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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cystic fibrosis &#40;CF&#41; is a genetic disease&#44; inherited in an autosomal recessive fashion&#44; which causes the defective function of the cystic fibrosis transmembrane regulator &#40;CFTR&#41; protein&#46; It affects approximately 1 in 5000 newborns in Europe&#46; CF is caused by abnormalities in salt transportation that result from the defective CFTR protein&#44; a chloride channel that regulates the salt content in the fluid that covers cell surfaces in the nose and lungs&#46; Transport of ions such as sodium and chloride generates an electrical potential difference across the airway lining&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common mutation that causes CF is F508del&#44; which affects 28&#37; of Spanish CF patients&#44; and causes various defects such as reductions in the folding and trafficking of the CFTR protein to the epithelial cell surface and defective channel gating&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Lumacaftor is a CFTR corrector which selectively increases the processing and trafficking of F508del CFTR to the cell surface&#46; Ivacaftor is a CFTR potentiator which increases the channel opening probability of CFTR on the cell surface&#44; facilitating chloride transport&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">TRAFFIC and TRANSPORT were two phase 3 trials&#44; both of which were multi-national&#44; randomised&#44; double-blind&#44; placebo-controlled&#44; parallel group studies in which lumacaftor and ivacaftor were orally administered for 24 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> Both studies revealed improvements in percent predicted forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;ppFEV1&#41;&#44; nutritional status and pulmonary exacerbation rates&#46; The patients included for both studies were 12 and upwards&#44; with a ppFEV1<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46; A subsequent efficacy analysis showed decreased values in ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37; between screening and baseline in fewer than 10&#37; of the patients&#46; At week 24&#44; improvements in the absolute change in ppFEV1 were observed&#46; Increases in body-mass index &#40;BMI&#41; and a reduction in the number of pulmonary exacerbation events were also observed in both the lumacaftor&#47;ivacaftor dose groups compared with the placebo group&#46; The treatment was generally well tolerated&#44; although the incidence of some respiratory adverse events &#40;AEs&#41; was higher under lumacaftor&#47;ivacaftor than with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Between 24 October 2013 and 7 April 2016&#44; 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS&#44; and 1029 subjects subsequently received at least one dose of the drug under study&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> The subjects of the study were treated with lumacaftor 400<span class="elsevierStyleHsp" style=""></span>mg&#47;ivacaftor 250<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&#46; The most common adverse events observed were infective pulmonary exacerbations&#44; cough&#44; increased sputum and haemoptysis&#46; The results showed a slight improvement in ppFEV1 and BMI in week 96&#44; with a reduction of the annual rate of ppFEV1 decline in lumacaftor&#47;ivacaftor treated patients compared to matched controls&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">There has been little research regarding the benefits of lumacaftor&#47;ivacaftor outside of clinical trials and even less data on its safety and effectiveness among patients with ppFEV1 lower than 40&#37;&#46; We therefore sought to obtain data on real-life initiation of lumacaftor&#47;ivacaftor in CF adults with severe lung disease in Spain&#44; where lumacaftor&#47;ivacaftor has been available for compassionate use since February 2016&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The European Medicines Agency &#40;EMA&#41; defines &#8220;compassionate use&#8221; as a treatment option that allows the use of an unauthorised medicinal product which is under development&#46; In Spain&#44; compassionate use is permitted under the following conditions&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">&#8226;</span></span><p id="par0040" class="elsevierStylePara elsevierViewall">The patient must have a chronically or seriously debilitating disease or one that is considered to be life-threatening&#44; and which cannot be treated satisfactorily with authorised products&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">The product must be subject to an application for marketing authorisation&#44; or undergoing clinical trials&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">The sponsor of the clinical trials or the applicant for marketing authorisation must have consented to supply the product for compassionate use&#46;</p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">While there are few real-life studies on CF patients who are homozygous F508del treated with lumacaftor&#47;ivacaftor&#44; those that have been undertaken have revealed more respiratory-related AEs and initial declines in lung function compared to the results of clinical trials&#46; Approximately 20&#8211;25&#37; patients did not tolerate the treatment due to respiratory AEs&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> which demonstrates the need for better strategies to prevent these effects&#44; as well as the development of newer drugs with better AE profiles&#46; Against this background&#44; our cohort of patients should be closely monitored following initiation of lumacaftor&#47;ivacaftor treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><p id="par0060" class="elsevierStylePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; observational study to describe the effects of lumacaftor&#47;ivacaftor treatment in real life in Spain&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The inclusion criteria were as follows&#58; CF patients&#44; male or female&#44; aged at least 6 years old at the time of signing informed consent form&#44; homozygous for the F508del-CFTR mutation with ppFEV1 value &#60;40&#37;&#44; adjusted for age&#44; sex&#44; and height at screening and able to understand and comply with the protocol requirements&#46; Beyond this&#44; patients who had experienced a rapid and persistent decline in lung function&#44; defined as at least 20&#37; relative decrease in ppFEV1&#44; could also be included in the study&#44; as well as patients in an active waiting list for lung transplant&#46; Those criteria were the established by the programme MyMAPs for compassionate use of lumacaftor&#47;ivacaftor&#46; In the cases where the patient was younger than 18 years old&#44; the consent form was signed by their parents&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The exclusion criteria were as follows&#58; Patients currently receiving invasive mechanical ventilation&#44; those with abnormal liver function&#44; haemoglobin &#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;dL or abnormal renal function&#44; history of solid organ or hematologic transplantation&#44; those who were currently pregnant and breast-feeding&#44; and patients who were sexually active with reproductive potential but unwilling to follow contraception requirements&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">20 CF patients were included from different CF units around the country and treated with lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg&#44; two tablets twice a day&#44; on compassionate use throughout the year 2016&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">These 20 patients were all homozygous F508del&#44; at least 6 years old&#44; with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46; All patients were monitored for the first 24<span class="elsevierStyleHsp" style=""></span>h following each administration of a dose&#44; including via spirometry and physiological measures such as oxygen saturation&#44; heart rate&#44; respiratory rate&#44; blood pressure and BMI&#46; Every patient who started lumacaftor&#47;ivacaftor had systematic visits &#40;24<span class="elsevierStyleHsp" style=""></span>h&#44; 6&#8211;12&#8211;18&#8211;24 weeks from the date of start treatment&#41; which included pulmonary function tests&#46; Adverse events data were collected in each visit&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">We collected data on number of pulmonary exacerbation from the year prior to the beginning of treatment &#40;distinguishing between mild&#44; moderate and severe&#41; in each visit&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The primary endpoint was measured in all the sampled patients&#46; Data were analysed to ppFEV1 at baseline &#40;&#60;40&#37;&#41; and BMI&#44; was measured for 24 weeks&#46; We considered p values lower than 0&#46;05 as statistically significant&#46; The means of the differences from baseline changes in ppFEV1 and BMI were calculated with a model for repeated measures Greenhouse&#8211;Geisser that included study treatment by each visit&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A Shapiro&#8211;Wilk test determined a non-normal data distribution&#46; The association between exacerbations in the previous and current year was analysed using the Wilcoxon test&#46; All statistical analyses were performed via the statistical software SPSS&#44; version 19&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">20 patients started lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg treatment&#46; The mean age was 26&#46;65 &#40;range 10&#8211;45 years old&#41;&#44; the mean ppFEV1 before the treatment was 32&#46;4&#37; and mean BMI 19&#46;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; 60&#37; of the cohort was female&#44; 100&#37; had chronic bronchial infection&#44; 60&#37; by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> and 35&#37; by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; 30&#37; had diabetes&#46; Almost all the patients used nebulised antibiotics&#44; 55&#37; DNAse&#44; 90&#37; hypertonic saline and 30&#37; oxygen &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; We analysed the absolute changes in ppFEV1 and BMI during the lumacaftor&#47;ivacaftor treatment &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">figs&#46; 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">We observed a moderate association between the days of intravenous &#40;i&#46;v&#46;&#41; antibiotic and the use of lumacaftor&#47;ivacaftor treatment&#44; analysed using the Wilcoxon test &#8211; which is statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Also&#44; severe pulmonary exacerbations which required hospitalisation were statistically less common during the year under the lumacaftor&#47;ivacaftor treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Almost all patients show increase subjective levels of energy and the sensation of less exacerbation&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">75&#37; of our population presented with AEs&#44; 25&#37; had headaches&#44; 40&#37; dyspnoea&#44; 45&#37; chest tightening and 25&#37; weight loss &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Consequently&#44; 35&#37; of the subjects discontinued the treatment&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The treatment with lumacaftor&#47;ivacaftor resulted in an improvement of some factors in our CF patients who are F508del homozygous with severe lung diseases&#44; and reported less days of i&#46;v&#46; antibiotics in severe pulmonary exacerbations&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Pulmonary exacerbation &#40;PEx&#41; is a hallmark of cystic fibrosis&#46; The incidence of PEx seems to increase with age&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a> In an analysis of data from 11&#46;692 consecutive CF patients included in a large prospective multicentre database &#40;Epidemiologic Study of Cystic Fibrosis&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> the percentage of patients with a PEx during the 6-month observation period increased from 23&#37; for those aged &#60;6 years to 63&#37; for those aged &#62;18 years&#46; Identified risk factors include changes in bacterial density&#44; acquisition of new microorganisms as <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; viral infections&#44; impaired lung function&#44; CF related diabetes and other external precipitating&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main consequences of PEx in patients with CF include higher drug consumption&#44; the need for in-patient care&#44; and patient absenteeism&#44; which results in an increase in the total cost of the disease&#46; Furthermore&#44; PEx has a negative impact on physical and psychosocial health-related quality of life&#46; In addition to the increased morbidity of CF caused by PEx&#44; the annual number of exacerbations has a considerable impact on survival&#46; Therefore&#44; reducing the number of PEx and the total duration of iv antibiotics will reduce the economic cost of the disease&#46; Moreover&#44; the health-related quality of life and surveillance will also improve&#44; which means that reducing severe PEx has very important clinical consequences&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Nevertheless&#44; we did not observe an improvement in lung function after 24 weeks&#46; Our patients presented a decrease of around 5&#37; on ppFEV1 in the first 24<span class="elsevierStyleHsp" style=""></span>h after lumacaftor&#47;ivacaftor administration&#44; and this decline did not recover until week 12 onwards&#46; We had to stop the treatment for one of our patients&#46; Finally&#44; while we observed a slight increase in BMI&#44; this was not statistically significant&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The initial decline in pulmonary function and the increase in respiratory AEs have been described in a study by an Australian research group&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> in which they concluded that lumacaftor&#47;ivacaftor respiratory-related adverse events and declines in lung function are common in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#44; meaning that this cohort of patients should be closely monitored following lumacaftor&#47;ivacaftor initiation&#46; Notwithstanding&#44; in a real-life study carried on by a French research group with 53 patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> the mean absolute change in ppFEV1 was &#43;2&#46;06&#37; after 1 month of treatment with lumacaftor&#47;ivacaftor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;086&#41;&#44; and &#43;3&#46;19&#37; after 3 months &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#59; after 1 and 3 months of treatment&#44; about one third of all patients had an absolute change in ppFEV1 of 5&#37; or more in comparison to baseline and 13&#37; had an increase of at least 10&#37; in ppFEV1&#46; Nevertheless&#44; more studies to evaluate the efficacy of lumacaftor&#47;ivacaftor therapy in severe CF lung disease are needed to help us to better-informed future therapeutic decisions&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In our cohort&#44; the patients showed a high percentage of AEs&#44; 25&#37; had headache&#44; 40&#37; dyspnoea&#44; 45&#37; chest tightening and 25&#37; weight loss&#44; and this resulted in the discontinuation of the treatment for 35&#37; of the patients&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">As with the study by Dominique Hubert et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> the level of treatment discontinuation was markedly higher than rates in phase 3 clinical trials&#46; This could be explained by the fact that the patients in real-life studies with treatment on compassionate use are not in such stable conditions as in clinical trials&#46; Elborn et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> reported that the incidence of dyspnoea in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37; was two times higher than in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">This highlights that the evolution of CF patients taking lumacaftor&#47;ivacaftor with low lung function over the longer term should be further studied&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The median predicted survival for patients with CF is steadily increasing in Europe&#44; and currently life expectancy for cystic fibrosis patients surpasses 40 years&#46; This new class of drugs that is mutation-specific and modulate CFTR function have the potential to be transformational&#46; The editorial written by Schwarz and Harti published in the European Respiratory Journal forecasts that the adult CF population in Europe will increase by 50&#37; by 2025&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> The editorial further highlights that an early and correct diagnosis is paramount and it is our responsibility to improve our knowledge of CF healthcare&#44; and to pass this on to future generations in order to optimise the limited resources for CF care&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Limitations in our study included the retrospective nature of the study&#44; the small sample size and that the selection of patients was based on compassionate use requests for severely ill patients&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; we conclude that our Spanish study in severe CF patients taking lumacaftor&#47;ivacaftor treatment shows an improvement in the number of pulmonary severe exacerbations but no improvement in ppFEV1 and BMI was reported&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">Rosa Mar&#237;a Gir&#243;n-Moreno has received honoraria for workshops from Vertex&#44; Teva&#44; Zambon and Esteve&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Esther Quintana-Gallego has received honoraria for workshops and expert comitte from Chiesi&#44; Gilead&#44; Novartis&#44; Praxis y Vertex&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Luis Maiz has received honoraria for workshops from Vertex&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Marta Mar&#237;a Garc&#237;a-Clemente has received honoraria for workshops from GSK and Chiesi&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Carmen Luna-Paredes has received honoraria for workshops and participate in advisory boards from Vertex&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Pedro Mondejar-L&#243;pez has received honoraria for workshops from Vertex&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Alejandro L&#243;pez-Neyra has received honoraria for workshops from Vertex&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The rest of authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Resumen"
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              "titulo" => "M&#233;todos"
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          "titulo" => "References"
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    "fechaRecibido" => "2017-10-27"
    "fechaAceptado" => "2018-05-01"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1057094"
          "palabras" => array:5 [
            0 => "Cystic fibrosis"
            1 => "Lumacaftor&#47;ivacaftor"
            2 => "Compassionate use"
            3 => "ppFEV1"
            4 => "Pulmonary exacerbation"
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        ]
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Fibrosis qu&#237;stica"
            1 => "Lumacaftor&#47;ivacaftor"
            2 => "Uso compasivo"
            3 => "ppFEV1"
            4 => "Exacerbaci&#243;n pulmonar"
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Background</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The most common cystic fibrosis &#40;CF&#41;-causing mutation is deltaF508 &#40;F508del&#41;&#44; which is present in 28&#37; of CF Spanish patients&#46; While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor&#47;ivacaftor is limited&#44; it demonstrates the need for better strategies to prevent related adverse events &#40;AEs&#41; as well as the development of newer drugs&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; observational study to describe the effects of lumacaftor&#47;ivacaftor treatment in real-life in Spain&#46; 20 CF patients were included&#44; all aged 6 and upwards and presented with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37;&#44; chosen from CF units country-wide&#46; For the purposes of the study&#44; they were treated with lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg two tablets twice a day on a compassionate use programme throughout 2016&#46; The primary endpoint was measured in all of the sample patients&#46; Data were analysed from ppFEV1 at baseline and was measured every 6 months&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The mean age was 26&#46;65 &#40;range of 10&#8211;45&#41;&#44; while the mean ppFEV1 before the treatment was 32&#46;4&#37; and mean BMI was 19&#46;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor&#47;ivacaftor&#44; but no differences were found&#46; However&#44; a moderate association between days of intravenous antibiotic needed and the use of lumacaftor&#47;ivacaftor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; was established&#46; Indeed&#44; under the lumacaftor&#47;ivacaftor&#44; patients required 5&#46;8 days of intravenous antibiotic treatment compared to 14&#46;9 days prior to study&#46; Also&#44; severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor&#47;ivacaftor treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; Finally&#44; 75&#37; of the sample presented with AEs&#44; which led 35&#37; of the subjects to discontinue the treatment&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">While treatment with lumacaftor&#47;ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations&#44; no improvement in ppFEV1 or BMI was found&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Background"
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            "identificador" => "abst0015"
            "titulo" => "Methods"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La mutaci&#243;n causante de fibrosis qu&#237;stica &#40;FQ&#41; m&#225;s frecuente es la deltaF508 &#40;F508del&#41;&#44; presente en el 28&#37; de los pacientes espa&#241;oles con FQ&#46; Aunque la literatura sobre estudios en vida real en pacientes de FQ homocigotos para F508del tratados con lumacaftor&#47;ivacaftor es escasa&#44; pone de manifiesto la necesidad de contar con mejores estrategias para prevenir los efectos adversos &#40;EA&#41; relacionados con el tratamiento&#44; as&#237; como del desarrollo de nuevos f&#225;rmacos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un estudio observacional&#44; retrospectivo multic&#233;ntrico para describir los efectos del tratamiento con lumacaftor&#47;ivacaftor en vida real en Espa&#241;a&#46; Se incluyeron 20 pacientes con FQ&#44; edad superior a los 6 a&#241;os y ppFEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37;&#44; procedentes de unidades de FQ de todo el pa&#237;s&#46; Para los fines del estudio&#44; fueron tratados con 2 comprimidos de lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg&#47;2 veces al d&#237;a como parte de un programa de uso compasivo a lo largo de 2016&#46; El criterio de valoraci&#243;n primario se midi&#243; en las muestras de todos los pacientes&#46; Los datos de ppFEV<span class="elsevierStyleInf">1</span> se analizaron al inicio y cada 6 meses&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La mediana de edad fue de 26&#44;65 &#40;rango&#58; 10-45&#41;&#44; mientras que la mediana de ppFEV<span class="elsevierStyleInf">1</span> antes del tratamiento fue del 32&#44;4&#37; y la mediana del IMC 19&#44;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; No se encontraron diferencias al analizar los cambios de ppVEF<span class="elsevierStyleInf">1</span> e IMC desde el inicio y durante el tratamiento con lumacaftor&#47;ivacaftor&#46; Sin embargo&#44; se estableci&#243; una asociaci&#243;n moderada entre los d&#237;as requeridos de antibi&#243;tico intravenoso y el uso de lumacaftor&#47;ivacaftor &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; De hecho&#44; con lumacaftor&#47;ivacaftor&#44; los pacientes requirieron 5&#44;8 d&#237;as de tratamiento intravenoso con antibi&#243;tico&#44; comparado con los 14&#44;9 d&#237;as previos al estudio&#46; Adem&#225;s&#44; el n&#250;mero de exacerbaciones pulmonares graves que requirieron hospitalizaci&#243;n fue estad&#237;sticamente menor con lumacaftor&#47;ivacaftor &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;003&#41;&#46; Por &#250;ltimo&#44; el 75&#37; de la muestra present&#243; EA&#44; lo cual supuso la discontinuaci&#243;n del tratamiento en un 35&#37; de los casos&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con lumacaftor&#47;ivacaftor mejor&#243; el n&#250;mero de exacerbaciones pulmonares severas&#44; pero no supuso mejora ni en el ppFEV<span class="elsevierStyleInf">1</span> ni el IMC&#46;</p></span>"
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            "apendice" => "<p id="par0220" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix"
            "titulo" => "Supplementary data"
            "identificador" => "sec0035"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Differences in ppFEV1&#44; by visit&#46; In each visit the mean difference between each visit and the beginning of the treatment &#40;baseline&#41; is represented&#46; ppFEV1&#58; percent predicted forced expiratory volume in one second&#46; CI&#58; confidence interval&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#46; SD&#58; standard deviation&#46; BL&#58; baseline&#46; H&#58; hours&#46; W&#58; week&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Differences in BMI by visit&#46; In each visit the mean difference between each visit and the beginning of the treatment &#40;baseline&#41; is represented&#46; BMI&#58; body mass index&#46; CI&#58; confidence interval&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#46; SD&#58; standard deviation&#46; CI&#58; confidence interval&#46; BL&#58; baseline&#46; W&#58; week&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Analysis of the severe pulmonary exacerbations&#46; &#40;a&#41; Mean and confidence interval of days of intravenous antibiotics one year prior and during the study year&#46; &#40;b&#41; Mean and confidence interval of hospitalisation rates one year prior and during the study year&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#59; SD&#58; standard deviation&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">MRSA&#58; Methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus&#46;</span></p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ABPA&#58; Allergic bronchopulmonary aspergillosis&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">ppFEV1&#58; percent predicted forced expiratory volume in one second&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#47;&#40;<span class="elsevierStyleItalic">n</span>&#41; percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#46;88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ppFEV1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Pseudomonas&#46; aeruginosa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;12&#41; 60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;7&#41; 35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">MRSA</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Achromobacter xylosoxidans</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;1&#41; 5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ABPA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertonic Saline<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Hyaluronic acid&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Azithromycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;19&#41; 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inhaled corticosteroid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;16&#41; 80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DNase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;11&#41; 55&#37;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Demographic features&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse events&nbsp;\t\t\t\t\t\t\n
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Original Article
Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience
Uso compasivo de lumacaftor/ivacaftor en fibrosis quística: experiencia española
Layla Diab-Cáceresa,
Corresponding author
layladch@gmail.com

Corresponding author.
, Rosa María Girón-Morenoa, María Teresa Pastor-Sanza, Esther Quintana-Gallegob, Isabel Delgado-Pecellínb, Marina Blanco-Aparicioc, Luis Maizd, Marta María García-Clementee, Carmen Luna-Paredesf, Pedro Mondéjar-Lópezg, Marta Ruiz-de-Valbuenah, Ofelia Fernándezi, Maribel Barrioi, Maribel Gonzálezj, Alejandro López-Neyrak, María Cols-i-Roigl, Alexandre Palou-Rotgerm, Francisco Javier Gómez-de-Terreros-Caroi
a Hospital de La Princesa, Respirology, Madrid, Spain
b Hospital Universitario Virgen del Rocío, Sevilla, Spain. Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
c Complejo Hospitalario La Coruña, Respirology, La Coruña, Spain
d Hospital Ramón y Cajal, Respirology, Madrid, Spain
e Hospital Central de Asturias, Respirology, Oviedo, Spain
f Hospital 12 de Octubre, Madrid, Spain
g Hospital Arrixaca, Murcia, Spain
h Hospital La Paz, Madrid, Spain
i Hospital San Pedro de Alcántara, Cáceres, Spain
j Hospital Infantil Niño Jesús, Madrid, Spain
k Hospital Ramón y Cajal, Paediatric, Madrid, Spain
l Hospital San Joan de Déu, Barcelona, Spain
m Hospital Son Espases, Palma de Mallorca, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cystic fibrosis &#40;CF&#41; is a genetic disease&#44; inherited in an autosomal recessive fashion&#44; which causes the defective function of the cystic fibrosis transmembrane regulator &#40;CFTR&#41; protein&#46; It affects approximately 1 in 5000 newborns in Europe&#46; CF is caused by abnormalities in salt transportation that result from the defective CFTR protein&#44; a chloride channel that regulates the salt content in the fluid that covers cell surfaces in the nose and lungs&#46; Transport of ions such as sodium and chloride generates an electrical potential difference across the airway lining&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The most common mutation that causes CF is F508del&#44; which affects 28&#37; of Spanish CF patients&#44; and causes various defects such as reductions in the folding and trafficking of the CFTR protein to the epithelial cell surface and defective channel gating&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Lumacaftor is a CFTR corrector which selectively increases the processing and trafficking of F508del CFTR to the cell surface&#46; Ivacaftor is a CFTR potentiator which increases the channel opening probability of CFTR on the cell surface&#44; facilitating chloride transport&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">TRAFFIC and TRANSPORT were two phase 3 trials&#44; both of which were multi-national&#44; randomised&#44; double-blind&#44; placebo-controlled&#44; parallel group studies in which lumacaftor and ivacaftor were orally administered for 24 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> Both studies revealed improvements in percent predicted forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;ppFEV1&#41;&#44; nutritional status and pulmonary exacerbation rates&#46; The patients included for both studies were 12 and upwards&#44; with a ppFEV1<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46; A subsequent efficacy analysis showed decreased values in ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37; between screening and baseline in fewer than 10&#37; of the patients&#46; At week 24&#44; improvements in the absolute change in ppFEV1 were observed&#46; Increases in body-mass index &#40;BMI&#41; and a reduction in the number of pulmonary exacerbation events were also observed in both the lumacaftor&#47;ivacaftor dose groups compared with the placebo group&#46; The treatment was generally well tolerated&#44; although the incidence of some respiratory adverse events &#40;AEs&#41; was higher under lumacaftor&#47;ivacaftor than with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Between 24 October 2013 and 7 April 2016&#44; 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS&#44; and 1029 subjects subsequently received at least one dose of the drug under study&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> The subjects of the study were treated with lumacaftor 400<span class="elsevierStyleHsp" style=""></span>mg&#47;ivacaftor 250<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&#46; The most common adverse events observed were infective pulmonary exacerbations&#44; cough&#44; increased sputum and haemoptysis&#46; The results showed a slight improvement in ppFEV1 and BMI in week 96&#44; with a reduction of the annual rate of ppFEV1 decline in lumacaftor&#47;ivacaftor treated patients compared to matched controls&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">There has been little research regarding the benefits of lumacaftor&#47;ivacaftor outside of clinical trials and even less data on its safety and effectiveness among patients with ppFEV1 lower than 40&#37;&#46; We therefore sought to obtain data on real-life initiation of lumacaftor&#47;ivacaftor in CF adults with severe lung disease in Spain&#44; where lumacaftor&#47;ivacaftor has been available for compassionate use since February 2016&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The European Medicines Agency &#40;EMA&#41; defines &#8220;compassionate use&#8221; as a treatment option that allows the use of an unauthorised medicinal product which is under development&#46; In Spain&#44; compassionate use is permitted under the following conditions&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel"><span class="elsevierStyleItalic">&#8226;</span></span><p id="par0040" class="elsevierStylePara elsevierViewall">The patient must have a chronically or seriously debilitating disease or one that is considered to be life-threatening&#44; and which cannot be treated satisfactorily with authorised products&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0045" class="elsevierStylePara elsevierViewall">The product must be subject to an application for marketing authorisation&#44; or undergoing clinical trials&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0050" class="elsevierStylePara elsevierViewall">The sponsor of the clinical trials or the applicant for marketing authorisation must have consented to supply the product for compassionate use&#46;</p></li></ul></p><p id="par0055" class="elsevierStylePara elsevierViewall">While there are few real-life studies on CF patients who are homozygous F508del treated with lumacaftor&#47;ivacaftor&#44; those that have been undertaken have revealed more respiratory-related AEs and initial declines in lung function compared to the results of clinical trials&#46; Approximately 20&#8211;25&#37; patients did not tolerate the treatment due to respiratory AEs&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> which demonstrates the need for better strategies to prevent these effects&#44; as well as the development of newer drugs with better AE profiles&#46; Against this background&#44; our cohort of patients should be closely monitored following initiation of lumacaftor&#47;ivacaftor treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><p id="par0060" class="elsevierStylePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; observational study to describe the effects of lumacaftor&#47;ivacaftor treatment in real life in Spain&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The inclusion criteria were as follows&#58; CF patients&#44; male or female&#44; aged at least 6 years old at the time of signing informed consent form&#44; homozygous for the F508del-CFTR mutation with ppFEV1 value &#60;40&#37;&#44; adjusted for age&#44; sex&#44; and height at screening and able to understand and comply with the protocol requirements&#46; Beyond this&#44; patients who had experienced a rapid and persistent decline in lung function&#44; defined as at least 20&#37; relative decrease in ppFEV1&#44; could also be included in the study&#44; as well as patients in an active waiting list for lung transplant&#46; Those criteria were the established by the programme MyMAPs for compassionate use of lumacaftor&#47;ivacaftor&#46; In the cases where the patient was younger than 18 years old&#44; the consent form was signed by their parents&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The exclusion criteria were as follows&#58; Patients currently receiving invasive mechanical ventilation&#44; those with abnormal liver function&#44; haemoglobin &#60;10<span class="elsevierStyleHsp" style=""></span>mg&#47;dL or abnormal renal function&#44; history of solid organ or hematologic transplantation&#44; those who were currently pregnant and breast-feeding&#44; and patients who were sexually active with reproductive potential but unwilling to follow contraception requirements&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">20 CF patients were included from different CF units around the country and treated with lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg&#44; two tablets twice a day&#44; on compassionate use throughout the year 2016&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">These 20 patients were all homozygous F508del&#44; at least 6 years old&#44; with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46; All patients were monitored for the first 24<span class="elsevierStyleHsp" style=""></span>h following each administration of a dose&#44; including via spirometry and physiological measures such as oxygen saturation&#44; heart rate&#44; respiratory rate&#44; blood pressure and BMI&#46; Every patient who started lumacaftor&#47;ivacaftor had systematic visits &#40;24<span class="elsevierStyleHsp" style=""></span>h&#44; 6&#8211;12&#8211;18&#8211;24 weeks from the date of start treatment&#41; which included pulmonary function tests&#46; Adverse events data were collected in each visit&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">We collected data on number of pulmonary exacerbation from the year prior to the beginning of treatment &#40;distinguishing between mild&#44; moderate and severe&#41; in each visit&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The primary endpoint was measured in all the sampled patients&#46; Data were analysed to ppFEV1 at baseline &#40;&#60;40&#37;&#41; and BMI&#44; was measured for 24 weeks&#46; We considered p values lower than 0&#46;05 as statistically significant&#46; The means of the differences from baseline changes in ppFEV1 and BMI were calculated with a model for repeated measures Greenhouse&#8211;Geisser that included study treatment by each visit&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">A Shapiro&#8211;Wilk test determined a non-normal data distribution&#46; The association between exacerbations in the previous and current year was analysed using the Wilcoxon test&#46; All statistical analyses were performed via the statistical software SPSS&#44; version 19&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">20 patients started lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg treatment&#46; The mean age was 26&#46;65 &#40;range 10&#8211;45 years old&#41;&#44; the mean ppFEV1 before the treatment was 32&#46;4&#37; and mean BMI 19&#46;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; 60&#37; of the cohort was female&#44; 100&#37; had chronic bronchial infection&#44; 60&#37; by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> and 35&#37; by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&#44; 30&#37; had diabetes&#46; Almost all the patients used nebulised antibiotics&#44; 55&#37; DNAse&#44; 90&#37; hypertonic saline and 30&#37; oxygen &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; We analysed the absolute changes in ppFEV1 and BMI during the lumacaftor&#47;ivacaftor treatment &#40;<a class="elsevierStyleCrossRefs" href="#fig0005">figs&#46; 1 and 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">We observed a moderate association between the days of intravenous &#40;i&#46;v&#46;&#41; antibiotic and the use of lumacaftor&#47;ivacaftor treatment&#44; analysed using the Wilcoxon test &#8211; which is statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; Also&#44; severe pulmonary exacerbations which required hospitalisation were statistically less common during the year under the lumacaftor&#47;ivacaftor treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Almost all patients show increase subjective levels of energy and the sensation of less exacerbation&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">75&#37; of our population presented with AEs&#44; 25&#37; had headaches&#44; 40&#37; dyspnoea&#44; 45&#37; chest tightening and 25&#37; weight loss &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Consequently&#44; 35&#37; of the subjects discontinued the treatment&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">The treatment with lumacaftor&#47;ivacaftor resulted in an improvement of some factors in our CF patients who are F508del homozygous with severe lung diseases&#44; and reported less days of i&#46;v&#46; antibiotics in severe pulmonary exacerbations&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Pulmonary exacerbation &#40;PEx&#41; is a hallmark of cystic fibrosis&#46; The incidence of PEx seems to increase with age&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a> In an analysis of data from 11&#46;692 consecutive CF patients included in a large prospective multicentre database &#40;Epidemiologic Study of Cystic Fibrosis&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a> the percentage of patients with a PEx during the 6-month observation period increased from 23&#37; for those aged &#60;6 years to 63&#37; for those aged &#62;18 years&#46; Identified risk factors include changes in bacterial density&#44; acquisition of new microorganisms as <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#44; viral infections&#44; impaired lung function&#44; CF related diabetes and other external precipitating&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The main consequences of PEx in patients with CF include higher drug consumption&#44; the need for in-patient care&#44; and patient absenteeism&#44; which results in an increase in the total cost of the disease&#46; Furthermore&#44; PEx has a negative impact on physical and psychosocial health-related quality of life&#46; In addition to the increased morbidity of CF caused by PEx&#44; the annual number of exacerbations has a considerable impact on survival&#46; Therefore&#44; reducing the number of PEx and the total duration of iv antibiotics will reduce the economic cost of the disease&#46; Moreover&#44; the health-related quality of life and surveillance will also improve&#44; which means that reducing severe PEx has very important clinical consequences&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Nevertheless&#44; we did not observe an improvement in lung function after 24 weeks&#46; Our patients presented a decrease of around 5&#37; on ppFEV1 in the first 24<span class="elsevierStyleHsp" style=""></span>h after lumacaftor&#47;ivacaftor administration&#44; and this decline did not recover until week 12 onwards&#46; We had to stop the treatment for one of our patients&#46; Finally&#44; while we observed a slight increase in BMI&#44; this was not statistically significant&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The initial decline in pulmonary function and the increase in respiratory AEs have been described in a study by an Australian research group&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> in which they concluded that lumacaftor&#47;ivacaftor respiratory-related adverse events and declines in lung function are common in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#44; meaning that this cohort of patients should be closely monitored following lumacaftor&#47;ivacaftor initiation&#46; Notwithstanding&#44; in a real-life study carried on by a French research group with 53 patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> the mean absolute change in ppFEV1 was &#43;2&#46;06&#37; after 1 month of treatment with lumacaftor&#47;ivacaftor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;086&#41;&#44; and &#43;3&#46;19&#37; after 3 months &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;009&#41;&#59; after 1 and 3 months of treatment&#44; about one third of all patients had an absolute change in ppFEV1 of 5&#37; or more in comparison to baseline and 13&#37; had an increase of at least 10&#37; in ppFEV1&#46; Nevertheless&#44; more studies to evaluate the efficacy of lumacaftor&#47;ivacaftor therapy in severe CF lung disease are needed to help us to better-informed future therapeutic decisions&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In our cohort&#44; the patients showed a high percentage of AEs&#44; 25&#37; had headache&#44; 40&#37; dyspnoea&#44; 45&#37; chest tightening and 25&#37; weight loss&#44; and this resulted in the discontinuation of the treatment for 35&#37; of the patients&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">As with the study by Dominique Hubert et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a> the level of treatment discontinuation was markedly higher than rates in phase 3 clinical trials&#46; This could be explained by the fact that the patients in real-life studies with treatment on compassionate use are not in such stable conditions as in clinical trials&#46; Elborn et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> reported that the incidence of dyspnoea in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37; was two times higher than in patients with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>40&#37;&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">This highlights that the evolution of CF patients taking lumacaftor&#47;ivacaftor with low lung function over the longer term should be further studied&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The median predicted survival for patients with CF is steadily increasing in Europe&#44; and currently life expectancy for cystic fibrosis patients surpasses 40 years&#46; This new class of drugs that is mutation-specific and modulate CFTR function have the potential to be transformational&#46; The editorial written by Schwarz and Harti published in the European Respiratory Journal forecasts that the adult CF population in Europe will increase by 50&#37; by 2025&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> The editorial further highlights that an early and correct diagnosis is paramount and it is our responsibility to improve our knowledge of CF healthcare&#44; and to pass this on to future generations in order to optimise the limited resources for CF care&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Limitations in our study included the retrospective nature of the study&#44; the small sample size and that the selection of patients was based on compassionate use requests for severely ill patients&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Finally&#44; we conclude that our Spanish study in severe CF patients taking lumacaftor&#47;ivacaftor treatment shows an improvement in the number of pulmonary severe exacerbations but no improvement in ppFEV1 and BMI was reported&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interest</span><p id="par0175" class="elsevierStylePara elsevierViewall">Rosa Mar&#237;a Gir&#243;n-Moreno has received honoraria for workshops from Vertex&#44; Teva&#44; Zambon and Esteve&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Esther Quintana-Gallego has received honoraria for workshops and expert comitte from Chiesi&#44; Gilead&#44; Novartis&#44; Praxis y Vertex&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Luis Maiz has received honoraria for workshops from Vertex&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Marta Mar&#237;a Garc&#237;a-Clemente has received honoraria for workshops from GSK and Chiesi&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Carmen Luna-Paredes has received honoraria for workshops and participate in advisory boards from Vertex&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Pedro Mondejar-L&#243;pez has received honoraria for workshops from Vertex&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Alejandro L&#243;pez-Neyra has received honoraria for workshops from Vertex&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The rest of authors declare no conflict of interests&#46;</p></span></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Background</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The most common cystic fibrosis &#40;CF&#41;-causing mutation is deltaF508 &#40;F508del&#41;&#44; which is present in 28&#37; of CF Spanish patients&#46; While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor&#47;ivacaftor is limited&#44; it demonstrates the need for better strategies to prevent related adverse events &#40;AEs&#41; as well as the development of newer drugs&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We conducted a multicenter&#44; retrospective&#44; observational study to describe the effects of lumacaftor&#47;ivacaftor treatment in real-life in Spain&#46; 20 CF patients were included&#44; all aged 6 and upwards and presented with ppFEV1<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37;&#44; chosen from CF units country-wide&#46; For the purposes of the study&#44; they were treated with lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg two tablets twice a day on a compassionate use programme throughout 2016&#46; The primary endpoint was measured in all of the sample patients&#46; Data were analysed from ppFEV1 at baseline and was measured every 6 months&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The mean age was 26&#46;65 &#40;range of 10&#8211;45&#41;&#44; while the mean ppFEV1 before the treatment was 32&#46;4&#37; and mean BMI was 19&#46;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor&#47;ivacaftor&#44; but no differences were found&#46; However&#44; a moderate association between days of intravenous antibiotic needed and the use of lumacaftor&#47;ivacaftor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; was established&#46; Indeed&#44; under the lumacaftor&#47;ivacaftor&#44; patients required 5&#46;8 days of intravenous antibiotic treatment compared to 14&#46;9 days prior to study&#46; Also&#44; severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor&#47;ivacaftor treatment &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46; Finally&#44; 75&#37; of the sample presented with AEs&#44; which led 35&#37; of the subjects to discontinue the treatment&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">While treatment with lumacaftor&#47;ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations&#44; no improvement in ppFEV1 or BMI was found&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La mutaci&#243;n causante de fibrosis qu&#237;stica &#40;FQ&#41; m&#225;s frecuente es la deltaF508 &#40;F508del&#41;&#44; presente en el 28&#37; de los pacientes espa&#241;oles con FQ&#46; Aunque la literatura sobre estudios en vida real en pacientes de FQ homocigotos para F508del tratados con lumacaftor&#47;ivacaftor es escasa&#44; pone de manifiesto la necesidad de contar con mejores estrategias para prevenir los efectos adversos &#40;EA&#41; relacionados con el tratamiento&#44; as&#237; como del desarrollo de nuevos f&#225;rmacos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se realiz&#243; un estudio observacional&#44; retrospectivo multic&#233;ntrico para describir los efectos del tratamiento con lumacaftor&#47;ivacaftor en vida real en Espa&#241;a&#46; Se incluyeron 20 pacientes con FQ&#44; edad superior a los 6 a&#241;os y ppFEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37;&#44; procedentes de unidades de FQ de todo el pa&#237;s&#46; Para los fines del estudio&#44; fueron tratados con 2 comprimidos de lumacaftor&#47;ivacaftor 200&#47;125<span class="elsevierStyleHsp" style=""></span>mg&#47;2 veces al d&#237;a como parte de un programa de uso compasivo a lo largo de 2016&#46; El criterio de valoraci&#243;n primario se midi&#243; en las muestras de todos los pacientes&#46; Los datos de ppFEV<span class="elsevierStyleInf">1</span> se analizaron al inicio y cada 6 meses&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La mediana de edad fue de 26&#44;65 &#40;rango&#58; 10-45&#41;&#44; mientras que la mediana de ppFEV<span class="elsevierStyleInf">1</span> antes del tratamiento fue del 32&#44;4&#37; y la mediana del IMC 19&#44;9<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#46; No se encontraron diferencias al analizar los cambios de ppVEF<span class="elsevierStyleInf">1</span> e IMC desde el inicio y durante el tratamiento con lumacaftor&#47;ivacaftor&#46; Sin embargo&#44; se estableci&#243; una asociaci&#243;n moderada entre los d&#237;as requeridos de antibi&#243;tico intravenoso y el uso de lumacaftor&#47;ivacaftor &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#46; De hecho&#44; con lumacaftor&#47;ivacaftor&#44; los pacientes requirieron 5&#44;8 d&#237;as de tratamiento intravenoso con antibi&#243;tico&#44; comparado con los 14&#44;9 d&#237;as previos al estudio&#46; Adem&#225;s&#44; el n&#250;mero de exacerbaciones pulmonares graves que requirieron hospitalizaci&#243;n fue estad&#237;sticamente menor con lumacaftor&#47;ivacaftor &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;003&#41;&#46; Por &#250;ltimo&#44; el 75&#37; de la muestra present&#243; EA&#44; lo cual supuso la discontinuaci&#243;n del tratamiento en un 35&#37; de los casos&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">El tratamiento con lumacaftor&#47;ivacaftor mejor&#243; el n&#250;mero de exacerbaciones pulmonares severas&#44; pero no supuso mejora ni en el ppFEV<span class="elsevierStyleInf">1</span> ni el IMC&#46;</p></span>"
        "secciones" => array:4 [
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            "titulo" => "Introducci&#243;n"
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            "identificador" => "abst0035"
            "titulo" => "M&#233;todos"
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            "identificador" => "abst0040"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Conclusi&#243;n"
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            "apendice" => "<p id="par0220" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article&#58;<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix"
            "titulo" => "Supplementary data"
            "identificador" => "sec0035"
          ]
        ]
      ]
    ]
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        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Differences in ppFEV1&#44; by visit&#46; In each visit the mean difference between each visit and the beginning of the treatment &#40;baseline&#41; is represented&#46; ppFEV1&#58; percent predicted forced expiratory volume in one second&#46; CI&#58; confidence interval&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#46; SD&#58; standard deviation&#46; BL&#58; baseline&#46; H&#58; hours&#46; W&#58; week&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Differences in BMI by visit&#46; In each visit the mean difference between each visit and the beginning of the treatment &#40;baseline&#41; is represented&#46; BMI&#58; body mass index&#46; CI&#58; confidence interval&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#46; SD&#58; standard deviation&#46; CI&#58; confidence interval&#46; BL&#58; baseline&#46; W&#58; week&#46;</p>"
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        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
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        "figura" => array:1 [
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Analysis of the severe pulmonary exacerbations&#46; &#40;a&#41; Mean and confidence interval of days of intravenous antibiotics one year prior and during the study year&#46; &#40;b&#41; Mean and confidence interval of hospitalisation rates one year prior and during the study year&#46; <span class="elsevierStyleItalic">N</span>&#58; number of patients&#59; SD&#58; standard deviation&#46;</p>"
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">MRSA&#58; Methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus&#46;</span></p><p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">ABPA&#58; Allergic bronchopulmonary aspergillosis&#46;</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">ppFEV1&#58; percent predicted forced expiratory volume in one second&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&#47;&#40;<span class="elsevierStyleItalic">n</span>&#41; percentage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;65<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BMI &#40;kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#46;88<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ppFEV1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32&#46;37<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Pseudomonas&#46; aeruginosa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;12&#41; 60&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Staphylococcus aureus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;7&#41; 35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">MRSA</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;3&#41; 15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Achromobacter xylosoxidans</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;3&#41; 15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Chronic infection by <span class="elsevierStyleItalic">Mycobacterium abscessus</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;1&#41; 5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ABPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;4&#41; 20&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;6&#41; 30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertonic Saline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;10&#41; 50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertonic Saline<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Hyaluronic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;8&#41; 40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Azithromycin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;19&#41; 95&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inhaled corticosteroid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;16&#41; 80&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">DNase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#40;11&#41; 55&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Demographic features&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adverse events&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="char" valign="top" scope="col" style="border-bottom: 2px solid black">&#40;15&#41; 75&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;5&#41; 25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dyspnoea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;8&#41; 40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thoracic pressure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;9&#41; 45&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lost weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;5&#41; 25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Asthenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;3&#41; 15&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Abdominal pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#40;2&#41; 10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sickness&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypertransaminasemia&nbsp;\t\t\t\t\t\t\n
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ISSN: 15792129
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