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Background The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. Methods We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. Results Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was −3.2% (95% CI: −9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was −3.2% (95% CI: −8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. Conclusions Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

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 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 Student's 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.

BackgroundNocturnal oxyhaemoglobin desaturation is common in cystic fibrosis (CF) but the effect on quality of life (QoL) remains unknown.MethodsSixty stable CF outpatients with mean age 31±8years (mean±1SD), BMI 20.8±3.2kg/m2 and FEV1 42±13% predicted had arterial blood gas sampling, lung function testing, overnight pulse oximetry and completed the CF QoL questionnaire, Epworth Sleepiness Scale and Medical Research Council dyspnoea scale.Results11 (18%) of the CF patients were ‘desaturators,’ (SpO2

With increasing numbers of cystic fibrosis (CF) patients surviving to adulthood, issues related to vocation inevitably arise and warrant specific attention. We examined the percentage of participants with CF currently working and explored risk factors for work disability among adults with CF.We recruited 50 consecutive patients from an adult cystic fibrosis service. Demographic, employment history, illness severity indicators and CF-attributed work disability factors were evaluated. Demographic risk factors for work disability using the illness severity measures of FEV(1), S-K score, CRDQ, and recent hospitalisation as independent variables were determined.Factorial analysis of a disability index (DI) indicated no dependency on FEV(1) or S-K score, but dependency on quality of life indices (p0.05), age (p0.05) and hospital admission rate (p0.05). Hours worked per week were dependent on quality of life (p0.01) (mastery of disease domain), fewer hospital admissions (p0.01) and age (p0.05). Sixty-eight percent of the sample reported that CF resulted in significant impediments to employment. However, few had sought vocational guidance (6%).Determinants of workforce participation shows that hours worked and perceived disability are more dependent on mastery of disease, age, and time in hospital, than on clinical severity scores. Health professionals may assist productivity through career counselling or tailored programs.

More women with CF now become pregnant. Clinicians and patients have many questions about the evolution and prognosis of these pregnancies. Aim: To describe evolution of pregnancies and clinical status of pregnant women in the French CF Registry. Methods: Data collected between 1992 and 2011 from women aged 15−49 registered in the Registry were used. For some incomplete data, only follow-up data collected between 2002 and 2011 were analyzed. Results: During those 20 years, 322 women became pregnant, for a total of 394 pregnancies (average number of pregnancies per woman: 1.2). The annual number of cases has increased (8 in 1992 to 48 in 2011). Age at first pregnancy remains steady (mean±SD: 26.8±5.4 years). Mean VEMS was 51.6% in 1992 and 71.1% in 2011 and is concordant with evolution of VEMS in CF adult women. BMI collected the year preceding pregnancy is constant over the period (mean±SD: 20.4±3). Between 2002 and 2011, the early pregnancy rate was 24.7‰; 72.5% of the women were PI and 22% had diabetes. In total, 35 deaths were registered, occurring 5±3.8 years after pregnancy on average. Mean age at death (31.4±8.3 years) exceeds that of the CF population as a whole (29 years in 2010). Interestingly, 24 women became pregnant after transplant (mean time to pregnancy after transplantation: 3.9±2.3 years). Conclusion: The annual number of pregnancies has increased dramatically over the last 20 years. The clinical status of pregnant women evolves in a similar manner to that of other adult women in the Registry. This work highlights the increasing number of pregnancies in transplanted patients and it will be interesting to study this specific population.

Background: Postural changes have been reported in patients with CF as they age. Aims: To measure musculoskeletal and postural function in adults with CF; to identify problems related to disease progression and to further develop a clinically appropriate musculoskeletal assessment screening tool. Method: A physiotherapy screening tool was developed to assess musculoskeletal function in the inpatient and outpatient settings when patients were at baseline function. Spinal curves, head, shoulder and scapulae positions, thoracic extension & shoulder flexion, thoracic lateral flexion and rotation, hamstring, calf and quads muscle length were assessed. Results: 94 patients were screened aged 18 to 50 years with 11% with normal lung function; 31% with mild; 32% with moderate and 26% with severe lung disease. The following postural changes were found in this sample: cervical changes 33%; thoracic kyphosis 42%; increased lumbar lordosis 35%; anterior shoulder protraction 51%; elevated shoulders 34%; abducted or winged scapulae 49%; decreased thoracic lateral flexion 31%; restricted thoracic rotation 31%; tight hamstrings 52%; tight calf muscles 26%. Quadriceps length was normal in all subjects. Thoracic kyphosis, scapulae abduction/winging and anterior shoulder protraction appeared to be related to disease severity. Conclusions: The results of this sample of postural screening highlights the importance of regular review of musculoskeletal function in adults with CF in order to prevent problems developing and to manage problems as they are diagnosed. The screening tool has been further developed. Musculoskeletal screening should be considered as part of the annual review in CF.

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.

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.

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.

Objective To determine the possibility and likelihood of inaccurate genotype results in CF. Methods Over 500 genotype results were collected at a centre for adult CF care. Genotype results were entered into a database to generate study data. Genotype results were repeated if a.the result was unclear and repeat testing was requested by the genetic testing laboratory, b.the managing clinician had significant concerns regarding genotype/phenotype correlation or c.results held in the database were incomplete, i.e. one single mutation was identified and no second mutation was found, using an older (smaller) panel of probes. Results From over 500 genotypes collected between 1991 and 2014, there were 5 results that were found to be inaccurate/misread on repeat testing. AB was described as having the same mutation as her brother CD, being F508del/F508del. On subsequent testing, he had R117H/unk. F508del was not proven on re-testing. EF had been treated as CF. On repeat testing he was found to be homogygous for R117H. GH was found to be 3454G>C with a typographical error. IJ was identified as unk/unk, and extended testing was unhelpful, however like siblings AB and CD, was found to have a gene abnormality (unspecified) like his brother. PatientInitialSubsequentChange statusABF508del/F508delunk/unkYCDF508del/F508delRII7H/unkYEFR117H/unkR117H/R117HYGHF508del/345G>CF508del/3454G>CNIJunk/unkunk/unkN Conclusion Genotype results may be incorrect or misinterpreted in 1% of patients. Retesting and consultation is important if doubt exists.

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.

WS9.1 Effectiveness of airway clearance techniques when patients choose their airway clearance technique M.P. McIlwaine1, J.L. Agnew2, N. Alarie3, L.C. Lands4, G.F. Davidson1, F. Ratjen5. 1BC Children’s Hospital, Cystic Fibrosis Clinic, Vancouver, Canada; 2The Hospital for Sick Children, Respiratory Medicine, Toronto, Canada; 3The Montreal Children’s Hospital, Cystic Fibrosis Clinic, Montreal, Canada; 4The Montreal Children’s Hospital, Division of Pediatric Respiratory Medicine, Montreal, Canada; 5The Hospital for Sick Children, Department of Respiratory Medicine, Toronto, Canada