Peter van Mourik

174 Chapter 8 this study is the collaboration with the European Cystic Fibrosis Society – Clinical Trials Network (ECFS-CTN). This network consists of 58 sites in 17 countries that share standardized working procedures and training, and have been involved in the study design. The study will be run only in ECFS-CTN sites, which will enable a quick start-up and ensures smooth communication between the sites and sponsor. A risk of this project is that the drugs screened have yet to be clinically approved. It is therefore unclear whether all of these drugs will eventually reach the market and become publicly available. By involving three different pharmaceutical companies with several drugs in the pipeline and including ivacaftor and tezacaftor/ivacaftor in the drug screening, this risk is minimized. Another uncertainty is the number of responsive subjects that we expect to find. The current prediction of ~16% responsive subjects is based on a small dataset, and these numbers could differ depending on geographical distribution and efficacy of the experimental compounds. However, since drugs with innovative modes-of-action are investigated, the responsive population could be larger than previously anticipated. Moreover, efficacy of the experimental compounds is expected to be better than currently available drugs, which could result in a higher power in our clinical studies and therefore a reduced number of responsive subjects could be sufficient. An important outcome of this study will be the large dataset created by combining all the individual results. This dataset will generate extensive knowledge on how different genotypes respond to drugs, and will become publicly available, which can be of great use to the scientific community. Furthermore, if the subjects consent, organoids that have been generated will be made available for future research. This biobank can be accessed by other scientists, and newly developed drugs can be tested on those organoids. Around 14 companies are currently developing drugs that aim to restore CFTR function (https://www.cff.org/Trials/pipeline ) 35 . The impact of this study is therefore amplified, since many of these new drugs or experimental compounds could be screened. The HIT-CF Organoid Study creates the opportunity of CFTR-modulating treatment in a CF patient population that has previously been largely ignored. Several drugs will be tested in vitro to stratify patients according to the best possible drug, thereby tailoring treatment to the individual patient. Moreover, extensive knowledge will be generated about the effects of drugs on a spectrum of genotypes, and the subsequently available biobank will be very useful for future drug development and research into Cystic Fibrosis.