BACKGROUND AND RATIONALE: In-stent restenosis (ISR) remains the leading cause of treatment failure following percutaneous coronary intervention (PCI) with contemporary drug-eluting stents. Especially in small caliber coronary arteries, restenosis is common following PCI and represents a treatment challenge. Drug-coated balloons (DCB) are an attractive alternative to stents for treatment of both ISR and small vessel disease. The safety and efficacy of the Prevail DCB will be assessed for (1) the treatment of ISR and (2) de novo lesions in small vessels. TRIAL DESIGN: Prevail Global is a prospective, international, dual cohort clinical study enrolling (1) patients undergoing PCI for ISR in a randomized controlled trial (1:1) design comparing the Prevail DCB versus an FDA-approved DCB (Agent CONCLUSIONS: The Prevail Global study will directly assess the safety and efficacy of the Prevail DCB for the treatment of ISR and de novo small vessel lesions. TRIAL REGISTRATION: Prevail Global, NCT06535854, is registered at https://clinicaltrials.gov/study/NCT06535854.