Obstruction Event, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Upper Gastrointestinal Perforation Event, as Adjudicated by the Clinical Event Committee (CEC) [From randomization up to end of study (up to approximately 3 years)]
• Time to First All Gastrointestinal Bleeding Event (Upper and Lower), Including International Society on Thrombosis and Haemostasis (ISTH) Major Bleeding or clinically relevant non-major bleeding (CRNMB) [From randomization up to end of study (up to approximately 3 years)]
• Time to First Lower Gastrointestinal Bleeding Event [From randomization up to end of study (up to approximately 3 years)]
• Time to First Non-Gastrointestinal ISTH Major Bleeding or CRNMB Event [From randomization up to end of study (up to approximately 3 years)]
• Time to First Clinically Significant Non-Bleeding Upper Gastrointestinal Event [From randomization up to end of study (up to approximately 3 years)]
• Time to First Hemoglobin-Related Event [From randomization up to end of study (up to approximately 3 years)]
• Time to First Cerebrovascular or Cardiovascular Event [From randomization up to end of study (up to approximately 3 years)]: Time from randomization to the first occurrence of a cerebrovascular or cardiovascular event, including ischemic stroke, transient ischemic attack, systemic embolism, myocardial infarction, or vascular death.
• All-Cause Mortality [From randomization up to end of study (up to approximately 3 years)]

Other outcomes

• Subgroup Analyses of the Primary Composite Upper Gastrointestinal Bleeding Event [From randomization up to end of study (up to approximately 3 years)]: Exploratory subgroup analyses of the primary efficacy outcome (time to first composite clinical event of upper GI bleeding), performed across the following pre-specified subgroups: (1) timing of zastaprazan initiation relative to onset of ischemic stroke/TIA (acute phase, within 4 weeks vs. subacute phase, after 4 weeks); (2) history of prior gastrointestinal bleeding (yes vs. no); (3) concomitant treatment type (dual antiplatelet therapy vs. anticoagulant therapy); (4) age (<65 years vs. ≥65 years); (5) baseline renal function (eGFR ≥60 mL/min/1.73m² vs. <60 mL/min/1.73m²); and (6) stroke mechanism.

Sex: All, ages: 19 Years to any

Inclusion Criteria:

1. Adults aged 19 years or older
2. Onset of transient ischemic attack (TIA) or ischemic stroke within 180 days prior to randomization
3. Currently initiating or receiving, at the time of randomization, one of the following treatments, with an expected treatment duration of at least 3 weeks:

   A. Dual antiplatelet therapy (DAPT) - aspirin in combination with one of the following: clopidogrel, ticagrelor, prasugrel, or cilostazol B. Oral anticoagulant therapy - a NOAC (apixaban, rivaroxaban, dabigatran, or edoxaban) or warfarin
4. Provision of written informed consent by the participant (or legally authorized representative)

Exclusion Criteria:

1. Clinically significant peptic ulcer or gastrointestinal bleeding within 1 year prior to enrollment
2. Moderate to severe hepatic impairment (e.g., diagnosis of cirrhosis or confirmed esophageal/gastric varices)
3. Severe thrombocytopenia (platelet count <50,000/µL)
4. End-stage renal disease requiring dialysis, or unstable renal function precluding safe anticoagulant dose adjustment (eGFR <15 mL/min/1.73m²)
5. Known hypersensitivity to potassium-competitive acid blockers (P-CABs) or to the investigational product
6. History of major gastrointestinal surgery resulting in malabsorption, bowel obstruction, or inability to take oral medication
7. History of osteoporotic fracture or fragility fracture
8. Diagnosis of a condition requiring long-term, high-dose systemic corticosteroid therapy
9. Diagnosis of a condition requiring long-term concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs)
10. Pregnant or breastfeeding women
11. Life expectancy of less than 6 months due to pre-existing comorbid conditions
12. Current participation in another interventional clinical trial that could affect the results of this study
13. Any condition that, in the investigator's judgment, precludes participation
14. Participant or partner of childbearing/reproductive potential who does not agree to use a medically acceptable method of contraception, or to abstain from sexual activity with risk of pregnancy, during the study period
15. Currently receiving, or having received within 5 half-lives prior to randomization, a prohibited concomitant medication expected to interact with the investigational product (products containing atazanavir, nelfinavir, or rilpivirine)
16. History of peptic ulcer complications, including bleeding, perforation, or stricture, regardless of timing
17. Active bleeding at the time of enrollment, history of a coagulation disorder, or hemodynamic instability at the time of enrollment
18. Known hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption

• Bum Joon Kim, Ph.D., Principal investigator, Asan Medical Center