(301) A multi-center study exploring the impact of co-adherence to inhaled therapies on FEV₁ response in people with CF taking Trikafta within the CFHealthHub learning health system.

Background: Studies of Trikafta for people with cystic fibrosis (CF) showed a forced expiratory volume in one second (FEV₁) increase in excess of 10% [1,2]. An efficacy-effectiveness gap was seen for Ivacaftor with a 10.6% improvement in FEV₁ in clinical trials [3] versus effectiveness of 6% within real-world data [4]. There are no data to determine whether the efficacy-effectiveness gap seen with Ivacaftor [3,4] exists for Trikafta. FEV₁ and objective adherence data, collected through the CFHealthHub learning health system, will be used to determine real-world effectiveness of Trikafta and changes in adherence to preventative inhaled therapy pre- and post-Trikafta initiation in adults with CF in the UK.

Methods: This multi-center, observational cohort study utilizes data from research and routine clinical care. The CFHealthHub learning health system, of over 60% of adult CF centers in England, routinely collects adherence data via nebulizers with electronic data capture capability (eTrack® & Ineb®). Adults within CFHealthHub centers who are or have been prescribed Trikafta will be identified. Data will be analyzed including FEV₁, body mass index, age at starting Trikafta, CFTR genotype, sex, Pseudomonas status, medications, co-morbidities, healthcare utilization, adherence to Trikafta (measured by medication possession ration) and adherence to preventative inhaled therapies. Data will be analyzed from six months before and after Trikafta initiation, then at 12-monthly intervals up to five years post-initiation.

Results: As of April 2022, 887 adults with CF who participate in the CFHealthHub learning health system are or have been prescribed Trikafta. Of these, 566 people (mean age 33 years, 55% male) currently have objective adherence data. A decline in adherence to preventative inhaled therapy is demonstrated following initiation of Trikafta (figure 1). The first interim timepoint analysis up to six months post-initiation of Trikafta will be completed by September 2022 and the results presented.

Conclusions: This study will identify whether an efficacy-effectiveness gap exists for Trikafta. The clinical outcome and objective adherence data within the CFHH learning health system present a unique opportunity to understand the impact of co-adherence to Trikafta and preventative inhaled therapy. Co-adherence will be explored as a target to explain any efficacy-effectiveness gap and to optimize the outcomes for people with CF taking Trikafta.

Acknowledgements: This work is supported by the Cystic Fibrosis Foundation [grant number 00908321].

References: [1] Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019; 381(19):1809-1819. doi: 10.1056/NEJMoa1908639.

[2] Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous forthe F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019; 394(10212):1940-1948. doi:10.1016/s0140-6736(19)32597-8.

[3] Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. Nov 3, 2011;365(18):1663-72. doi:10.1056/NEJMoa1105185.

[4] Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73(8):731-740. doi:10.1136/thoraxjnl-2017-210394.