ORIGIN-1 trial: study protocol for an organoid-guided N-of-1 trial evaluating CFTR modulator response in cystic fibrosis with rare non-F508del mutations.

backgroundCystic fibrosis (CF) is a genetic condition caused by mutation of the cystic fibrosis transmembrane regulator (CFTR) gene. Recently licensed modulator therapies target the defective CFTR protein and have transformed the formerly life-limiting trajectory of people with CF (pwCF). elexacaftor/tezacaftor/ivacaftor (ETI) has shown outstanding clinical efficacy in pwCF homozygous for F508del (approximately 50%), and those with a F508del mutation paired with any of the > 2000 other mutations identified in the CFTR gene (heterozygous pairing). However, clinical response to modulators is variable and people with rare CF mutations are often excluded from modulator access worldwide. The ORIGIN-1 trial aims to determine whether an organoid-guided n-of-1 trial can predict and demonstrate clinical response to ETI in pwCF with rare mutations.

methodsBased on the in vitro testing, participants will be eligible to enter the interventional phase of the trial. Participants will be administered blinded study drug (i.e. ETI or placebo) for a 14-day treatment block followed by a 14-day washout period prior to beginning the alternate treatment, again for a 14-day period. A treatment cycle will be defined as one ETI treatment block, one placebo treatment block and the intervening washout period. Treatment blocks sequence will be randomly assigned. Participants will complete a minimum of two treatment cycles and up to four consecutive cycles depending on the results of planned interim analyses. DISCUSSION: The ORIGIN-1 trial is designed to demonstrate a precision medicine approach that targets CFTR modulator therapy to ensure the optimal use of these very high-cost therapies. This pathway may expand the application of CFTR modulators to include pwCF with rare mutations of the CFTR gene for whom CFTR modulators' efficacy has not been (and are unlikely to ever be) proven by conventional, parallel-group clinical trials. We anticipate that a personalised organoid model that measures patient-specific CFTR responses to modulators in vitro will enable the reliable identification of pwCF with these rare CFTR mutations who are likely to respond to existing modulator therapy.

trial registrationAustralia New Zealand Clinical Trials Registry (ANZCTR) ID: ACTRN12623001136695 Registered on November 03, 2023.