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

Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
Clinical Drug Investigation (Impact Factor: 1.56). 06/2010; 30(6):351-64. DOI: 10.2165/11533390-000000000-00000
Source: PubMed


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 Of the 19 patients who had informed consent from their parent/legally acceptable representative, one was withdrawn as a screen failure and was excluded from the safety and efficacy analyses; thus, 18 patients completed the study.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.

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    • "Eur. units [13]. Clinical trials have demonstrated the efficacy and safety of Creon Micro in infants and young children [14] [15] and Creon Minimicrospheres capsules in children b 7 years [16] and 7–11 years [17] with EPI due to CF. This prospective, open-label, multicentre study was carried out in Russia for compliance with local regulatory requirements, and its objective was to assess the safety, efficacy, and ease-of-use of Creon Micro in children with EPI due to CF. "
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    ABSTRACT: Background Pancreatic enzyme replacement therapy is the foundation of nutritional management for exocrine pancreatic insufficiency (EPI). Methods A 3-month, open-label, multicentre study in Russia assessing safety, efficacy, and ease-of-use of Creon® Micro (5000 lipase units/spoon) in children aged 1 month to < 4 years with EPI due to cystic fibrosis. Efficacy assessments included growth parameters. Results All 40 subjects (mean age 26.5 months) completed treatment. Adverse events occurred in 40% of the subjects (most commonly respiratory tract infection [15%], frequent bowel movements [8%], rhinitis, stomatitis, nasopharyngitis, and diarrhoea [all 5%]), none were serious or led to discontinuation. After 3 months, mean ± SD increases from baseline z-scores were height/length-for-age 0.13 ± 0.48, weight-for-age 0.20 ± 0.39, and BMI-for-age 0.29 ± 0.65. Treatment was rated ‘easy’ to administer by 95% caregivers and acceptance ‘good’/‘very good’ by 90%. Conclusions Creon Micro was well tolerated. Growth development parameters increased over the 3-month treatment period. Treatment was considered easy to use and acceptance was good.
    Journal of Cystic Fibrosis 07/2014; 14(2). DOI:10.1016/j.jcf.2014.07.006 · 3.48 Impact Factor
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    ABSTRACT: Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS). Our objective was to assess the efficacy and safety of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules (CREON) in patients with EPI due to CP or PS. This was a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling patients ≥18 years old with confirmed EPI due to CP or PS conducted in clinical research centers or hospitals. After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units per meal; 36,000 per snack) or placebo for 7 days. All patients received an individually designed diet to provide at least 100 g of fat per day. The primary efficacy measure was the change in coefficient of fat absorption (CFA) from baseline to end of the double-blind period, analyzed using non-parametric analysis of covariance. Secondary outcomes included the coefficient of nitrogen absorption (CNA), clinical symptoms, and safety parameters. In total, 25 patients (median age of 54 years, 76% male) received pancrelipase and 29 patients (median age of 50 years, 69% male) received placebo. Th e mean ± s.d. change from baseline in CFA was significantly greater with pancrelipase vs. placebo: 31.9 ± 18.6 vs. 8.7 ± 12.4 % ( P < 0.0001) [corrected]. Similarly, the mean ± s.d. change from baseline in CNA was greater for pancrelipase vs. placebo: 35.2 ± 29.1 vs. 8.9 ± 28.0 % ( P = 0.0005) [corrected].Greater improvements from baseline in stool frequency, stool consistency, abdominal pain, and flatulence were observed with pancrelipase vs. placebo. Treatment-emergent adverse events (TEAEs) were reported in five patients (20.0%) in the pancrelipase group and in six (20.7%) in the placebo group; the most common were gastrointestinal (GI) events and metabolism/nutrition disorders. There were no treatment discontinuations due to TEAEs. Pancrelipase delayed-release 12,000-lipase unit capsules were effective in treating fat and nitrogen maldigestion with a TEAE rate similar to that of placebo in patients with EPI due to CP or PS.
    The American Journal of Gastroenterology 10/2010; 105(10):2276-86. DOI:10.1038/ajg.2010.201 · 10.76 Impact Factor
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    ABSTRACT: Exocrine pancreatic insufficiency (EPI) is associated with conditions including cystic fibrosis (CF), chronic pancreatitis (CP), and pancreatic surgery (PS). The symptoms include maldigestion, malnutrition, weight loss, flatulence, and steatorrhea. Pancreatic enzyme replacement therapy (PERT) is the standard treatment for EPI; it is regulated in many countries and most recently in the USA following a US FDA mandate for all PERT manufacturers to submit new drug applications. Pancrelipase delayed-release capsules (CREON®, Abbott, Marietta, GA, USA) have been available in Europe since 1984 and in the USA since 1987; a new formulation was the first PERT to gain approval in the USA in 2009. The efficacy and safety of CREON have been demonstrated in double-blind, randomized, placebo-controlled trials in patients with CF aged ≥7 years and in patients with CP or post-PS. The data consistently demonstrate significantly better fat and nitrogen absorption with CREON versus placebo, and improvements in clinical symptoms, stool frequency, and body weight. Additionally, efficacy and safety of CREON have been shown in open-label studies in young children with CF (aged 1 month to 6 years), with control of fat malabsorption and control of clinical symptoms. The most commonly reported adverse events (AEs) with PERT are gastrointestinal disorders and allergic skin reactions. In clinical studies, CREON was well tolerated with very few withdrawals due to AEs and a low frequency of AEs judged treatment related, regardless of patient age. To further support the known safety profile of PERT, all manufacturers are required to investigate risk factors for fibrosing colonopathy, a rare gastrointestinal complication of CF, and the theoretical risk of viral transmission from porcine-derived PERT products. Together, the clinical study data and wealth of clinical experience suggest that CREON is effective and safe in patients with EPI regardless of etiology, with a very favorable risk-benefit profile.
    Advances in Therapy 11/2010; 27(12):895-916. DOI:10.1007/s12325-010-0085-7 · 2.27 Impact Factor
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