Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial

Kronmal, Richard A.; Stukovsky, Karen D. Hinckley; Jorgensen, Neal W.; Kerby, Gwen; Kopecky, Carol; Anthony, Meg; Mogayzel, Peter J.; Walker, Doug; Zeglin, Britany; Hoover, Wynton; Hathorne, Heather; Slaten, Katie; Dorkin, Henry L.; Fowler, Robert; Fenton, Cole; Ulles, Monica; Goetz, Danielle; Caci, Nadine; Cahill, Beth; Roach, Christine; Retsch‐Bogart, George; Johnson, Robert P.; Cunnion, Rose; McColley, Susanna A.; Ward, Steven; Bell, Emily; McPhail, Gary L.; Keller, Kurtis; Thornton, Kelly; Parsons, Ashlee; Chmiel, James F.; Schaefer, Cindy; Tribout, Megan; Consiglio, Brittany; Tribout, Heather; McCoy, Karen; Johnson, Terri; Olson, Patti; Raterman, Laura; Hiatt, Peter; Walker, B.F.; Schaap, Nicoline; Davis, Michael F.; Davis, Stephanie D.; Clem, Charles; Bendy, Lisa; Starner, Timothy D.; Lux, Cheri; Carver, Terrence W.; Thompson, Rose; Williams, Alexus; Schmoll, Candy; Hastings, Patricia M.; Noe, Julie; Roth, Laura; Kump, Theresa; McNamara, John J.; Thompson, Elizabeth Franck; Yousef, Shatha; Wezel, Germaine; Oquendo, Omar; Darling, Amanda; Valencia, Wendy; Milla, Carlos; Zirbes, Jackie; Rubenstein, Ronald C.; Donnelly, Erin; Malpass, Jean; Weiner, Daniel J.; Agostini, Brittani; Hartigan, Elizabeth; Cornell, Alexandra; Klein, Brendan; Bucher, Jenna; Nusbaum, Pierce; Rosenfeld, Margaret; McNamara, Sharon; Genatossio, Alan; Pittman, Jessica E.; Hicks, Tina; Bauer, Irma; Siegel, Molly; Isaac, Sarah; Jensen, Renée; Au, Jacky; Stanojevic, Sanja; Ratjen, Félix; McDonald, Nancy; Prentice, Carley; Chilvers, Mark; Richmond, M.

doi:10.1016/s2213-2600(19)30187-0

Cited by 95 publications

(60 citation statements)

References 32 publications

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“…Compared to our study, the SHIP study being the largest interventional study that used the change in LCI as primary end-point in preschool children with CF to date reported a slightly higher overall success rate of 89% [17]. This may be explained by several differences compared to our study including: 1) up to six repeated investigations per patient in the SHIP study, which may have led to a learning effect in the children; 2) the use of a face mask as interface, which may be easier for children to perform MBW; and 3) inclusion of children from the age of 3 years instead of 2 years as in our study [17].…”

Section: Discussioncontrasting

confidence: 73%

“…Feasibility and transferability of our results to a broader multicentre clinical trial setting may be strongly influenced by the established infrastructure. Recent studies on the effect of inhaled hypertonic saline and CFTR modulators in preschool children at sites highly experienced in preschool MBW using LCI as an end-point support transferability of our results to multicentre clinical trials [17,31]. However, replication studies in larger networks, such as the ECFS-Clinical Trial Network or the CF Therapeutics Development Network, will be necessary to determine whether our findings can be replicated in other trial networks before LCI can be used as a widespread outcome measure in multicentre clinical trials in preschool children.…”

Section: Discussionsupporting

confidence: 64%

“…The sensitivity of the LCI to detect response to therapy with a spectrum of interventions including inhaled hypertonic saline, inhaled DNase, CF transmembrane conductance regulator (CFTR) modulators and antibiotic therapy for pulmonary exacerbation, has been demonstrated for several paediatric age groups from infancy to school-age, including multicentre studies with performance of MBW either in sedated infants and preschool children or in awake children 3 years and older at centres highly experienced in this technique in the corresponding age group [6,10,[13][14][15][16][17]. In addition, observational studies across two MBW-experienced sites of the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) and an observational study across three MBW-experienced North American CF centres used the LCI as end-point in preschool children [11,18].…”

Section: Introductionmentioning

confidence: 99%

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Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases

et al. 2020

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BackgroundMultiple-breath washout (MBW)-derived lung clearance index (LCI) detects early cystic fibrosis (CF) lung disease. LCI was used as an end-point in single- and multicentre settings at highly experienced MBW centres in preschool children. However, multicentre feasibility of MBW in children aged 2–6 years, including centres naïve to this technique, has not been determined systematically.MethodsFollowing central training, 91 standardised nitrogen MBW investigations were performed in 74 awake preschool children (15 controls, 46 with CF, and 13 with other lung diseases), mean age 4.6±0.9 years at investigation, using a commercially available device across five centres in Germany (three experienced, two naïve to the performance in awake preschool children) with central data analysis. Each MBW investigation consisted of several measurements.ResultsOverall success rate of MBW investigations was 82.4% ranging from 70.6% to 94.1% across study sites. The number of measurements per investigation was significantly different between sites ranging from 3.7 to 6.2 (p<0.01), while the mean number of successful measurements per investigation was comparable with 2.1 (range, 1.9 to 2.5; p=0.46). In children with CF, the LCI was increased (median 8.2, range, 6.7–15.5) compared to controls (median 7.3, range 6.5–8.3; p<0.01), and comparable to children with other lung diseases (median 7.9, range, 6.6–13.9; p=0.95).ConclusionThis study demonstrates that multicentre MBW in awake preschool children is feasible, even in centres previously naïve, with central coordination to assure standardised training, quality control and supervision. Our results support the use of LCI as multicentre end-point in clinical trials in awake preschoolers with CF.

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Section: Discussioncontrasting

confidence: 73%

Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases

et al. 2020

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“…Hypertonic saline is the only inhaled agent that has been systematically evaluated in children with CF <6 years of age. [13][14][15] These randomized, controlled trials demonstrated an effect of hypertonic saline on lung function (lung clearance index 14,15 and infant pulmonary function tests) 13 but not on symptoms or pulmonary exacerbations, [13][14][15] suggesting that physiologic endpoints may be necessary to detect treatment effects in infants and preschool children given their relatively minimal symptoms.…”

Section: Hypertonic Salinementioning

confidence: 99%

Treating the Airway Consequences of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction

Toprak

Davis

Rosenfeld

2019

Semin Respir Crit Care Med

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In cystic fibrosis (CF), absent or dysfunctional CF transmembrane conductance regulator (CFTR) on the surface of airway epithelial cells causes abnormal mucociliary clearance, leading to chronic endobronchial infection and inflammation, in turn resulting in life-shortening progressive obstructive lung disease and structural airway damage. Fortunately, CF-specific therapies have been developed that improve lung function and reduce pulmonary exacerbations, contributing significantly to improved survival over the past 4 decades. Therapies not originally developed for CF, such as bronchodilators and corticosteroids, are also widely used by people living with CF. Therapies to be reviewed in this article include mucolytics, airway surface liquid hydrators, anti-inflammatory medications, bronchodilators, inhaled and oral antibiotics, and airway clearance techniques. Determining which therapies to utilize can be challenging, as there is variable evidence for each treatment, differing national guidelines, few head-to-head studies, potential for drug–drug interactions, and synergistic toxicities, as well as issues with burden of care. In this review, we summarize the mechanism of action and available evidence, and compare national guidelines for each major medication used to treat the airway consequences of CFTR dysfunction.

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“…Ideally, we seek demonstration that a therapy can reverse or attenuate abnormal findings of diagnostic tests. Although hypertonic saline inhalation has shown LCI improvements in preschool children [11], it remains to be seen whether consistent hypertonic saline treatments over years will be associated with reduced structural lung disease later in life. This is the next hurdle for CT imaging as an outcome measure: to demonstrate resolution or attenuation of abnormalities following effective interventions.…”

mentioning

confidence: 99%

Leveraging early markers of cystic fibrosis structural lung disease to improve outcomes

Flume

VanDevanter

2020

Eur Respir J

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Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial

Cited by 95 publications

References 32 publications

Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases

Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases

Treating the Airway Consequences of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction

Leveraging early markers of cystic fibrosis structural lung disease to improve outcomes

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