This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The pancreas provides a variety of exocrine and endocrine functions required for proper digestion, nutrition, and metabolism. Pancreatic exocrine activities include the secretion of proteins that function in the small intestine as enzymes to digest fat, proteins, and carbohydrates. Pancreatic enzymes catalyze the hydrolysis of fat into glycerol and fatty acids, protein into amino acids, and carbohydrate into dextrins and glucose. When diseased, the pancreas may become unable to produce sufficient enzymes, resulting in malabsorption of nutrients, which is clinically manifest as abdominal bloating, cramping, diarrhea, and weight loss. If pancreatic insufficiency is left untreated in CF subjects, the resulting malnutrition may be life threatening. This condition of exocrine pancreatic insufficiency (PI) is a characteristic of cystic fibrosis (CF) and chronic pancreatitis. PI is present in greater than 85% of all patients with CF by the age of 8 to 9 years.3 Both the abnormal amounts and viscosity of mucus in cystic fibrosis patients impede the secretion of sufficient pancreatic enzymes (lipases, proteases and amylases). CF patients with PI typically absorb less than 60% of dietary fat.6,7 Uncorrected maldigestion and malabsorption lead to malnutrition, failure to gain or maintain weight, decreased growth, and worsening of chronic suppurative lung disease.4,5.,6 Regardless of etiology, standard treatment of PI includes enzyme supplementation containing porcine derived pancreatic enzyme concentrate, which contains many proteins including lipase, protease and amylase. These products have demonstrated an increase in fat absorption although the range of correction is quite wide (Mitchell et al. 1982, Gow et al. 1981). Altus Biologics has developed a pancreatic enzyme replacement product, TheraCLEC -Total, which consists of lipase, protease and amylase, intended to aid in the digestion of fats, proteins and carbohydrates, in pancreatic insufficient patients. These three enzymes are synthesized and processed in such ways as to provide stable and potent enzyme activity within the small intestine. Lipase and protease are both crystallized to provide enhanced enzyme stability and potency. In addition, lipase undergoes cross-linking to provide added stability at extremes of pH and protection against proteolysis, while the protease and amylase maintain their maximum solubility for effective dissolution within the duodenum. The crystallization and cross-linking (lipase only) processes are intended to provide enhanced enzyme activity at lower dosages, in order to meet physiologic pancreatic exocrine function requirements while potentially avoiding any untoward side effects of higher dose pancreatic enzyme supplementation, such as fibrosing colonopathy. This is an international, multicenter, phase 2, randomized, double blind for TheraCLEC-Total and single blind for Creon, parallel, dose ranging trial in CF subjects with exocrine pancreatic insufficiency. Efficacy of malabsorption control, biological safety of dose ranges and pharmacokinetics of enzyme concentrations are the objectives of the study. The study is separated into four distinct periods of observation and assessment: Screening, Baseline, Treatment and Follow-up. The Treatment Period includes a combination of both outpatient care and inpatient care. Subjects take the randomly assigned study drug in the middle of each of three (3) meals and two (2) snacks per day for twenty-eight (28) days. Initial safety studies will focus on healthy volunteers and the CF study populations. Subsequent studies will evaluate efficacy in patients with malabsorption due to exocrine pancreatic insufficiency. The study plans to enroll a total of approximately 140 subjects at three dose levels of TheraCLEC-Total and one arm of Creon (approximately 35 subjects per arm). It is anticipated that TheraCLEC-Total will be indicated for the treatment of intestinal malabsorption that results from exocrine pancreatic insufficiency.
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