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Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

ABSTRACT: BACKGROUND:In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA). OBJECTIVE:To determine if the Encala™ treatment effect varied by severity of baseline fat malabsorption. METHODS:Subjects (n = 66, 10.5±3.0 yrs, 39% female) with baseline CFA who completed a three-month treatment with Encala™ or a calorie and macronutrient-matched placebo were included in this subgroup analysis. Subjects were categorized by median baseline CFA: low CFA (<88%) and high CFA (?88%). At baseline and 3-month evaluations, CFA (72-hour stool, weighed food record) and height (HAZ), weight (WAZ) and BMI (BMIZ) Z-scores were calculated. Fasting plasma fatty acid (FA) concentrations were also measured. RESULTS:Subjects in the low CFA subgroup had significantly improved CFA (+7.5±7.2%, mean 86.3±6.7, p = 0.002), and reduced stool fat loss (-5.7±7.2 g/24 hours) following three months of EncalaTM treatment. These subjects also had increased plasma linoleic acid (+20%), ?-linolenic acid (+56%), and total FA (+20%) (p?0.005 for all) concentrations and improvements in HAZ (0.06±0.08), WAZ (0.17±0.16), and BMIZ (0.20±0.25) (p?0.002 for all). CFA and FA were unchanged with placebo in the low CFA group, with some WAZ increases (0.14±0.24, p = 0.02). High CFA subjects (both placebo and Encala™ groups) had improvements in WAZ and some FA. CONCLUSIONS:Subjects with CF, PI and more severe fat malabsorption experienced greater improvements in CFA, FA and growth after three months of Encala™ treatment. Encala™ was safe, well-tolerated and efficacious in patients with CF and PI with residual fat malabsorption and improved dietary energy absorption, weight gain and FA status in this at-risk group.

SUBMITTER: Stallings VA

PROVIDER: S-EPMC7209323 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

Stallings Virginia A VA Tindall Alyssa M AM Mascarenhas Maria R MR Maqbool Asim A Schall Joan I JI

PloS one 20200508 5

<h4>Background</h4>In the primary analysis of a 12-month double-blind randomized active placebo-controlled trial, treatment of children with cystic fibrosis (CF) and pancreatic insufficiency (PI) with a readily absorbable structured lipid (Encala™, Envara Health, Wayne, PA) was safe, well-tolerated and improved dietary fat absorption (stool coefficient of fat absorption [CFA]), growth, and plasma fatty acids (FA).<h4>Objective</h4>To determine if the Encala™ treatment effect varied by severity o ...[more]

PMID: 32384122

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

Project description:BACKGROUND: F508del-CFTR, the most frequent disease-causing mutation among Caucasian cystic fibrosis (CF) patients, has been characterised as a mutant defective in protein folding, processing and trafficking. We have investigated the two neighbouring cytokeratin genes KRT8 and KRT18 in a candidate gene approach to ask whether variants in KRT8 and/or KRT18 modify the impaired ion conductance known as the CF basic defect, and whether they are associated with correct trafficking of mutant CFTR and disease severity of CF. METHODS: We have selected contrasting F508del-CFTR homozygous patient subpopulations stratified for disease severity, comparing 13 concordant mildly affected sib pairs vs. 12 concordant severely affected sib pairs, or manifestation of the CF basic defect in intestinal epithelium, comparing 22 individuals who exhibit CFTR-mediated residual chloride secretion vs. 14 individuals who do not express any chloride secretion, for an association. The KRT8/KRT18 locus was initially interrogated with one informative microsatellite marker. Subsequently, a low density SNP map with four SNPs in KRT8 and two SNPs in KRT18, each selected for high polymorphism content, was used to localize the association signal. RESULTS: KRT8, but not KRT18, showed an association with CF disease severity (Pbest=0.00131; Pcorr=0.0185) and CFTR mediated residual chloride secretion (Pbest=0.0004; Pcorr=0.0069). Two major four-marker-haplotypes spanning 13 kb including the entire KRT8 gene accounted for 90% of chromosomes, demonstrating strong linkage disequilibrium at that locus. Absence of chloride secretion was associated with the recessive haplotype 1122 at rs1907671, rs4300473, rs2035878 and rs2035875. The contrasting haplotype 2211 was dominant for the presence of CFTR mediated residual chloride secretion. In consistency, the KRT8 haplotype 2211 was associated with mild CF disease while 1122 was observed as risk haplotype. Analysis of microsatellite allele distributions on the SNP background suggests that the mild KRT8 haplotype 2211 is phylogenetically older than its severe counterpart. CONCLUSIONS: The two opposing KRT8 alleles which have been identified as a benign and as a risk allele in this work are likely effective in the context of epithelial cell differentiation. As the mild KRT8 allele is associated with CFTR mediated residual chloride secretion among F508del-CFTR homozygotes, the KRT8/KRT18 heterodimeric intermediary filaments of the cytoskeleton apparently are an essential component for the proper targeting of CFTR to the apical membrane in epithelial cells.

Dataset Information

Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

Publications

Improved residual fat malabsorption and growth in children with cystic fibrosis treated with a novel oral structured lipid supplement: A randomized controlled trial.

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