D. Edgeworth

Improvement in exercise duration, lung function and well-being in G551D-cystic fibrosis patients: a double-blind, placebo-controlled, randomized, cross-over study with ivacaftor treatment

G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of VO2max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %ΔVO2max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5-14,1, P=0.0222) significantly increased as did %ΔFEV1 (11.7%, range 5.3-18.1, P<0·005) and %ΔBMI (1.2%, range 0.1-2.3, P=0·0393) whereas sweat chloride decreased (mean -43.4; range -55.5-18.1 mmol·l-1, P<0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in VO2max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time. TRIAL REGISTRATION NUMBER ClinicalTrials.gov-NCT01937325.

Antibiotic exposure and interpersonal variance mask the effect of ivacaftor on respiratory microbiota composition

BACKGROUND G551D is a class III mutation of the cystic fibrosis transmembrane regulator (CFTR) that results in impaired chloride channel function in cystic fibrosis (CF). Ivacaftor, a CFTR-potentiating agent improves sweat chloride, weight, lung function, and pulmonary exacerbation rate in CF patients with G551D mutations, but its effect on the airway microbiome remains poorly characterised. METHODS Twenty CF patients with at least one G551D mutation from a single centre were recruited to a 4month double-blind, placebo-controlled, crossover study of ivacaftor with 28days of active treatment. Sputum microbiota composition was assessed by 16S rRNA gene amplicon sequencing and quantitative PCR at five key time points, along with regular clinical review, respiratory function assessment, and peripheral blood testing. RESULTS No significant difference in microbiota composition was observed in subjects following ivacaftor treatment or placebo (PERMANOVA P=0.95, square root ECV=-4.94, 9479 permutations). Microbiota composition variance was significantly greater between subjects, than within subjects over time (P<0.0001, Mann Whitney U test), and an additional within-patient paired assessment of microbiota similarity was therefore performed. Again, change in microbiota composition was not significantly greater during treatment with ivacaftor compared to placebo (Wilcoxon test, P=0.51). A significant change in microbiota composition was however associated with any change in antibiotic exposure, regardless of whether ivacaftor or placebo was administered (P=0.006). In a small, subgroup analysis of subjects whose antibiotic exposure did not change within the study period, a significant reduction in total bacterial load was observed during treatment with ivacaftor (P=0.004, two-tailed paired Students t-test). CONCLUSIONS The short-term impact of ivacaftor therapy on sputum microbiota composition in patients with G551D mutations are modest compared to those resulting from antibiotic exposure, and may be masked by changes in antibiotic treatment regimen.

WS09.5 Effect of ivacaftor on wellness, quality of life and cognitive function in adults with cystic fibrosis and G551D mutation

The effects of the potentiating agent ivacaftor on well-being and cognitive function are little known in adults with CF and G551D mutation. Objectives To evaluate the effects of ivacaftor on wellness, quality of life (QOL) and cognitive function in adults with CF; to evaluate a new wellness score for adults with CF. Methods In a placebo controlled crossover trial with 28 days of treatment in 20 adult patients the following were measured at 5 timepoints: The Cystic Fibrosis Questionnaire-Revised (CFQ-R), The Alfred Wellness Score for CF (AweScoreCF) and the Montreal Objective Cognitive Function Assessment (MOCA). Results See the table. In the CFQ-R change in social, health, physical, role and overall QOL improved significantly as did energy, exercise participation and total wellness in the AweScoreCF. There was strong agreement between the CFQ-R and the AweScoreCF. Patients found the AweScoreCF (10 questions) quicker to complete compared to the CFQ-R (50 questions). There were more completed AweScoreCF questionnaires than CFQ-R. There were some improvements in the MOCA in some patients following treatment. EndpointPercentage change from baseline, median (IQR)PlaceboIvacaftorCFQ-R18.1 (−30.8, 67.0)90.6 (41.7, 139.5) * AweScoreCF−0.5 (−6.9, 5.9)10.2 (3.8, 16.6) * MOCA0.1 (−0.7, 0.9)0.7 (−0.2, 1.5)*p Conclusions Treatment with ivacaftor resulted in significant improvements in quality of life, increased wellness, energy and exercise participation. There was strong agreement between the CFQ-R and AweScoreCF. The AweScoreCF may be a useful wellness assessment tool in the CF clinic. Study supported by Vertex Inc.

ePS03.4 Patient reported adherence to ivacaftor

Introduction The improvements in lung function, symptom burden and quality of life with the use of the gene potentiator ivacaftor in patients with G551D CF mutations have been established. Previous studies have suggested that adherence to medication in chronic illness is poor. Objectives To compare patient perception of adherence to ivacaftor to pharmacy dispensing data. Methods Twenty adult patients with at least one copy of the G551D mutation were recruited to a placebo-controlled trial. This consisted of 2 active phases during which participants were randomised to ivacaftor vs placebo. On completion all participants entered an open-label extension of 6 months. Medication returns within blister packs were examined following Active Phase 1 and Active Phase 2. During the Open Label extension pharmacy dispensing was recorded. Patients self-reported a percentage adherence during Active Phases 1 and 2 and also during the Open Label Extension. Results See the table. Adherence (%)Patient reportedActualActive Phase 196.797.6 a Active Phase 296.996.3Open Label Extension94.494.5aA 1% change in reported adherence is approximately equivalent to a 10 tablet difference for this study. Conclusion Patient-reported adherence was similar to medication return and dispensing data. Adherence when receiving open label medication declined slightly but remain higher than average rates in chronic illness. Supported by a grant from Vertex Inc.

WS14.1 Ivacaftor improves exercise capacity in patients with G551D CF gene mutations

Introduction G551D is a CFTR mutation that results in impaired chloride channel function in Cystic Fibrosis (CF). Ivacaftor, a CFTR potentiating agent improves lung function and sweat chloride but its effect on exercise is unproven. Objectives To evaluate exercise capacity in response to correction of the chloride channelopathy with ivacaftor. Methods In a placebo-controlled crossover study of ivacaftor over 4 months with a 3 month open label extension we performed cardiopulmonary exercise tests (CPET) at six time points. 20 patients were included in the study. The primary outcome was VO2max as a percentage of baseline at the end of the crossover study (END X) and 3 month open label extension (OLE). A training program was not included in the study. Results There was a stepwise increase in maximal exercise capacity based on VO2max in the treated group above baseline at END X and 3 month OLE treatment periods. FEV1 and sweat chloride were also improved as expected. EndpointEnd X, mean (95% CI)OLE, mean (95% CI)%Δ absolute exercise time8.0 (1.4–14.6) * 12.1 (5.8–18.4) *** %Δ VO2max, ml/kg/min6.7 (2.7–10.8) ** 12.6 (6.3–18.9) *** %Δ VO2 ml/min7.8 (3.7–12.0) *** 15.6 (9.7–21.4) *** %Δ Watts5.0 (1.4–8.6) ** 10.9 (5.6–16.3) *** *p Conclusion Treatment of G551D patients with ivacaftor has a positive effect on exercise capacity which is independent of training. Improved VO2max has not been previously examined in clinical trials with ivacaftor and may have prognostic implications for patients with the G551D mutation. Supported by a grant from Vertex Inc.

ePS05.3 Ivacaftor and its effects on body composition in adults with G551D related cystic fibrosis

Background Ivacaftor, a potentiating agent has been shown to improve weight and BMI in patients with at least one copy of CFTR-G551D mutation. Effects on body composition are less well reported. Objectives To evaluate changes in body composition following ivacaftor therapy. Methods Twenty patients were included in a placebo-controlled crossover study of ivacaftor (28day treatment period), with 3 month open label extension. Bioelectrical impedance analysis (BIA) was conducted to measure weight, fat mass (FM), fat free mass (FFM), skeletal muscle mass (SMM) and total body water (TBW). Results Weight significantly increased above baseline at 1 month and post 3 months of ivacaftor treatment. FFM, SMM and TBW significantly increased following 1 month. FM did not significantly increase with 1 month of ivacaftor treatment but increased significantly above baseline post 3 months. Endpoint1 month (Crossover Study)+ 3 month Follow-Up (Open Label)% D Weight, kg1.6 (0.7, 2.5) *** 3.9 (2.4, 5.3) *** % D FM, kg0.9 (−2.4, 4.2)13.3 (5.0, 21.6) ** % D FFM, kg1.9 (0.9, 2.8) *** 0.6 (−1.9, 3.2)% D SMM, kg2.4 (0.6, 4.2) ** 1.6 (0.04, 3.2) * % D TBW, L2.0 (0.8, 3.2) *** 1.7 (0.3, 3.1) * Values are mean (95% CI).*P Conclusion The significant increase in weight is comparable to other seminal papers. The increase in FFM and SMM in the first 28days reflects an increase in TBW. Increase in FM did not occur until after 1month of treatment. These changes impact on nutrition practice. To our knowledge, this study is the first to investigate body composition with ivacaftor treatment using the BIA method. Validation with DEXA is underway. This study was supported by Vertex Inc.