Background: Elexacaftor-tezacaftor-ivacaftor (ETI) has led to clinically significant improvements in ppFEV 1 and respiratory-related quality-of-life in people with CF.Although decreasing trends of spontaneous sputum expectoration have been observed in the clinical setting according to the Cystic Fibrosis Foundation patient registry, data supporting the changing landscape of specimen collection in research are limited.Methods: We aimed to describe the sputum expectoration patterns of two observational cohorts, following adolescents and adults with CF in a single CF center over a 6-year period (March 2017 to February 2023).For each cohort, people with CF without a history of solid organ transplantation were followed, with sputum collected every 6 months.When sputum was not spontaneously expectorated, a throat swab was collected for clinical use, or no specimen was collected.Sputum induction was attempted if subject reported very rare spontaneous sputum expectoration.Home sputum collection was introduced in October 2020.Cohort 1 was followed before ETI approval, and ETI was introduced early after the start of Cohort 2. Study visits were suspended from March 20, 2020, to June 15, 2020, because of the COVID-19 pandemic.We describe a proportion of respiratory samples collected at 6-month intervals.Mixed-effects logistic regression was used to determine the association between ETI and sputum collection over time, adjusted for baseline age, sex, pancreatic insufficiency, and ppFEV 1 percent predicted, which was treated as a time-variant covariate.Results: Cohort 1 comprised 206 people with CF aged 14 and older who had a total of 577 visits from March 2017 to October 2019.Cohort 2 included 229 people with CF aged 10 and older who had a total of 783 visits from September 2019 and February 2023.101 (44%) participants in Cohort 2 were also followed in Cohort 1. Proportion of spontaneously expectorated sputum samples collected from Cohort 2 was lower than in Cohort 1, (43.3% vs. 84.3%).Figure 1 summarizes the trends of respiratory specimen types and collection over time (over 6-month periods) in Cohorts 1 and 2. Proportion of spontaneously expectorated sputum samples collected

were asked to fill out the Acceptability and Usability Questionnaire, which consisted of six questions ranked on a 4-point Likert scale.Results: Cohort 1 included 21 children aged 3 to 18 (mean age 9.25 ± 4.85), and Cohort 2 included 12 children aged 7 to 18 (mean age 12.15 ± 4.42).On 31 (94%) questionnaires returned, 35.5% of participants strongly agreed and 61.3% agreed with the statement "I [or my child] like(s) wearing the cough sensor."Similarly, most participants found the cough sensor easy to use (74.2% strongly agreed, 25.8% agreed) and comfortable to wear (64.5% strongly agreed, 29.0% agreed), although they found the adhesive sticker difficult to take off and the device too obvious or large.Conclusions: Although qualitative and quantitative acceptability and usability data were overall positive, we have redesigned the cough sensor for comfort and are continuing enrollment.The new sensor, 3.5 × 1.6 × 0.8 cm, is smaller and sits lower on the neck so participants can better conceal it underneath clothing (Figure 1).We are providing universal adhesive remover wipes to all participants.Future work includes long-term monitoring (1-2 weeks) of pulmonary exacerbations using the new devices and further assessing usability and acceptability from participants.

Introduction/Aim: Orkambi (lumacaftor/ivacaftor) is approved for patients with cystic fibrosis ≥2 years, homozygous for Phe508del CFTR (F/F) in Australia. Limited studies showed increased medication exposure (AUC0-12hr by approximately 50% and maximum drug concentration [Cmax] by approximately 30%) in adults with moderately impaired hepatic function (Child-Pugh B). Patients with severe liver disease were excluded from these studies. The dosing and efficacy of Orkambi for pulmonary and nutritional optimization in F/F patients with severe liver disease is not known. The aim was to describe the pharmacokinetics of Orkambi in this patient group. Methods: A prospective study was conducted at the Queensland Children's Hospital. Patients aged 6 to 18 years, meeting the inclusion and exclusion criteria were recruited. Baseline investigations were performed prior to commencement of twice daily Orkambi at half-dose, for 4 days. Patients aged 6 to 11 received lumacaftor 100 mg/ivacaftor 125 mg and patients ≥12 years received lumacaftor 200 mg/ivacaftor 125 mg. Pharmacokinetic studies of lumacaftor/ivacaftor were collected on day 1 at 0 hours (h), 2 h, 4 h, 6 h, 8 h, 24 h, on day 4 at 0 h, 2 h and 8 h post dose. Liver function was monitored for four weeks. Results: Four patients completed the study. The expected mean AUC0-12 concentration for patients on lumacaftor 200 mg/ivacaftor 250 mg twice a day was lumacaftor 198 mg.h/L (65) and ivacaftor 250 mg was 3.66 mg.h/L (2.25). In comparison, our patient cohort had mean AUC0-12 for lumacaftor of 24.08 mg.h/L (5.26) and ivacaftor of 0.63 mg.h/L (0.32). Our patients had low drug exposure and achieved 12% of expected lumacaftor and 17% of target ivacaftor levels. Liver functions were stable. Conclusion: Low lumacaftor and ivacaftor levels could be due to decreased drug availability secondary to protein losing enteropathy and lower protein binding in severe liver disease. Further studies are required to evaluate optimal Orkambi dosing in these patients.

Introduction and Objectives ARRIVAL, a single-arm Phase 3 study, characterises pharmacokinetics, safety and tolerability of ivacaftor in children aged <24 months with CFTR gating mutations. Data from 6 to <12 and 12 to <24 months cohorts show that ivacaftor is safe and well tolerated (Davies JC, et al. Presented at ECFS 2019; Rosenfeld M, et al. Lancet Respir Med. 2018;6:545–53); results for the 4 to <6 months cohort are presented here. Methods Infants received ivacaftor q12h for 4 days (Part A; 5 to <7 kg: 25 mg; 7 to <14 kg: 50 mg) and 24 weeks (Part B; <6 months: 25 mg q12h; ≥6 months: weight-based dosing per A). Primary endpoints: safety (A, B), including serum lipase and amylase, and pharmacokinetics (A). Secondary/tertiary endpoints (B): pharmacokinetics, changes in sweat chloride (SwCl), growth, faecal elastase-1 (FE-1) and serum immunoreactive trypsinogen (IRT). Results Twelve infants, six each in A (mean [SD] age, 4.2 [0.98] months) and B (4.5 [0.55] months), received ivacaftor. Pharmacokinetics was consistent with older groups; most AEs were mild/moderate. Most common AE in B was cough (n=3; 50%). Two infants had SAEs (A: thrombocytopenia [suspected causal agent: omeprazole]; B: bronchiolitis), both assessed as not/unlikely related to ivacaftor. No deaths or AEs leading to treatment interruption/discontinuation occurred. No notable transaminase elevations or clinically relevant findings in laboratory tests (except one thrombocytopenia), vital signs or electrocardiogram parameters were reported. Improvements were seen in SwCl and FE-1 (Table). Baseline elevations of serum IRT and lipase, although not amylase, improved. All growth parameters increased on average. Conclusions This first CFTR modulation study in infants aged 4 to <6 months suggests ivacaftor can be dosed safely in infants; no notable liver function test elevations were observed. Substantial improvements in SwCl indicate improved CFTR function. Improvements in lipase, IRT and FE-1 demonstrate potential of ivacaftor to reduce pancreatic inflammation and obstruction and improve function. Findings are consistent with observations in children aged 6 to <12 and 12 to <24 months treated with ivacaftor supporting treating the underlying cause of CF in children aged ≥4 months. Further data will accrue during the extension 770–126 study (NCT03277196). Please refer to page A239 for declarations of interest related to this abstract.

Objectives: TEZ/IVA was efficacious and generally safe and well tolerated in pts ≥ 12 y with F/F or F/RF mutations in pivotal Phase 3 studies. EXTEND, a 96-wk OLE study, assessed the long-term safety, tolerability, and efficacy of TEZ/IVA in pts ≥ 12 y with F/F or F/RF genotypes who completed TEZ/IVA parent studies.