Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study. STUDY DESIGN: We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. RESULTS: A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P < .001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. CONCLUSIONS: Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01710644.

Single-breath counting: a pilot study of a novel technique for measuring pulmonary function in children.

INTRODUCTION: Although peak expiratory flow rate is the conventional way to measure asthma severity in adults, its use is problematic in children because it is effort dependent. Forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) are more accurate, but generally not available in the emergency department (ED). A better test is needed. Single-breath counting (SBC) is the measurement of how far an individual can count in a normal speaking voice after a maximal effort inhalation. The count is in cadence to a metronome set at 2 beats per second. Previous work has suggested that SBC correlates with standard measures of pulmonary function in adults. However, it has never been tested in children. OBJECTIVES: The aims of this study are to determine if SBC can be easily performed by children and to assess the correlation between SBC and standard measures of pulmonary function in a pediatric population. METHODS: This was a prospective observational study of a convenience sample of children presenting to the pulmonary clinic for scheduled pulmonary function testing (PFT). Peak expiratory flow rate, FEV1, FVC, forced expiratory flow 25% to 75%, and FEV1/FVC were measured and recorded. After PFT, subjects were asked to perform SBC. Three attempts were allowed, and the average was recorded. Correlation was determined by the Pearson coefficient. RESULTS: Sixty-seven children (ages 5-18 years, 64% male) were enrolled. All were able to understand and complete the testing. Indications for PFT included asthma and/or allergies (n = 44), cystic fibrosis (n = 9), and other chronic diseases (n = 14). The correlations (r) of SBC to peak expiratory flow rate, FEV1, FVC, forced expiratory flow 25% to 75%, and FEV1/FVC were 0.55, 0.66, 0.71, 0.44, and -0.29, respectively (P < .05 for all results). CONCLUSION: Single-breath counting is easy to perform in children, seems to correlate well with standard measures of pulmonary function, and shows promise for measuring asthma severity in children. Further work to define the range of reference SBC values (as a function of age and/or body size) and an evaluation of the utility of SBC in an ED population of acute asthmatics is indicated.

The Influence of Sociodemographic Heterogeneity on the Perceptions of COVID-19: A Countrywide Survey Study in the USA.

Background: Sociodemographic factors such as age, race, education, family income, and sex have been reported to influence COVID-related perceptions, reflected by knowledge, stress, and preventive behavior. We conducted a US-based survey to estimate the difference in COVID-related perceptions among diverse sociodemographic groups and the influence of sociodemographic heterogeneity on COVID-related perceptions. Methods: The survey enquired about sociodemographic parameters and relevant information to measure knowledge, stress, and preventive behavior. COVID-perception scores among sociodemographic subgroups were compared with ANOVA (Bonferroni). The general linear model (GLM) was used to estimate the association among sociodemographic factors and COVID-related perceptions. Results: Females (75%) and White participants (78%) were the predominant (N = 3734). Females, White participants, wealthy, and educated participants demonstrated better knowledge, while participants of minority races, younger ages, low incomes, and females experienced high stress. Females, African-Americans, and educated participants better adopted preventive behaviors. Race, family income, and sex were the highest contributors to the predictive model. Sociodemographic determinants had statistically significant associations with knowledge (F-score = 7.72, p < 0.001; foremost predictor: race), stress (F-score = 16.46, p < 0.001; foremost predictor: income), and preventive behavior (GLM: F-score = 7.72, p < 0.001, foremost predictor: sex). Conclusion: Sociodemographic heterogeneity significantly influenced COVID-related perceptions, while race, family income, and sex were the strongest determinants of COVID-related perceptions.

Safety and tolerability of a new formulation of pancrelipase delayed-release capsules (CREON) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an open-label, multicentre, single-treatment-arm study.

Exocrine pancreatic insufficiency (EPI) is a deficiency of digestive enzymes caused by diseases such as cystic fibrosis (CF). Patients with EPI due to CF require pancreatic enzyme replacement therapy (PERT) in order to maintain adequate nutrition. A new formulation of pancrelipase delayed-release capsules (CREON) recently received US FDA approval and has demonstrated efficacy and safety in patients with CF aged > or =7 years. The objectives of this study were to observe the safety and tolerability of new formulation pancrelipase delayed-release capsules (study drug) versus the standard of care PERT (standard therapy) in children aged <7 years with CF and EPI. Secondary objectives were to assess the ease of accurate dosing of study drug, monitor clinical symptoms and compare the efficacy of both treatments. This was an open-label, multicentre, single-treatment-arm study in children aged <7 years with a confirmed diagnosis of CF and EPI. After the screening period (approximately 14 days), all patients entered a 3-day assessment period on their usual PERT (standard therapy), followed by the study drug treatment phase (10-14 days; target dose 8000 lipase units/kg bodyweight/day), which included a second 3-day assessment period. The safety and tolerability of both treatments were documented by recording adverse events (AEs). Clinical symptoms (mean daily stool frequency, abdominal pain, stool consistency and flatulence) were monitored and ease of accurate dosing, as judged by caregivers, was reported. Efficacy was determined by comparison of percent stool fat in spot stool samples collected during both 3-day assessment periods. Of the 19 patients who had informed consent from their parent/legally acceptable representative, one was withdrawn as a screen failure and was excluded from the safety and efficacy analyses; thus, 18 patients completed the study. The median age (range) was 23 (4-71) months and 13 (72%) were male. During study drug treatment, patients received a mean +/- SD dose in lipase units/kg bodyweight/day of 7542 +/- 1335 versus 6966 +/- 3392 on standard therapy. Overall, nine (50%) patients had at least one treatment-emergent AE (TEAE) whilst receiving either treatment. All TEAEs in this study were reported as mild and none resulted in patient discontinuation. The caregivers had a slight preference for study drug over standard therapy in terms of ease of accurate dosing: six (33.3%) caregivers thought the study drug was easier to dose while only one (5.6%) thought the study drug was harder to dose than standard therapy. Clinical symptom assessment results were similar between treatments. There was no clinically meaningful difference (significance not tested) between study drug and standard therapy in the mean +/- SD percent of stool fat: 28.1 +/- 9.9 and 27.9 +/- 8.9, respectively. In this study in children aged <7 years with EPI due to CF, the new formulation pancrelipase delayed-release capsules (CREON) were clinically comparable with standard therapy in terms of safety, tolerability and efficacy.

Sleep disordered breathing in children in a general population sample: prevalence and risk factors.

STUDY OBJECTIVES: Assess the prevalence based on clinically meaningful criteria (i.e., blood pressure) and identify risk factors of sleep disordered breathing (SDB) in a representative sample of elementary school children. DESIGN: A random sample of the local elementary school children (K-5) were assessed using a two-phased strategy. In phase I a brief questionnaire was completed by a parent of each child in local elementary schools (N = 5,740), with a response rate of 78.5%. In phase II, randomly selected children and their parent spent a night in our sleep laboratory (N = 700) with a response rate of 70.0%. SETTING: University sleep laboratory. PARTICIPANTS: Children enrolled in local elementary schools. INTERVENTION: None. MEASUREMENT & RESULTS: Each child was assessed with a full polysomnogram and completed a history/physical examination including an electrocardiogram, otolaryngology examination, and pulmonary evaluation. The prevalence of moderate SDB (apnea-hypopnea index > or = 5) was 1.2%. The independent risk factors included nasal abnormalities and minority associated only with mild (1 < AHI < 5) SDB and snoring and waist circumference associated with all levels of SDB. Tonsil size, based on visual inspection, was not an independent risk factor. CONCLUSION: The prevalence of AHI > or = 5 was 1.2% in a representative sample of elementary school children. Risk factors for SDB included waist circumference, nasal abnormalities (e.g., chronic sinusitis/rhinitis), and minority. The strong linear relationship between waist circumference and BMI across all degrees of severity of SDB suggests that, as in adults, metabolic factors may be among the most important risk factors for SDB in children.

The role of microRNAs in chronic pseudomonas lung infection in Cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is the most common life limiting genetic disorder, characterized by chronic respiratory failure secondary to inflammation and chronic bacterial lung infection. Pseudomonas aeruginosa lung infection is associated with more severe lung disease and rapid progression of respiratory failure when compared to Staphylococcus aureus infection. We hypothesized that a specific signature of epigenetic factors targeting specific gene transcripts contributes to the increased morbidity seen in CF patients with chronic Pseudomonas infection. METHODS: We collected exhaled breath condensate (EBC) from 27 subjects and evaluated miRNA signatures in these samples using commercial PCR array. We identified predicted mRNA targets and associated signaling pathways using Ingenuity Pathway Analysis. RESULTS: We found 11 differentially expressed miRNAs in EBC of patients infected with Pseudomonas aeruginosa compared to EBC from CF patients who were not chronically infected with Pseudomonas aeruginosa (p < 0.05). Six of these miRNAs (hsa-miRNA-1247, hsa-miRNA-1276, hsa-miRNA-449c, hsa-miRNA-3170, hsa-miRNA-432-5p and hsa-miR-548) were significantly different in the CF Pseudomonas positive group when compared to both the CF Pseudomonas negative group and healthy control group. Ingenuity pathway analysis (IPA) revealed organismal injury and abnormalities, reproductive system disease and cancer as the top diseases and bio functions associated with these miRNAs. IPA also detected RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 and HIST1H3D as the top target genes for these miRNAs. CONCLUSION: Our study identified 6 miRNAs as epigenetic factors specifically associated with chronic Pseudomonas infection in patients with CF.

Palivizumab and Long-term Outcomes in Cystic Fibrosis.

BACKGROUND: The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. METHODS: We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores. RESULTS: The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9-99.5) and did not (97.3; 95% confidence interval: 96.1-98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. CONCLUSIONS: At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

Effect of topiramate on sweat chloride level while screening for cystic fibrosis.

Cystic fibrosis is the most common life-limiting genetic condition in Caucasians caused by Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene mutations. Sweat chloride is the current gold standard for diagnosis where values >60 mmol/L are diagnostic and values >30 mmol/L are indeterminate. There is limited literature on the effect of medications on the sweat chloride values. We report a case of topiramate being responsible for false-positive testing which resulted in overutilisation of medical resources and psychosocial stress on the family. Topiramate should be considered during the interpretation of the gold standard testing as one of the cause of false-positive sweat tests.

Vitamin D deficiency is associated with pulmonary dysfunction in cystic fibrosis.

BACKGROUND: Vitamin D deficiency is common in CF. Whether vitamin D affects pulmonary function in CF is unknown. METHODS: Data were abstracted from clinically stable CF patients who had pulmonary function studies and serum 25-hydroxyvitamin D [25(OH)D, ng/ml] levels drawn within 2 months of each other. Findings were adjusted for multiple variables known to affect pulmonary function in CF. RESULTS: Enrollees totaled 597. Overall mean 25(OH)D level was 29.6±12.8 ng/ml (SD). Serum 25(OH)D levels showed a significant correlation with forced expiratory volume in 1s (FEV1) % predicted (r=0.20, p<0.0001) and forced vital capacity % predicted (r=0.13, p=0.0019). Multivariate analysis revealed that serum 25(OH)D remained an independent predictor of FEV1 % predicted even after controlling for multiple other factors known to affect CF lung function. CONCLUSIONS: Serum 25(OH)D levels are significantly associated with pulmonary function in CF. Further study is required to determine whether this association is causal.

Factors affecting the incidence of Stenotrophomonas maltophilia isolation in cystic fibrosis.

STUDY OBJECTIVES: To identify factors predisposing cystic fibrosis (CF) patients to Stenotrophomonas maltophilia infection and to determine whether coinfection with S maltophilia affects the clinical response to therapy with tobramycin solution for inhalation (TSI), 300 mg bid. DESIGN: Retrospective review of data collected from two identical, 6-month, randomized, placebo-controlled trials. SETTING: Sixty-nine CF centers in the United States. INTERVENTIONS: Active drug administration of 300 mg TSI. PATIENTS: Five hundred twenty CF patients with chronic Pseudomonas aeruginosa endobronchial infections. MEASUREMENTS AND RESULTS: A logistic regression analysis identified factors contributing to increased S maltophilia isolation frequency. In this multivariate analysis, the only significant predictors of S maltophilia isolation during the last month of the trial were the concomitant use of oral quinolones (primarily ciprofloxacin; p = 0.0015) and S maltophilia isolation prior to treatment (p < 0.0001). Treatment group, gender, age, use of systemic or inhaled steroids, use of oral sulfonamide, IV cephalosporins, or penicillin antibiotics, baseline FEV(1) percent predicted, and pretreatment Aspergillus isolation were not significant predictors of subsequent S maltophilia infection. In addition, S maltophilia-positive culture frequency was compared to the change in pulmonary function. Patients who either never had culture results positive for S maltophilia or who were positive at <25% of observations had greater clinical response to TSI at the final study visit compared to patients who were positive at > or = 25% of observations. CONCLUSIONS: TSI therapy did not result in a greater risk for isolation of S maltophilia than standard care alone. In contrast, oral quinolone antibiotic use during the trial was associated with a 2.7-fold increased risk of having a culture positive for S maltophilia (p = 0.0015). The use of TSI to suppress P aeruginosa resulted in improved lung function, regardless of S maltophilia culture frequency. However, improvement was not as great among patients who were persistently coinfected with S maltophilia.

Safety and efficacy of ketamine sedation for infant flexible fiberoptic bronchoscopy.

OBJECTIVE: To describe our experience with ketamine sedation during infant flexible fiberoptic bronchoscopy. DESIGN: Retrospective chart review. Infants were sedated with midazolam and ketamine with or without fentanyl. The sedation regimen, final procedure performed, procedure duration, and complications were recorded. Complication rates between infants 6 months of age and between infants with upper vs lower airway symptoms were compared by chi(2) test with a contingency table. RESULTS: Fifty-nine procedures were performed in 55 patients aged 6.1 +/- 3.1 months (mean +/- SD). Sedation was achieved with ketamine and midazolam (n = 30) or ketamine, midazolam, and fentanyl (n = 29). Bronchoscopy with BAL was performed in 44 patients and bronchoscopy alone in 3 patients. In 11 patients, severe upper airway obstruction and/or anomalies prevented subglottic passage of the bronchoscope. One patient could not be adequately sedated. There were no major complications. Minor complications occurred in 14 patients (23.7%), most commonly mild hypoxemia (n = 9). Brief central apnea developed in three patients. Complication rates were unaffected by age or indication for bronchoscopy. CONCLUSIONS: Infant flexible fiberoptic bronchoscopy can be safely and effectively performed using ketamine sedation. Complications, especially mild hypoxemia, appear more common in infants, likely due to smaller airway diameter. Regardless of the sedative(s) used, additional vigilance is required when performing bronchoscopy in this population.

Administration of the first dose of palivizumab immunoprophylaxis against respiratory syncytial virus in infants before hospital discharge: what is the evidence for its benefit?

BACKGROUND: Palivizumab is 1 of 2 agents used to prevent severe lower respiratory tract disease due to respiratory syncytial virus (RSV) infection. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend administering the first dose of RSV immunoprophylaxis to eligible infants before hospital discharge. Unfortunately, third-party payers frequently do not separately reimburse administration of this therapy to hospitalized infants. OBJECTIVE: Because palivizumab is commonly used to provide RSV immunoprophylaxis, we systematically reviewed all published data on this drug to determine whether the evidence supports the recommendation of administering the first dose before hospital discharge. METHODS: MEDLINE was searched for all articles published in English from January 1, 1996, to October 31, 2003, using the search terms palivizumab and Synagis, and the following data were extracted onto a standardized form: author(s), year of publication, study design, patient population, sample size, criteria used for administration of RSV prophylaxis, location of palivizumab prophylaxis (inpatient or outpatient), parental satisfaction with administration of prophylaxis, incidence of RSV infection, and hospitalization rates for RSV. All selected publications were reviewed to determine whether they reported differences in the incidence of RSV infection or hospitalization in patients who received palivizumab before discharge compared with those who received it after discharge. Only those publications that specifically documented administration of the first dose of palivizumab before hospital discharge were included in the final analysis. RESULTS: Six of the 166 studies reviewed met the selection criteria. Although all 6 studies reported reduced RSV hospitalization rates with palivizumab prophylaxis, no study directly compared inpatient and outpatient administration with regard to parental satisfaction or rates of RSV infection or hospitalization. Furthermore, based on the data in these studies, it was not possible to detect any differences in parental satisfaction or rates of RSV infection or hospitalization between the 2 locations of administration. CONCLUSIONS: Based on our literature review, there is no evidence to support the recommendation that palivizumab be administered before hospital discharge in every infant who meets the criteria for RSV immunoprophylaxis. Eligible infants may be given the initial dose of RSV prophylaxis as outpatients, reducing the cost to institutions that currently provide palivizumab before hospital discharge.

Aortic hiatus gastric hernia.

Congenital diaphragmatic hernias are a relatively common anomaly that can present with significant respiratory morbidity and mortality. We report on a case of an aortic-hiatal gastric hernia that initially presented with repeated episodes of respiratory distress, which was diagnosed as asthma. The diagnosis of a diaphragmatic hernia was made at 18 months of age. In the operating room, it was noted that it was an aortic hiatal hernia, which was surgically repaired. Subsequently, there has been improvement in daily respiratory symptoms.

Efficacy and safety of a unique enteric-coated bicarbonate-buffered pancreatic enzyme replacement therapy in children and adults with cystic fibrosis.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is used to treat exocrine pancreatic insufficiency in cystic fibrosis. RESULTS/METHODS: Efficacy and safety of a unique enteric-coated (EC) bicarbonate-buffered PERT product (PERTZYE®/PANCRECARB®; Digestive Care, Inc., Bethlehem, PA, USA) was studied in a randomized, double-blind, placebo-controlled cross-over design. Subjects were stabilized on EC-bicarbonate-buffered PERT and a high-fat diet. During two treatment periods, subjects were randomized to EC-bicarbonate-buffered PERT or placebo, followed by a 72-h stool collection employing an ingested stool dye marker. Mean coefficient of fat absorption with EC-bicarbonate-buffered PERT was 82.5% compared with 46.3% with the placebo (absolute difference 36.2%; p < 0.001), a 78.2% improvement for active over placebo. Similar improvements in nitrogen absorption were observed. Overall stool frequency and stool weight decreased (p < 0.001). No safety concerns were identified. SUMMARY: EC-bicarbonate-buffered PERT is effective in treating cystic fibrosis-associated exocrine pancreatic insufficiency.

Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is essential for maintaining adequate nutrition in children with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). The US Food and Drug Administration regulations now require all PERT products to undergo clinical efficacy and safety studies before they can be considered for marketing approval. OBJECTIVE: This study was conducted to compare the efficacy of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules with placebo in children with EPI due to CF. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover, superiority study of the new formulation of pancrelipase delayed-release 12,000-lipase unit capsules in children aged 7 to 11 years with CF and EPI. In each period, pancrelipase or identical placebo capsules were taken for 5 days. The primary outcome measure was the coefficient of fat absorption (CFA); secondary outcome measures were the coefficient of nitrogen absorption (CNA) and clinical symptoms. The latter were assessed based on patient-reported daily stool frequency, stool consistency (hard, formed/normal, soft, or watery), flatulence (none, mild, moderate, or severe), and abdominal pain (none, mild, moderate, or severe). Safety measures included vital signs, physical examinations, standard laboratory safety tests (hematology and biochemistry), and adverse events. RESULTS: Seventeen patients were randomized to treatment and 16 completed the study; 1 patient withdrew consent during the first treatment period and was not included in the efficacy analysis. Patients' median age was 8.0 years (range, 7-11 years); 12 patients (70.6%) were male. CFA values were significantly greater for pancrelipase compared with placebo, with least squares mean (SE) values of 82.8% (2.7%) and 47.4% (2.7%), respectively (P < 0.001). The results were similar for CNA, with mean values of 80.3% (3.2%) and 45.0% (3.2%) (P < 0.001). Pancrelipase treatment had significantly greater effects on CFA and CNA in patients with a placebo CFA <50% than in those with a placebo CFA >50% (both parameters, P < 0.001 and P = 0.008, respectively). Significant improvements in stool fat, weight, and nitrogen and a significant reduction in daily stool frequency were observed with pancrelipase compared with placebo (all, P < 0.001). Symptoms of EPI were less severe and remained relatively stable during pancrelipase treatment, but worsened slightly during receipt of placebo. Treatment-emergent adverse events were reported in 5 patients (29.4%) during receipt of pancrelipase and in 9 patients (56.3%) during receipt of placebo; these were predominantly gastrointestinal events. There were no discontinuations due to treatment-emergent adverse events and no serious adverse events. CONCLUSIONS: In this study in children with EPI due to CF, the new formulation of pancrelipase delayedrelease capsules was associated with improvements in CFA, CNA, stool properties, and EPI symptoms compared with placebo. Pancrelipase delayed-release capsules appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00690820. (Clin Ther.

Efficacy and Safety of a New Formulation of Pancrelipase (Ultrase MT20) in the Treatment of Malabsorption in Exocrine Pancreatic Insufficiency in Cystic Fibrosis.

Background. Pancreatic enzyme replacement therapy is the standard of care for treatment of malabsorption in patients with cystic fibrosis (CF) and exocrine pancreatic insufficiency (PI). Aim. To evaluate efficacy and safety of a new formulation of pancrelipase (Ultrase MT20) in patients with CF and PI. Coefficients of fat absorption (CFA%) and nitrogen absorption (CNA%) were the main efficacy parameters. Safety was evaluated by monitoring laboratory analyses, adverse events (AEs), and overall signs and symptoms. Methods. Patients (n = 31) were randomized in a crossover design comparing this pancrelipase with placebo during 2 inpatient evaluation periods (6-7 days each). Fat and protein/nitrogen ingestion and excretion were measured from food diaries and 72-hour stool collections. CFA% and CNA% were calculated for each period and compared. Results. Twenty-four patients provided analyzable data. This pancrelipase increased mean CFA% and CNA% (+34.7% and +25.7%, resp., P < .0001 for both), reduced stool frequency, and improved stool consistency compared with placebo. Placebo-treated patients reported more AEs, with gastrointestinal symptoms being the most frequently reported AE. Conclusions. This pancrelipase is a safe and effective treatment for malabsorption associated with exocrine PI in patients with CF.

Baseline characteristics and factors associated with nutritional and pulmonary status at enrollment in the cystic fibrosis EPIC observational cohort.

SUMMARY BACKGROUND: The EPIC Observational Study is an ongoing prospective cohort study investigating risk factors for and clinical outcomes associated with early Pseudomonas aeruginosa (Pa) acquisition in young children with cystic fibrosis (CF). OBJECTIVES AND HYPOTHESIS: To describe the baseline characteristics of the cohort and evaluate associations between potential risk factors and nutritional and respiratory characteristics at enrollment. We hypothesized that distinct demographic and environmental risk factors could be identified for poorer nutritional status and lung function at enrollment. METHODS: During 2004-2006, 1,700 children with CF were enrolled at 59 US CF centers. Children