Introduction: Early eradication of methicillin-resistant Staphylococcus aureus (MRSA) in cystic fibrosis is desirable. Prospective studies are challenging owing to the feasibility of recruiting patients with a rare event in an orphan disease. Our prior randomised study (Staph Aureus Resistance-Treat Or Observe (STAR-too)) showed improved clearance and outcomes with aggressive therapy compared to no treatment. We present a novel trial design to guide treatment for eradicating incident infection with a focus on feasibility. Methods: Subjects with cystic fibrosis with incident MRSA infection were enrolled into the Staph Aureus Resistance-Treat Early And Repeat (STAR-ter) protocol and treated with a combination of an oral antibiotic and topical (nare and throat) decolonisation. The primary outcome was MRSA-negative respiratory culture at Day 28, i.e. 14 days after completion of oral antibiotics. What was novel about this study design was that the control/comparator group was the untreated group of the STAR-too trial. This design was developed because having a "no treatment" group would be unethical given prior findings and a superiority design would delay the time to results based on small numbers of eligible subjects. Both studies used the same inclusion and exclusion criteria and drew subjects from the same geographic regions. The main difference between the studies was the use of a single oral antibiotic, trimethoprim-sulfamethoxazole, rather than the combination with oral rifampin used in STAR-too. Discussion: An innovative approach to address a clinical question for a rare event in an orphan disease, cystic fibrosis, is presented to enhance current clinical evidence to guide cystic fibrosis care in relation to new MRSA infection.