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1.
Lancet Respir Med ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31570318

RESUMO

The past six decades have seen remarkable improvements in health outcomes for people with cystic fibrosis, which was once a fatal disease of infants and young children. However, although life expectancy for people with cystic fibrosis has increased substantially, the disease continues to limit survival and quality of life, and results in a large burden of care for people with cystic fibrosis and their families. Furthermore, epidemiological studies in the past two decades have shown that cystic fibrosis occurs and is more frequent than was previously thought in populations of non-European descent, and the disease is now recognised in many regions of the world. The Lancet Respiratory Medicine Commission on the future of cystic fibrosis care was established at a time of great change in the clinical care of people with the disease, with a growing population of adult patients, widespread genetic testing supporting the diagnosis of cystic fibrosis, and the development of therapies targeting defects in the cystic fibrosis transmembrane conductance regulator (CFTR), which are likely to affect the natural trajectory of the disease. The aim of the Commission was to bring to the attention of patients, health-care professionals, researchers, funders, service providers, and policy makers the various challenges associated with the changing landscape of cystic fibrosis care and the opportunities available for progress, providing a blueprint for the future of cystic fibrosis care. The discovery of the CFTR gene in the late 1980s triggered a surge of basic research that enhanced understanding of the pathophysiology and the genotype-phenotype relationships of this clinically variable disease. Until recently, available treatments could only control symptoms and restrict the complications of cystic fibrosis, but advances in CFTR modulator therapies to address the basic defect of cystic fibrosis have been remarkable and the field is evolving rapidly. However, CFTR modulators approved for use to date are highly expensive, which has prompted questions about the affordability of new treatments and served to emphasise the considerable gap in health outcomes for patients with cystic fibrosis between high-income countries, and low-income and middle-income countries (LMICs). Advances in clinical care have been multifaceted and include earlier diagnosis through the implementation of newborn screening programmes, formalised airway clearance therapy, and reduced malnutrition through the use of effective pancreatic enzyme replacement and a high-energy, high-protein diet. Centre-based care has become the norm in high-income countries, allowing patients to benefit from the skills of expert members of multidisciplinary teams. Pharmacological interventions to address respiratory manifestations now include drugs that target airway mucus and airway surface liquid hydration, and antimicrobial therapies such as antibiotic eradication treatment in early-stage infections and protocols for maintenance therapy of chronic infections. Despite the recent breakthrough with CFTR modulators for cystic fibrosis, the development of novel mucolytic, anti-inflammatory, and anti-infective therapies is likely to remain important, especially for patients with more advanced stages of lung disease. As the median age of patients with cystic fibrosis increases, with a rapid increase in the population of adults living with the disease, complications of cystic fibrosis are becoming increasingly common. Steps need to be taken to ensure that enough highly qualified professionals are present in cystic fibrosis centres to meet the needs of ageing patients, and new technologies need to be adopted to support communication between patients and health-care providers. In considering the future of cystic fibrosis care, the Commission focused on five key areas, which are discussed in this report: the changing epidemiology of cystic fibrosis (section 1); future challenges of clinical care and its delivery (section 2); the building of cystic fibrosis care globally (section 3); novel therapeutics (section 4); and patient engagement (section 5). In panel 1, we summarise key messages of the Commission. The challenges faced by all stakeholders in building and developing cystic fibrosis care globally are substantial, but many opportunities exist for improved care and health outcomes for patients in countries with established cystic fibrosis care programmes, and in LMICs where integrated multidisciplinary care is not available and resources are lacking at present. A concerted effort is needed to ensure that all patients with cystic fibrosis have access to high-quality health care in the future.

2.
J Cyst Fibros ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31405730

RESUMO

BACKGROUND: In cystic fibrosis (CF), omalizumab has been used for difficult-to-treat asthma and allergic bronchopulmonary aspergillosis (ABPA) but safety and efficacy data are limited for this population. METHODS: We assessed patients receiving omalizumab for asthma or ABPA in the Toronto adult CF center between 2005 and 2017. We evaluated treatment safety and efficacy by analyzing changes in FEV1% predicted (FEV1pp) max value, slope and variability captured by the area under the curve (AUC), the cumulative dose of systemic corticosteroids (SCS), use of intravenous (IV) antibiotics and hospitalization days before omalizumab and up to 1 year after treatment initiation. Linear mixed effects model was used for FEV1pp slope and the trapezoidal rule for FEV1pp AUC. RESULTS: Twenty-seven CF patients received omalizumab, 16 (59.3%) for asthma and 11 (40.7%) for ABPA. No significant omalizumab-related adverse effects were observed. In the asthmatic group, the max value of FEV1pp improved on omalizumab and the cumulative dose of SCS decreased. In the ABPA group, the rate of FEV1pp decline (slope) and the variability of FEV1pp (AUC) improved on omalizumab. In ABPA patients, the cumulative SCS dose was not significantly different but 4 (36%) patients decreased their SCS dose by >50% compared to baseline. Days on IV antibiotics and hospital days did not differ significantly before and while on omalizumab therapy. CONCLUSIONS: In adult CF patients with difficult-to-treat asthma or ABPA, omalizumab should be considered. Larger studies are needed to identify patient characteristics that may predict response to omalizumab.

3.
Pulm Pharmacol Ther ; 58: 101819, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302339

RESUMO

BACKGROUND: ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS: Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS: All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS: SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION: NCT03056989.

4.
Ann Am Thorac Soc ; 16(7): 861-867, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30874447

RESUMO

Rationale: Intravenous tobramycin is frequently used to treat pulmonary exacerbations (PExs) in patients with cystic fibrosis (CF), but there is concern that azithromycin may interact with tobramycin, making it less effective against Pseudomonas aeruginosa. Objectives: The objective of this study was to determine whether oral azithromycin use was associated with worse lung function response to intravenous tobramycin treatment for PExs in a cohort of pediatric patients with CF with chronic P. aeruginosa infection. Methods: Pediatric patients from the Toronto CF database were included if they had at least one PEx and had chronic P. aeruginosa infection. Response to treatment was defined as change in forced expiratory volume in 1 second (FEV1) from start to end of treatment as well as recovery of FEV1 to greater than or equal to 90% of baseline (best FEV1 in the previous 6 mo). Response to treatment was compared between patients who had received chronic azithromycin (azithromycin users) and those who had not (azithromycin nonusers), using marginal structural modeling to account for baseline FEV1 as both a confounder and mediator. Results: There were 67 exacerbations (33 patients). Overall, 69% of azithromycin users and 61% of azithromycin nonusers returned to greater than or equal to 90% of baseline FEV1. However, after taking into account that azithromycin users had worse baseline FEV1 than azithromycin nonusers, relative improvement in FEV1 was 9.5% (95% confidence interval, -18.7 to -0.3) lower in azithromycin users than azithromycin nonusers. Conclusions: Although a similar proportion of children with CF with chronic P. aeruginosa infection on azithromycin recovered lung function compared with those not on azithromycin, when we consider these patients are sicker, azithromycin use was associated with less improvement in relative (but not absolute) FEV1 in patients treated with intravenous tobramycin for PExs.

5.
J Cyst Fibros ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30482682

RESUMO

BACKGROUND: Mortality risk stratification is essential in lung transplantation (LTx) to allow listing, prioritization and mitigating strategies. In cystic fibrosis (CF) patients, predictors of post-LTx mortality are not established. METHODS: For this systematic review and meta-analysis, seven databases were searched until January 3, 2018 to identify predictors of post-LTx mortality in CF. We excluded studies of multi-organ transplantation, re-transplantation and graft survival. For multiple studies assessing the same population during overlapping time-periods, the largest one was analyzed. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). Pooled hazard ratios were calculated using random-effects models. RESULTS: Fifty-four studies were included in the systematic review and 11 studies in the meta-analyses (low-to-moderate bias risk, NOS score ≥ 5). Among 10 factors assessed in the meta-analysis, B. cepacia complex (BCC) (N = 1451, unadjusted HR = 2.35, 95%CI:1.80-3.06; I2 = 20.4% and adjusted HR = 2.49, 95%CI:1.74-3.57; I2 = 46.2%) and ascending chronological year of LTx (N = 4207, unadjusted HR = 0.98, 95%CI:0.97-0.98, I2 = 4.8%) were predictors of post-LTx mortality. Male gender (N = 2903, adjusted HR = 1.12, 95%CI:1.0-1.26, I2 = 0%) and age in adults (N = 3677, unadjusted HR = 0.99, 95%CI:0.97-1.00; I2 = 64.1% and N = 2605, adjusted HR = 0.98, 95%CI:0.97-0.99; I2 = 34.3%) had borderline significant associations with post-LTx mortality. P. aeruginosa colonization, forced expiratory volume in one second (FEV1), pulmonary hypertension, body mass index (BMI), pancreatic insufficiency and CF-related diabetes (CFRD) were not predictors of mortality. CONCLUSIONS: BCC was associated with a higher post-LTx mortality whereas FEV1, pulmonary hypertension, BMI, CFRD and female gender were not associated with post-LTx mortality. These findings indicate that CF-specific risk estimates of post-LTx mortality should be considered.

6.
N Engl J Med ; 379(17): 1612-1620, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30334692

RESUMO

BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and ivacaftor (VX-445-tezacaftor-ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Adulto , Alelos , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Cloretos/metabolismo , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Mutação , Quinolonas/efeitos adversos , Suor/química , Adulto Jovem
7.
N Engl J Med ; 379(17): 1599-1611, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30334693

RESUMO

BACKGROUND: The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. METHODS: We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). RESULTS: VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV1 through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV1. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations. CONCLUSIONS: Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Adulto , Alelos , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Células Cultivadas , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Mutação , Quinolonas/efeitos adversos , Suor/química , Adulto Jovem
8.
J Cyst Fibros ; 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30279124

RESUMO

BACKGROUND: The "mild" gene variant, p.Arg117His in cystic fibrosis (CF) results in highly variable phenotypes ranging from male infertility to severe lung disease. Due to current interest to include this group in CFTR-targeted therapies, this study aims to describe the disease spectrum. METHODS: Retrospective study of Toronto CF and CFTR-related p.Arg117His patients. Longitudinally captured clinical data were compared between patients with 5T/7T-variants and those with a CF or CFTR-related diagnosis. Comparison was made between p.Arg117His adults and infants identified through CF newborn screening (NBS). RESULTS: Twenty of fifty patients carried the 5T variant, all with a diagnosis of CF (p.Arg117His-5TCF), and 30/50 carried 7T, 7 diagnosed with CF (p.Arg117His-7TCF) and 23 with a CFTR-related disorder (p.Arg117His-7TCFTR). For those with chest HRCT results available, 75% p.Arg117His-5TCF, 33% p.Arg117His-7TCF and 27% p.Arg117His-7TCFTR patients had bronchiectasis. Further, 79% p.Arg117His-5T, 29% p.Arg117His-7TCF and 13% p.Arg117His-7TCFTR had abnormal lung function. Of those, 80% grew CF-related pathogens on respiratory culture. Interestingly, the mean maximum sweat chloride and the percentage of patients growing CF-related bacterial pathogens were identical in p.Arg117His-7 TCFTR adults and p.Arg117His infants. CONCLUSIONS: Generally, p.Arg117His-5T patients had more severe CF disease. However, a subset of p.Arg117His-7 T patients demonstrated equally severe disease, thus warranting clinical monitoring of all p.Arg117His patients including p.Arg117His infants identified via NBS.

9.
Can J Diabetes ; 2018 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30173928

RESUMO

OBJECTIVES: We sought to identify the gap in cystic fibrosis-related diabetes (CFRD) screening by means of an oral glucose tolerance test (OGTT) in our tertiary care clinic. Our second aim was to identify the glycated hemoglobin level (A1C) threshold that optimizes sensitivity and specificity for predicting CFRD and impaired glucose tolerance. METHODS: This retrospective study used data housed in the Toronto cystic fibrosis (CF) database. The study population included all adult (≥18 years of age) patients seen in the CF clinic between January 1, 2008, and December 31, 2015. Descriptive statistics were used for the OGTT gap analysis; the CFRD screening rate was calculated on an annual basis as the proportion of eligible patients who received OGTTs. Sensitivity and specificity were calculated using OGTTs as the reference standard and A1C levels as the index test on a sample size of 320 patients. RESULTS: On average, 48.5% of eligible individuals were screened each year for CFRD by OGTTs. A1C thresholds of 5.5% had a sensitivity of 91.8% (75%) and a specificity of 34.1% (33.4%) for the diagnosis of CFRD (and impaired glucose tolerance), respectively. Of the 229 patients with A1C levels <5.5%, 5 test results (2.2%) had OGTTs indicative of CFRD. CONCLUSIONS: The rate of CFRD screening is suboptimal. An alternative screening algorithm using an A1C threshold of 5.5% has the potential to reduce the requirement for OGTTs by 36.7%. A1C levels cannot be used to identify impaired glucose tolerance.

10.
Ann Intensive Care ; 8(1): 85, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30187270

RESUMO

BACKGROUND: Noninvasive ventilation (NIV) is the first-line treatment of adult patients with exacerbations of cystic fibrosis (CF). High-flow nasal oxygen therapy (HFNT) might benefit patients with hypoxemia and can reduce physiological dead space. We hypothesized that HFNT and NIV would similarly reduce work of breathing and improving breathing pattern in CF patients. Our objective was to compare the effects of HFNT versus NIV in terms of work of breathing, assessed noninvasively by the thickening fraction of the diaphragm (TFdi, measured with ultrasound), breathing pattern, transcutaneous CO2 (PtcCO2), hemodynamics, dyspnea and comfort. METHODS: Adult CF patients who had been stabilized after requiring ventilatory support for a few days were enrolled and ventilated with HFNT and NIV for 30 min in crossover random order. RESULTS: Fifteen patients were enrolled. Compared to baseline, HFNT, but not NIV, reduced respiratory rate (by 3 breaths/min, p = 0.01) and minute ventilation (by 2 L/min, p = 0.01). Patients also took slightly larger tidal volumes with HFNT compared to NIV (p = 0.02). TFdi per breath was similar under the two techniques and did not change from baseline. MAP increased from baseline with NIV and compared to HFNT (p ≤ 0.01). Comfort was poorer with the application of both HFNT and NIV than baseline. No differences were found for heart rate, SpO2, PtcCO2 or dyspnea. CONCLUSIONS: In adult CF patients stabilized after indication for ventilatory support, HFNT and NIV have similar effects on diaphragmatic work per breath, but high-flow therapy confers additional physiological benefits by decreasing respiratory rate and minute ventilation. CLINICAL TRIAL REGISTRATION: Ethics Committee of St. Michael's Hospital (REB #14-338) and clinicaltrial.gov (NCT02262871).

11.
Ann Am Thorac Soc ; 15(7): 827-836, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29911888

RESUMO

RATIONALE: The extent of the genetic relatedness among Pseudomonas aeruginosa isolates and its impact on clinical outcomes in the cystic fibrosis (CF) population is poorly understood. OBJECTIVES: The objectives of this study were to determine the prevalence of clonal P. aeruginosa infection in Canada and to associate P. aeruginosa genotypes with clinical outcomes. METHODS: This was an observational study of adult and pediatric patients with CF across Canada. Isolates were typed using multilocus sequence typing. A clone was defined as sharing at least six of seven alleles. Genotyping results were associated with clinical outcomes, including forced expiratory volume in 1 second, body mass index, rate of pulmonary exacerbation, and death/transplant. RESULTS: A total of 1,537 P. aeruginosa isolates were genotyped to 403 unique sequence types (STs) in 402 individuals with CF. Although 39% of STs were shared, most were shared only among a small number of subjects, and the majority (79%) of the genetic diversity in P. aeruginosa isolates was observed between patients. There were no significant differences in clinical outcomes according to genotype. However, patients with a dynamic, changing ST infection pattern had both a steeper decline in forced expiratory volume in 1 second (-2.9% predicted change/yr, 95% confidence interval [CI] = -3.8 to -1.9 compared with 0.4, 95% CI = -0.3 to 1.0; P < 0.001) and body mass index (-1.0 percentile change/yr, 95% CI = -1.6 to -0.3 compared with -0.1, 95% CI = -0.7 to 0.5; P = 0.047) than those with a stable infection with the same ST. CONCLUSIONS: There was no widespread sharing of dominant clones in our CF population, and the majority of the genetic diversity in P. aeruginosa was observed between patients. Changing genotypes over time within an individual was associated with worse clinical outcomes.

12.
Am J Respir Crit Care Med ; 197(2): 214-224, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-28930490

RESUMO

RATIONALE: Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. OBJECTIVES: To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). MEASUREMENTS AND MAIN RESULTS: Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV1 (ppFEV1) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). CONCLUSIONS: These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

13.
N Engl J Med ; 377(21): 2024-2035, 2017 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-29099333

RESUMO

BACKGROUND: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS: The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS: CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234 .).


Assuntos
Aminofenóis/uso terapêutico , Benzodioxóis/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Fibrose Cística/tratamento farmacológico , Indóis/uso terapêutico , Quinolonas/uso terapêutico , Adolescente , Adulto , Aminofenóis/efeitos adversos , Aminofenóis/farmacologia , Benzodioxóis/efeitos adversos , Benzodioxóis/farmacologia , Criança , Estudos Cross-Over , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos adversos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Heterozigoto , Humanos , Indóis/efeitos adversos , Indóis/farmacologia , Masculino , Mutação , Qualidade de Vida , Quinolonas/efeitos adversos , Quinolonas/farmacologia , Adulto Jovem
14.
Hum Brain Mapp ; 38(10): 4813-4831, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28759710

RESUMO

Drowning is a leading cause of accidental injury and death in young children. Anoxic brain injury (ABI) is a common consequence of drowning and can cause severe neurological morbidity in survivors. Assessment of functional status and prognostication in drowning victims can be extremely challenging, both acutely and chronically. Structural neuroimaging modalities (CT and MRI) have been of limited clinical value. Here, we tested the utility of resting-state functional MRI (rs-fMRI) for assessing brain functional integrity in this population. Eleven children with chronic, spastic quadriplegia due to drowning-induced ABI were investigated. All were comatose immediately after the injury and gradually regained consciousness, but with varying ability to communicate their cognitive state. Eleven neurotypical children matched for age and gender formed the control group. Resting-state fMRI and co-registered T1-weighted anatomical MRI were acquired at night during drug-aided sleep. Network integrity was quantified by independent components analysis (ICA), at both group- and per-subject levels. Functional-status assessments based on in-home observations were provided by families and caregivers. Motor ICNs were grossly compromised in ABI patients both group-wise and individually, concordant with their prominent motor deficits. Striking preservations of perceptual and cognitive ICNs were observed, and the degree of network preservation correlated (ρ = 0.74) with the per-subject functional status assessments. Collectively, our findings indicate that rs-fMRI has promise for assessing brain functional integrity in ABI and, potentially, in other disorders. Furthermore, our observations suggest that the severe motor deficits observed in this population can mask relatively intact perceptual and cognitive capabilities. Hum Brain Mapp 38:4813-4831, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Lesões Encefálicas/etiologia , Lesões Encefálicas/fisiopatologia , Encéfalo/fisiopatologia , Afogamento/fisiopatologia , Encéfalo/diagnóstico por imagem , Lesões Encefálicas/diagnóstico por imagem , Mapeamento Encefálico/métodos , Criança , Pré-Escolar , Avaliação da Deficiência , Afogamento/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Exame Neurológico , Descanso
15.
Physiother Can ; 69(2): 171-177, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28539697

RESUMO

Purpose: The literature on physical activity (PA) in adults with cystic fibrosis, particularly in those with cystic fibrosis-related diabetes (CFRD), is limited. PA may be an important part of blood glucose management in CFRD. The purpose of this study was to describe PA levels in adults with CFRD and determine their adherence to the Canadian Diabetes Association (CDA) aerobic exercise training guidelines. Methods: Adults with CFRD were recruited from a hospital-based CF clinic. PA was measured using the Seven-Day Physical Activity Recall (telephone interview), adherence to CFRD management with the Self-Care Inventory-Revised (questionnaire), and blood glucose control from glycated hemoglobin levels documented in participants' medical chart within 3 months. Results: Eighteen adults (mean age 41 [SD 9] y) with diagnosed CFRD participated in the study. They varied in volume of PA (range 13,080-17,362 metabolic equivalent min/wk). Of the study participants, 12 (67%) met the CDA guidelines of 150 minutes of moderate to vigorous PA per week with no more than 2 consecutive days without exercise. No differences were found in clinical factors between those who met the aerobic exercise guidelines and those who did not. Conclusion: The majority of individuals with CFRD are meeting the recommended amount of aerobic PA. The factors influencing PA and blood glucose control in adults with CFRD require further investigation.

16.
J Cyst Fibros ; 16(4): 492-495, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28262569

RESUMO

There is no effective chronic suppressive therapy Burkholderia cepacia complex infection in cystic fibrosis (CF) patients. This was a pilot, open-label clinical trial of tobramycin inhalation powder (TIP) delivered via Podhaler twice daily for 28days in adults and children with CF and chronic B. cepacia complex infection in Toronto, Canada. A total of 10 subjects (4 pediatric, 6 adult patients) were treated. There was a mean drop of 1.4 log (CFU/ml) in sputum bacterial density (p=0.01) and sputum IL-8 levels decreased significantly after 28days of TIP (p=0.04). The mean relative change in FEV1 (L) from Day 0 to Day 28 of TIP administration was a 4.6% increase but this was not statistically significant. The majority of patients (70%) had no or mild adverse events.


Assuntos
Infecções por Burkholderia , Complexo Burkholderia cepacia , Fibrose Cística , Infecções Respiratórias , Tobramicina/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Antibacterianos/administração & dosagem , Infecções por Burkholderia/diagnóstico , Infecções por Burkholderia/tratamento farmacológico , Complexo Burkholderia cepacia/efeitos dos fármacos , Complexo Burkholderia cepacia/isolamento & purificação , Canadá/epidemiologia , Criança , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Monitoramento de Medicamentos/métodos , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Projetos Piloto , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Escarro/microbiologia , Resultado do Tratamento
17.
Clin Transl Gastroenterol ; 8(3): e81, 2017 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-28300821

RESUMO

OBJECTIVES: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator. METHODS: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment. RESULTS: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P<0.05). Area under the pH curve analyses indicate increased bicarbonate mass (P<0.05 for select 5 min intervals and all segments >30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen. CONCLUSIONS: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.

18.
J Cyst Fibros ; 16(1): 58-63, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27346471

RESUMO

BACKGROUND: Previous studies have shown an association between higher Stenotrophomonas maltophilia antibody levels and decreased lung function in patients with cystic fibrosis (CF). The purpose of this study was to assess the serologic response to S. maltophilia over time and to determine whether changes in antibody levels could predict clinical outcomes. METHODS: Changes in S. maltophilia antibody levels in adult and pediatric patients with CF from 2008 to 2014 were assessed between groups of infection patterns. Regression models accounting for repeated measures were used to assess whether antibody levels could predict subsequent S. maltophilia microbiological status, and whether they are associated with lung function and subsequent pulmonary exacerbation. RESULTS: A total of 409 S. maltophilia antibody samples from 135 CF patients showed that antibody levels did not change significantly between study visits, regardless of infection group. Higher antibody levels were independently associated with future culture positivity (OR 1.62; 95% CI 1.09, 2.41; p=0.02). While higher antibody levels were not independently associated with decreases in FEV1% predicted, they were associated with an increased hazard ratio for subsequent pulmonary exacerbation (HR 1.3; 95% CI 1.1, 1.6; p<0.001). CONCLUSIONS: S. maltophilia antibody levels may be helpful to identify individuals at risk of exacerbation who may benefit from earlier antimicrobial treatment.


Assuntos
Stenotrophomonas maltophilia , Adolescente , Adulto , Anticorpos/sangue , Canadá/epidemiologia , Criança , Fibrose Cística/sangue , Fibrose Cística/epidemiologia , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Progressão da Doença , Feminino , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Testes de Função Respiratória/métodos , Testes Sorológicos/métodos , Stenotrophomonas maltophilia/imunologia , Stenotrophomonas maltophilia/isolamento & purificação
19.
Thorax ; 72(4): 327-332, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27539619

RESUMO

BACKGROUND: Despite extensive knowledge regarding the effect of pulmonary exacerbations treated with intravenous antibiotics on clinical outcomes in cystic fibrosis (CF), there is little known about the role of milder pulmonary exacerbations treated with oral antibiotics (oPEx). METHODS: This was a retrospective cohort study of patients with CF followed at the Hospital for Sick Children and St. Michael's Hospital from 2009 to 2014. We evaluated the effect of oPEx on short-term clinical outcomes as the proportion of oPEx events in which 100% or 90% of baseline FEV1% predicted was recovered at the end of treatment. We then examined the association of the number of oPEx events in the past 12 months on lung function (FEV1% predicted) and nutritional status (body mass index (BMI) z-score) using a mixed-effects model. RESULTS: There were a total of 2608 oPEx events in 570 subjects during the study period. In over half (53.4%) of oPEx events, lung function was already at 90% or higher of baseline FEV1 at the initiation of oral antibiotic therapy and 82% were at 90% or higher of baseline FEV1 at follow-up. In individuals with CF, one or more oPex events in the previous 12 months were associated with decreased FEV1 compared with 12 months periods without oPex events. When the cumulative effect of oPExs on lung function was examined over the entire study period, patients with six or more oPEx events had the steepest rate of FEV1 decline. oPEx events were not associated with changes in BMI. CONCLUSIONS: oPEx events are associated with short-term loss of FEV1 and have a negative effect on lung function over time.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/microbiologia , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Antibacterianos/administração & dosagem , Criança , Fibrose Cística/fisiopatologia , Progressão da Doença , Feminino , Humanos , Masculino , Estado Nutricional , Testes de Função Respiratória , Estudos Retrospectivos , Resultado do Tratamento
20.
Neuroimage Clin ; 11: 167-172, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26937385

RESUMO

Drowning is a leading cause of neurological morbidity and mortality in young children. Anoxic brain injury (ABI) can result from nonfatal drowning and typically entails substantial neurological impairment. The neuropathology of drowning-induced pediatric ABI is not well established. Specifically, quantitative characterization of the spatial extent and tissue distribution of anoxic damage in pediatric nonfatal drowning has not previously been reported but could clarify the underlying pathophysiological processes and inform clinical management. To this end, we used voxel-based morphometric (VBM) analyses to quantify the extent and spatial distribution of consistent, between-subject alterations in gray and white matter volume. Whole-brain, high-resolution T1-weighted MRI datasets were acquired in 11 children with chronic ABI and 11 age- and gender-matched neurotypical controls (4-12 years). Group-wise VBM analyses demonstrated predominantly central subcortical pathology in the ABI group in both gray matter (bilateral basal ganglia nuclei) and white matter (bilateral external and posterior internal capsules) (P < 0.001); minimal damage was found outside of these deep subcortical regions. These highly spatially convergent gray and white matter findings reflect the vascular distribution of perforating lenticulostriate arteries, an end-arterial watershed zone, and suggest that vascular distribution may be a more important determinant of tissue loss than oxygen metabolic rate in pediatric ABI. Further, these results inform future directions for diagnostic and therapeutic modalities.


Assuntos
Doença Cerebrovascular dos Gânglios da Base/patologia , Afogamento/fisiopatologia , Substância Cinzenta/patologia , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/patologia , Doença Cerebrovascular dos Gânglios da Base/diagnóstico por imagem , Doença Cerebrovascular dos Gânglios da Base/etiologia , Estudos de Casos e Controles , Pré-Escolar , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Hipóxia Encefálica/diagnóstico por imagem , Imagem Tridimensional , Lactente , Imagem por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
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