Rationale:The cystic fibrosis (CF) modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) proved highly effective in controlled clinical trials for individuals with ≥1 F508del allele, which occurs in at least 85% of people with CF (PwCF). Objective: PROMISE is a post-approval study to understand the broad effects of ETI through 30 months clinical use in a more diverse US patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 PwCF age ≥12 years with ≥1 F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in ppFEV 1 , sweat chloride concentration, body mass index, and selfreported respiratory symptoms. Results: average age was 25.1 years. 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor while 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV 1 improved 9.76 percentage points (95% CI 8.76, 10.76) from baseline, CFQ-R Respiratory Domain score improved 20.4 points (95% CI 18.3, 22.5), and sweat chloride decreased -41.7 mmol/L (95% ). BMI also significantly increased.Changes were larger in those naïve to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naïve to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV 1 in the overall study population.

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RationaleInhaled tobramycin and oral azithromycin are common chronic therapies in people with cystic fibrosis and Pseudomonas aeruginosa airway infection. Some studies have shown that azithromycin can reduce the ability of tobramycin to kill P. aeruginosa. This trial was done to test the effects of combining azithromycin with inhaled tobramycin on clinical and microbiological outcomes in people already using inhaled tobramycin. We theorised that those randomised to placebo (no azithromycin) would have greater improvement in forced expiratory volume in one second (FEV1) and greater reduction in P. aeruginosa sputum in response to tobramycin.MethodsA 6-week prospective, randomised, placebo-controlled, double-blind trial testing oral azithromycin versus placebo combined with clinically prescribed inhaled tobramycin in individuals with cystic fibrosis and P. aeruginosa airway infection.ResultsOver a 6-week period, including 4 weeks of inhaled tobramycin, the relative change in FEV1 did not statistically significantly differ between groups (azithromycin (n=56) minus placebo (n=52) difference: 3.44%; 95% CI: −0.48 to 7.35; p=0.085). Differences in secondary clinical outcomes, including patient-reported symptom scores, weight and need for additional antibiotics, did not significantly differ. Among the 29 azithromycin and 35 placebo participants providing paired sputum samples, the 6-week change in P. aeruginosa density differed in favour of the placebo group (difference: 0.75 log10 CFU/mL; 95% CI: 0.03 to 1.47; p=0.043).ConclusionsDespite having greater reduction in P. aeruginosa density in participants able to provide sputum samples, participants randomised to placebo with inhaled tobramycin did not experience significantly greater improvements in lung function or other clinical outcomes compared with those randomised to azithromycin with tobramycin.

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This study examines the critical assumption of a normal distribution for protein content in feedstuffs. Data were collected from broiler feed mills on the nutrient content of corn, meat and bone meal, and soybean meal. Tests of normality for protein within each feedstuff were performed by each of two methods: 1) the Shapiro-Wilk test (n < 50) or Kolmogorov-Smirnov test (n > 50); and 2) the D'Agostino-Pearson K2 test. Results indicate that protein is non-normally distributed in corn and in meat and bone meal, but protein is normally distributed in soybean meal.