Lumacaftor/ivacaftor reduces exacerbations in adults homozygous for Phe508del mutation with severe lung disease.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations. METHODS: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. RESULTS: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 - 0.676), p <  0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. CONCLUSIONS: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.

Trial Refresh: A Case for an Adaptive Platform Trial for Pulmonary Exacerbations of Cystic Fibrosis.

Cystic fibrosis is a genetic disease typically characterized by progressive lung damage and premature mortality. Pulmonary exacerbations, or flare-ups of the lung disease, often require hospitalization for intensive treatment. Approximately 25% of patients with cystic fibrosis do not recover their baseline lung function after pulmonary exacerbations. There is a relative paucity of evidence to inform treatment strategies for exacerbations. Compounding this lack of evidence, there are a large number of treatment options already as well as becoming available. This results in significant variability between medication regimens prescribed by different physicians, treatment centers and regions with potentially adverse impact to patients. The conventional strategy is to undertake essential randomized clinical trials to inform treatment decisions and improve outcomes for patients with exacerbations. However, over the past several decades, clinical trials have generally failed to provide information critical to improved treatment and management of exacerbations. Bayesian adaptive platform trials hold the promise of addressing clinical uncertainties and informing treatment. Using modeling and response adaptive randomization, they allow for the evaluation of multiple treatments across different management domains, and progressive improvement in patient outcomes throughout the course of the trial. Bayesian adaptive platform trials require substantial amounts of preparation. Basic preparation includes extensive stakeholder involvement including elicitation of consumer preferences and clinician understanding of the research topic, defining the research questions, determining the best outcome measures, delineating study sub-groups, in depth statistical modeling, designing end-to-end digital solutions seamlessly supporting clinicians, researchers and patients, constructing randomisation algorithms and importantly, defining pre-determined intra-study end-points. This review will discuss the motivation and necessary steps required to embark on a Bayesian adaptive platform trial to optimize medication regimens for the treatment of pulmonary exacerbations of cystic fibrosis.

Airway clearance by exercising in mild cystic fibrosis (ACE-CF): A feasibility study.

BACKGROUND: People with cystic fibrosis (CF) are encouraged to perform airway clearance techniques on a daily basis. Whilst several short-term studies support a potential role for exercise as an airway clearance technique, to date no medium to longer term studies have investigated the use of exercise as a stand-alone airway clearance technique. OBJECTIVE: To determine the feasibility of a protocol investigating the use of exercise as a stand-alone form of airway clearance in adults with CF. METHODS: Adults with CF and a FEV1 ≥ 70% predicted were eligible. After a four week wash-in period of daily positive expiratory pressure (PEP) and exercise, adherent participants were randomised to either daily PEP plus exercise or exercise-only for three months. Pre-specified thresholds for feasibility for the primary outcomes were rates of recruitment ≥30%, randomisation ≥80% and completion ≥80%. Secondary outcomes included respiratory function tests, respiratory exacerbation rate and health-related quality of life. RESULTS: Of the 57 eligible patients identified, 17 were recruited (30%). After the wash-in period, 13 of the 17 participants (76%) were randomised and all 13 (100%) completed the final assessment. The median (IQR) change in FEV1 (L) over the intervention period was 0.00 (-0.08 - 0.15) L for the PEP plus exercise group and -0.03 (-0.19 - 0.13) L for the exercise-only group. CONCLUSION: The study achieved its a priori target feasibility rates for recruitment and completion but failed to meet the randomisation target rate. Changes in lung function and quality of life were similar between groups. Further refinement of the protocol may be required prior to expansion to a multi-centred trial.

Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. METHODS: Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation-after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. RESULTS: DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs -0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. CONCLUSIONS: Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study.

This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU·g(-1) (range -9.78-5.02 log10 CFU·g(-1))) compared with placebo (-0.27 log10 CFU·g(-1) (range -7.96-5.25 log10 CFU·g(-1))); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis.

Automated medical literature retrieval.

BACKGROUND: The constantly growing publication rate of medical research articles puts increasing pressure on medical specialists who need to be aware of the recent developments in their field. The currently used literature retrieval systems allow researchers to find specific papers; however the search task is still repetitive and time-consuming. AIM: In this paper we describe a system that retrieves medical publications by automatically generating queries based on data from an electronic patient record. This allows the doctor to focus on medical issues and provide an improved service to the patient, with higher confidence that it is underpinned by current research. METHOD: Our research prototype automatically generates query terms based on the patient record and adds weight factors for each term. Currently the patient's age is taken into account with a fuzzy logic derived weight, and terms describing blood-related anomalies are derived from recent blood test results. Conditionally selected homonyms are used for query expansion. The query retrieves matching records from a local index of PubMed publications and displays results in descending relevance for the given patient. Recent publications are clearly highlighted for instant recognition by the researcher. RESULTS: Nine medical specialists from the Royal Adelaide Hospital evaluated the system and submitted pre-trial and post-trial questionnaires. Throughout the study we received positive feedback as doctors felt the support provided by the prototype was useful, and which they would like to use in their daily routine. CONCLUSION: By supporting the time-consuming task of query formulation and iterative modification as well as by presenting the search results in order of relevance for the specific patient, literature retrieval becomes part of the daily workflow of busy professionals.

Nonvolumetric echocardiographic indices of right ventricular systolic function: validation with cardiovascular magnetic resonance and relationship with functional capacity.

PURPOSE: Right ventricular (RV) systolic function as measured by right ventricular ejection fraction (RVEF) has long been recognized as an important predictor of outcome in heart failure patients. The echocardiographic measurement of RV volumes and RVEF is challenging, however, owing to the unique geometry of the right ventricle. Several nonvolumetric echocardiographic indices of RV function have demonstrated prognostic value in heart failure. Comparison studies of these techniques with each other using RVEF as a benchmark are limited, however. Furthermore, the contribution of these various elements of RV function to patient functional status is uncertain. We therefore aimed to: (1) Determine which nonvolumetric echocardiographic index correlates best with RVEF as determined by cardiac magnetic resonance (CMR) imaging (the accepted gold standard measure of RV systolic function) and (2) Ascertain which echocardiographic index best predicts functional capacity. METHODS: Eighty-three subjects (66 with systolic heart failure and 17 healthy controls) underwent CMR, 2D echocardiography, and cardiopulmonary exercise testing for comparison of echocardiographic indices of RV function with CMR RVEF, 6-minute walk distance and VO(2 PEAK). RESULTS: Speckle tracking strain RV strain exhibited the closest association with CMR RV ejection fraction. Indices of RV function demonstrated weak correlation with 6-minute walk distance, but basal RV strain rate by tissue velocity imaging had good correlation with VO(2 PEAK). CONCLUSION: Strain by speckle tracking echocardiography and strain rate by tissue velocity imaging may offer complementary information in the evaluation of RV contractility and its functional effects.

Changes in cystic fibrosis mortality in Australia, 1979-2005.

OBJECTIVE: To assess mortality trends among people with cystic fibrosis (CF) in Australia. DESIGN AND SETTING: We augmented Australian summary data for deaths from CF registered during 1979-2005 with information from Australian transplant centres on lung transplantation among CF patients for 1989-2005 to allow us to follow trends in all "mortality events" (death or lung transplantation). MAIN OUTCOME MEASURE: Age at death or lung transplantation. RESULTS: Between 1979 and 2005, the mean age at death increased from 12.2 years to 27.9 years for males and from 14.8 years to 25.3 years for females. Overall, female deaths in childhood (0-14 years) occurred at an age-standardised rate of 0.40 per 100,000 (95% CI, 0.34-0.45) during 1979-2005, which exceeded the corresponding rate for males of 0.24 (95% CI, 0.20-0.28) per 100,000. Among 0-14-year-old boys, event rates declined markedly after 1989, but they declined later and more gradually for girls, with the result that the age-standardised rate for girls was 2.38 times that of boys during 1989-2005 (95% CI, 1.69-3.36). CONCLUSIONS: The pattern of CF mortality in Australia has changed substantially. Mortality rates continue to be higher for girls than for boys, but death in childhood has become uncommon. Survival has increased since 1979, but females continue to have reduced length of life.

Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis--effects of pancreatic enzyme supplementation.

CONTEXT: Postprandial hyperglycemia is an important clinical problem in cystic fibrosis (CF), but the contribution of fat malabsorption, rapid gastric emptying, and the incretin axis has not been widely considered. OBJECTIVE: The aim of this study was to evaluate these aspects of gut function in nondiabetic CF patients. DESIGN AND SETTING: We conducted a randomized, double-blind, placebo-controlled crossover study at a clinical research laboratory. PATIENTS: Five nondiabetic CF patients (three males; age, 25.8 ± 1.0 yr; body mass index, 20.2 ± 1.1 kg/m(2)) with exocrine pancreatic insufficiency and six healthy subjects of similar age and body mass index participated in the study. INTERVENTIONS: CF patients consumed a radiolabeled mashed potato meal on 2 separate days, together with four capsules of Creon Forte (100,000 IU lipase) or placebo. Healthy subjects consumed the meal once, without pancreatic enzymes. MAIN OUTCOME MEASURES: Gastric emptying was measured using scintigraphy, and blood was sampled frequently for blood glucose and plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon concentrations. RESULTS: CF patients had more rapid gastric emptying (P < 0.001), impaired secretion of GLP-1 (P < 0.01) and GIP (P < 0.001), and greater postprandial glycemic excursions (P < 0.001) than healthy subjects. Pancreatic enzyme supplementation normalized gastric emptying and GLP-1 secretion and tended to increase glucagon (P = 0.08), but did not completely restore GIP secretion or normalize postprandial blood glucose. There was an excellent correlation between gastric emptying and blood glucose concentration at 60 min (R = 0.75; P = 0.01). CONCLUSIONS: Pancreatic enzyme supplementation plays an important role in incretin secretion, gastric emptying, and postprandial hyperglycemia in CF.

What is the best method for measuring renal function in adults and children with cystic fibrosis?

AIMS: To measure the glomerular filtration rate (GFR) in adults and children with cystic fibrosis (CF) using a radio-isotope technique as the gold standard and to compare this to serum creatinine based equations, serum cystatin C levels and tobramycin clearance, and to determine which method correlates most closely with measured GFR in this population.

Renal dysfunction in cystic fibrosis: is there cause for concern?

Most people associate cystic fibrosis (CF) with lung disease. Although this is the major cause of morbidity and mortality, CF is in fact a multi-organ disease. Patients with CF are living longer. Accompanying their increased life expectancy are complications not previously encountered. One of the less obvious concerns is that of renal dysfunction associated with long-term exposure to aminoglycosides as well as renally toxic immunosuppressants in lung transplant recipients. This article reviews what is known about the extent of the problem, summarizes what the current practices of measuring and monitoring renal function in patients with CF, and makes suggestions for alternative approaches. In particular, the potential role of cystatin C will be discussed.

Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF).

OBJECTIVE: Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Adult CF outpatient clinics at two hospitals. PATIENTS: Twenty-two non-transplanted CF patients aged > or = 18 years with a bone densitometry T-score of < -1.5 at one of three sites (lumbar spine, femoral neck, distal forearm) were studied. Participants were randomized to receive either 2 mg zoledronate i.v. (n = 10) or normal saline (placebo, n = 12) every 3 months for 2 years (8 infusions). All participants received calcium and vitamin D supplements twice daily. MEASUREMENTS: Percentage change in areal BMD from baseline. RESULTS: Lumbar spine BMD increased from baseline more with zoledronate than placebo at 6 months (5.35 +/- 0.76 vs. 1.19 +/- 1.20%, P = 0.012), 12 months (6.6 +/- 1.5 vs. 0.35 +/- 1.55%, P = 0.011) and 24 months (6.14 +/- 1.86 vs. 0.44 +/- 0.10, P = 0.021). Femoral neck BMD increased more after zoledronate than placebo at 6 months (3.2 +/- 1.6 vs.-1.43 +/- 0.43%, P = 0.019), 12 months (4.12 +/- 1.8 vs.-1.59 +/- 1.4%, P = 0.024) and 24 months (4.23 +/- 1.3 vs.-2.5 +/- 1.41%, P = 0.0028). Forearm BMD did not change. Zoledronate was associated with flu-like and musculoskeletal side effects, particularly after the first infusion. There were no fractures in either group. CONCLUSION: Intravenous zoledronate was significantly more effective than placebo for increasing BMD in adults with CF and osteopaenia, but side effects limited its tolerability.

Evaluation of the 13C-triolein breath test for fat malabsorption in adult patients with cystic fibrosis.

BACKGROUND AND AIMS: A simple non-invasive test not requiring the use of radioactive isotopes is required to assess fat malabsorption in adult cystic fibrosis (CF) patients. Breath tests using substrates labeled with 13C meet these conditions. The 14C-triolein breath test is sensitive and specific for measuring fat malabsorption, but involves radiation exposure. The aim of this study was to examine the utility of a test using a 13C label and to determine whether pancreatic replacement therapy would return the test to the values of a normal control group. METHODS: 13CO2 recovery was assessed after an overnight fast in six adult patients with CF, both with and without pancreatic enzyme replacement therapy (PERT) in the usual dose for a light snack, in a randomized order, on different days. Studies were also performed in eight healthy volunteers after oral ingestion. Subjects drank 50 mL of a liquid meal mixed with 200 microL 13C-triolein and breath samples were collected by blowing through a straw into collection tubes every 30 min for 6 h. The effect of gastric emptying was assessed by comparison of oral ingestion with intraduodenal infusion. Intra-individual variability was assessed in nine volunteers by repeating the breath test after drinking the test meal on a separate day. RESULTS: Compared with healthy subjects there was virtually no recovery of 13CO2 in CF patients without PERT. The median (interquartile range) cumulative percentage dose recovery (cPDR) at 6 h was 3% (0-8) in CF patients compared with 28% (22-41) in healthy controls (P < 0.01). Fat absorption was normalized (37%) (36-43) after ingestion of PERT. Gastric emptying delayed the peak in 13CO2 recovery, but there was no difference in the cPDR at 6 h. There was no difference in recovery between days 1 and 2. CONCLUSIONS: The 13C-triolein breath test is a simple and reproducible method to measure fat malabsorption. The test provides a screening technique for fat malabsorption in adult CF patients and may be useful for monitoring the lowest effective dose of PERT.