Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Effectiveness of lumacaftor/ivacaftor initiation in children with cystic fibrosis aged 2 through 5 years on disease progression: Interim results from an ongoing registry-based study.

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR). METHODS: The LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort). RESULTS: The LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021. CONCLUSIONS: This interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

Surgical or Percutaneous Repair of Sinus of Valsalva Rupture: Case Series and Literature Review.

The rupture of the sinus of the Valsalva aneurysm is a rare but very serious condition. Rapid and accurate diagnosis and prompt treatment are critical for these cases. We present two cases of sinus of Valsalva ruptures. One case was managed with open surgical repair and the second case was treated percutaneously. We have discussed these two therapeutic approaches available to treat sinus of Valsalva rupture.

Registry-based study in people with cystic fibrosis and an R117H variant treated with ivacaftor.

BACKGROUND: Ivacaftor approval was extended to people with cystic fibrosis (CF) and an R117H variant in 2014 in the USA. This observational, real-world, postapproval study evaluated long-term outcomes among people with CF and an R117H variant on ivacaftor using data from the US Cystic Fibrosis Foundation Patient Registry. METHODS: Key outcomes were evaluated in ivacaftor-treated people with CF and an R117H variant for up to 36 months before and after treatment initiation using within-group comparisons. Analyses were descriptive in nature, focused on evaluation of observed outcome patterns over time and were performed both overall and for age groups ≥2 to <6 years, ≥6 to <18 years and ≥18 years. Key outcomes included lung function, body mass index (BMI), pulmonary exacerbations (PEx) and hospitalisations. RESULTS: The ivacaftor cohort included 369 people with CF and an R117H variant who initiated therapy between 1 January 2015 and 31 December 2016. During each of the 12-month intervals following treatment initiation, the mean observed percent predicted forced expiratory volume in 1 s (ppFEV1) and BMI values were higher and the mean annualised number of PEx and hospitalisation events were lower than pretreatment values. Mean change in ppFEV1 from pretreatment baseline was an increase of 1.5 (95% CI 0.8 to 2.3), 1.7 (95% CI 0.7 to 2.7) and 1.8 (95% CI 0.6 to 3.0) percentage points in the first, second and third years of treatment, respectively. Similar trends were observed in adult and paediatric subgroups. CONCLUSIONS: The results support the clinical effectiveness of ivacaftor in people with CF and an R117H variant, including adult and paediatric subgroups.

Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial.

BACKGROUND: Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks. METHODS: Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate. RESULTS: 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A. CONCLUSIONS: TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

A Phase 3, Open-Label Study of Lumacaftor/Ivacaftor in Children 1 to Less Than 2 Years of Age with Cystic Fibrosis Homozygous for F508del-CFTR.

Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).

Nonpoint source arsenic contamination of soil and groundwater from legacy pesticides.

Arsenic (As) contamination in wells is common throughout the northeastern United States. It is well documented that lead-arsenate (PbHAsO4 ) pesticides were widely used on fruit tree orchards from the 1890s to 1950s. This study evaluates the potential for As contamination of groundwater from former orchards in Connecticut, where there were over 47,000 orchards in 1935. A proximity analysis involving 189 orchards and 114 domestic wells was conducted to assess the spatial relationship between historic orchards and As in wells. Field studies were then conducted to characterize As and lead (Pb) distributions in soils and wells near historic orchards. The proximity analysis found that the wells with no detected As were further away from historic orchards and had fewer historic orchards within their vicinity when compared with wells that contained As. The field investigations found that elevated levels of As and Pb were widespread in soils from orchards established by 1951, with some As concentrations exceeding 200 ppm. In some soils, As and Pb were leachable at concentrations exceeding USEPA drinking water standards in synthetic precipitation laboratory tests. It was also found that the wells nearest to the impacted soils tended to contain the highest As concentrations, while the wells located in areas that were forested prior to 1970 contained no As. Overall, this study found that As and Pb from legacy pesticide residues are still abundant in former orchard soils and that a strong spatial relationship exists between As-contaminated wells and historic orchards. Greater consideration should be given to historic orchard soils as a potential contributing nonpoint source of As to the groundwater in Connecticut, where domestic well contamination rates are high.

Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release.

Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.

Development and decay of procedural skills in surgery: A systematic review of the effectiveness of simulation-based medical education interventions.

CONTEXT: Changes to surgical training programmes in the UK has led to a reduction in theatre time for trainees, and an increasing reliance on simulation to provide procedural experience. Whilst simulation offers opportunity for repetitive practice, the effectiveness of simulation as an educational intervention for developing procedural surgical skills is unclear. METHODS: A systematic literature review was undertaken to retrieve all studies describing simulation-based medical education (SBME) interventions for the development of procedural surgical skills using the MEDLINE, PsycINFO, CINAHL, EMBASE and PUBMED databases. Studies measuring skill retention or demonstrating transferability of skills for improving patient outcomes were included in the review. RESULTS: SBME is superior to no training and can lead to improvement in procedural surgical skills, such that skills transfer from simulated environments into theatre. SBME results in minimal skill degradation after 2 weeks, although more significant decay results after >90 days. Many studies recruited <10 participants, used a variety of methods and were restricted to endoscopic surgical techniques. All studies did not compare interventions with non-SBME teaching methods for developing procedural surgical skills. No studies compared the curriculum design of different surgical training programmes. CONCLUSIONS: SBME interventions are effective for developing procedural skills in surgery. SBME interventions are also effective for preventing the decay of procedural surgical skills. Although no studies demonstrate non-inferiority of SBME interventions compared to time in theatre developing skills, SBME interventions do enable the transfer of skills into theatre, and the potential for improving patient outcomes.

Ivacaftor in Infants Aged 4 to <12 Months with Cystic Fibrosis and a Gating Mutation. Results of a Two-Part Phase 3 Clinical Trial.

Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months.Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations.Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B.Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event (n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved.Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations.Clinical trial registered with clinicaltrials.gov (NCT02725567).

Deliberate Practice in Simulation-Based Surgical Skills Training: A Scoping Review.

BACKGROUND: In recent years there has been a shift from traditional Halstedian methods toward more simulation-based medical education (SBME) for developing surgical skills. Questions remain about the role and value of SBME, although feedback and engagement in repetitive practice have been associated with positive learning outcomes. Regardless of approach, the principles of deliberate practice align with both the Halstedian traditions and ways of implementing SBME. Whilst deliberate practice is well described in the wider literature, the extent to which it is an effective instructional approach in surgical training remains unknown. OBJECTIVE: To explore the effectiveness of deliberate practice as an instructional design for developing surgical skills through SBME interventions, as assessed by improvements in trainee performance and/or patient outcomes. METHODS: A combined search was conducted in PUBMED, CINAHL, EMBASE, MEDLINE, PSYCHINFO, and Google Scholar. Three hundred one articles were screened and 17 met the inclusion criteria for analysis. RESULTS: There was heterogeneity of study methods with 6 randomized control trials, 7 pretest/post-test design, 2 nonrandomized comparisons and 2 observational studies. All articles demonstrated positive learner outcomes following SBME with deliberate practice, although there was no direct comparison to another instructional method. Two studies demonstrated skill transfer to the clinical environment and 1 demonstrated improved patient outcomes. CONCLUSION: Deliberate practice informed SBME interventions appeared effective for developing surgical skills among trainee surgeons, however the reliability of these conclusions was limited by the modest quality of the research studies and the design elements of deliberate practice were inconsistently applied. There was little evidence that deliberate practice led to skills retention beyond 30 days, although participant numbers were low and the quality of studies was modest.

A phase 3, randomized, double-blind, parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation.

BACKGROUND: Tezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes. METHODS: Enrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1). Key secondary endpoints were relative change in ppFEV1 and absolute change in CF Questionnaire-Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8. RESULTS: Sixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF. CONCLUSIONS: This Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).

G970R-CFTR Mutation (c.2908G>C) Results Predominantly in a Splicing Defect.

In previous work, participants with a G970R mutation in cystic fibrosis transmembrane conductance regulator (CFTR) (c.2908G>C) had numerically lower sweat chloride responses during ivacaftor treatment than participants with other CFTR gating mutations. The objective of this substudy was to characterize the molecular defect of the G970R mutation in vitro and assess the benefit of ivacaftor in participants with this mutation. This substudy assessed sweat chloride, spirometry findings, and nasal potential difference on and off ivacaftor treatment in three participants with a G970R/F508del genotype. Intestinal organoids derived from rectal biopsy specimens were used to assess ivacaftor response ex vivo and conduct messenger RNA splice and protein analyses. No consistent or meaningful trends were observed between on-treatment and off-treatment clinical assessments. Organoids did not respond to ivacaftor in forskolin-induced swelling assays; no mature CFTR protein was detected in Western blots. Organoid RNA analysis demonstrated that 3 novel splice variants were created by G970R-CFTR: exon 17 truncation, exons 13-15 and 17 skipping, and intron 17 retention. Functional and molecular analyses indicated that the c.2908G>C mutation caused a cryptic splicing defect. Organoids lacked an ex vivo response with ivacaftor and supported identification of the mechanism underlying the CFTR defect caused by c.2908G>C. Analysis of CFTR mutations indicated that cryptic splicing was a rare cause of mutation misclassification in engineered cell lines. This substudy used organoids as an alternative in vitro model for mutations, such as cryptic splice mutations that cannot be fully assessed using cDNA expressed in recombinant cell systems.

Use of bacteria community analysis to distinguish groundwater recharge sources to shallow wells.

In this study, bacteria community analysis was performed to supplement a preexisting evaluation of nitrate contamination in drinking water wells at a coastal site in Old Lyme, CT. Given well usage and coastal hydrogeologic conditions, the source(s) of nitrate contamination in domestic wells could not be discerned between local septic systems or a nearby farm where organic fertilizers were used. Groundwater bacteria communities are known to be sensitive to a variety of environmental conditions. As such, they are potentially useful in distinguishing groundwater recharge sources. Groundwater samples collected from wells were analyzed using polymerase chain reactions (PCR) and 16S rRNA sequencing to determine the bacteria distributions in each well. The biostatistical analysis of the data using Bray-Curtis nonmetric multidimensional scaling and permutational multivariate analysis of variance revealed three distinct bacteria community distributions that coincided with three different areas on the site. Additionally, principal component analysis (PCA) of the water quality data revealed that wells with similar bacteria shared similar water quality, all of which was indicative of local recharge. These findings suggested that the domestic well nitrate contamination was derived from local septic systems rather than the farm. Septic indicator analysis using ultra-performance liquid chromatography-tandem mass spectrometry determined the presence of caffeine in domestic wells, which was consistent with the conclusions from the bacteria analysis, PCA, and the known hydrogeologic conditions. The low cost, ease of sample collection, and growing availability of bioinformatics laboratory services and software are conducive to the application of microbial community analysis as a supplemental tool for groundwater investigations.

Long-Term Ivacaftor in People Aged 6 Years and Older with Cystic Fibrosis with Ivacaftor-Responsive Mutations.

INTRODUCTION: Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) affect the quantity and/or function of CFTR protein reaching the cell surface. Ivacaftor, a CFTR potentiator that enhances chloride transport, increases the channel-open probability of normal and dysfunctional CFTR. Initially approved for people with CF (pwCF) with G551D-CFTR gating mutations, ivacaftor demonstrated clinical benefit in pwCF with other gating mutations and certain residual function mutations, including R117H-CFTR, in clinical studies. We evaluated the long-term safety and efficacy of ivacaftor in pwCF aged 6 years and older with non-G551D-CFTR ivacaftor-responsive mutations. METHODS: Efficacy and safety data from a phase 3, multicenter, open-label, extension study for participants from Study 110 (R117H-CFTR mutations), Study 111 (non-G551D-CFTR gating mutations), and Study 113 (n-of-1 pilot study in participants with residual CFTR function) were analyzed. Following washout from the randomized parent study, participants received oral ivacaftor 150 mg once every 12 h for 104 weeks. RESULTS: Forty-one of 121 participants completed treatment through 104 weeks; 59 participants who did not complete the extension study continued treatment with commercial ivacaftor. The most common adverse events were pulmonary exacerbation (46.3%) and cough (33.9%). Most treatment-emergent adverse events were mild/moderate in severity and consistent with manifestations of CF or the ivacaftor safety profile. Rapid, durable improvement occurred across all efficacy endpoints. CONCLUSIONS: Ivacaftor was generally safe and well tolerated with no new safety concerns for up to 104 weeks in pwCF with ivacaftor-responsive mutations. The pattern of improvement across efficacy endpoints was durable and generally consistent with parent-study outcomes. TRIAL REGISTRATION: NCT01707290.

Real-World Outcomes Among Patients with Cystic Fibrosis Treated with Ivacaftor: 2012-2016 Experience.

INTRODUCTION: In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. METHODS: Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. RESULTS: Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. CONCLUSIONS: Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.

We performed a study to better understand the long-term impact of treatment with a drug called ivacaftor for patients with cystic fibrosis (CF). Our study used data from CF patient registries in the United Kingdom and the United States. These registries collect information about patients with CF, their health, and the treatments they receive. Using data from these registries, we compared patients treated with ivacaftor with a similar group of patients (similar age, sex, and disease severity) who did not receive ivacaftor. We looked at the clinical outcomes of each group every year for up to 5 years. In the final analysis from our study, we found no new safety concerns associated with ivacaftor treatment. Additionally, we found that patients treated with ivacaftor tended to have lower risks of death, organ transplant, pulmonary exacerbations, and hospitalizations. Overall, these results demonstrate the favorable impact of ivacaftor treatment on long-term outcomes of patients with CF.

Identifying the World Health Organization's fifth moment for hand hygiene: Infection prevention in the operating room.

BACKGROUND: The World Health Organization have designed the fifth of their '5 moments' for hand hygiene to account for microbial transfer from patients to equipment in a narrow area around that patient, known as the patient zone. The study was prompted by emerging local confusion about application of the patient zone in the operating room (OR). AIM/OBJECTIVES: In two phases, we aimed to create a '5 moments' style poster displaying an OR patient zone: phase 1, quantify equipment, in direct contact with the patient and, touched by non-scrubbed staff immediately after touching the patient; and phase 2, categorise equipment identified in phase 1 into patient zone and healthcare zone. An objective is to produce a '5 moments' poster for the OR. METHODS: The first phase used non-participant direct overt observation. In phase 2, phase 1 data were collaboratively assigned to patient zone or healthcare zone. Photography and graphic design were used to produce the OR '5 moments' poster. RESULTS: In 11 full-length surgeries, 20 pieces of equipment were in direct contact with the patient and 57 pieces of equipment were touched. In phase 2, a '5 moments' poster showing an OR patient zone was designed. DISCUSSION: Content of the patient zone was identified and displayed in a novel resource. Having shared understanding of the patient zone has potential to sustain hand hygiene compliance and equipment cleaning in the OR. CONCLUSION: Limitations in methods were balanced by collaboration with frontline staff. The study has been used as a teaching tool in the OR and similar settings.

Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries.

BACKGROUND: Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years. METHODS: Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity. RESULTS: US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012-2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, -0.7 percentage points with ivacaftor vs -8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings. CONCLUSIONS: This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

Ivacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study.

BACKGROUND: Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design. METHODS: Patients aged ≥12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV1) after 2 weeks of treatment with ivacaftor relative to placebo. RESULTS: Absolute change (SD) from study baseline in ppFEV1 favored ivacaftor by 2.3 (1.0) percentage points (95% credible interval, 0.4-4.1) after 2 weeks of treatment. Absolute mean change (SD) from open-label baseline (defined as day 1 of the open-label ivacaftor treatment period) in ppFEV1 after 8 weeks of treatment was 4.7 (4.2) percentage points (P<.0001). Safety of ivacaftor was consistent with that observed in prior studies. CONCLUSIONS: Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function (ClinicalTrials.gov, NCT01685801).