RESUMO
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.