CF EXOCRINE PANCREATIC INSUFFICIENCY

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。胰腺提供各种消化、营养和新陈代谢所需的外分泌和内分泌功能。胰腺外分泌活动包括分泌蛋白质，这些蛋白质在小肠中作为消化脂肪、蛋白质和碳水化合物的酶发挥作用。胰酶催化脂肪分解成甘油和脂肪酸，蛋白质分解成氨基酸，碳水化合物分解成葡聚糖和葡萄糖。当患病时，胰腺可能无法产生足够的酶，导致营养吸收不良，临床表现为腹胀、痉挛、腹泻和体重减轻。如果胰腺功能不全在慢性胰腺炎患者中得不到治疗，由此导致的营养不良可能危及生命。胰腺外分泌功能不全是囊性纤维化和慢性胰腺炎的特征。在8至9岁的所有CF患者中，超过85%的患者存在PI。3囊性纤维化患者粘液的异常数量和粘度都阻碍了足够的胰酶(脂肪酶、蛋白酶和淀粉酶)的分泌。Cf PI患者通常吸收不到60%的膳食脂肪。6，7未经纠正的消化不良和吸收不良会导致营养不良、体重无法增加或保持、生长减慢，以及慢性化脓性肺部疾病的恶化。4、5、6无论病因如何，PI的标准治疗包括补充含有猪源性胰酶浓缩物的酶，其中含有许多蛋白质，包括脂肪酶、蛋白酶和淀粉酶。这些产品已经证明了脂肪吸收的增加，尽管校正的范围相当宽(Mitchell等人)。1982年，Gow等人。(1981年)。Altus Biologics开发了一种胰腺酶替代产品TheraCLEC-Total，该产品由脂肪酶、蛋白酶和淀粉酶组成，旨在帮助胰腺功能不足的患者消化脂肪、蛋白质和碳水化合物。这三种酶的合成和加工方式是为了在小肠内提供稳定和有效的酶活性。脂肪酶和蛋白酶都是结晶的，以提供更好的酶稳定性和效价。此外，脂肪酶经历交联化，以在极端的pH条件下提供额外的稳定性并防止蛋白质分解，而蛋白酶和淀粉酶保持其最大的溶解度，以便在十二指肠内有效溶解。结晶法和交联法(仅限脂肪酶)的目的是在较低剂量下提供增强的酶活性，以满足生理胰腺外分泌功能的要求，同时潜在地避免补充较高剂量的胰酶的任何不良副作用，如纤维化结肠病。这是一项国际性、多中心、2期随机、TheraCLEC-Total的双盲试验和Creon的单盲平行剂量范围试验，用于治疗有胰腺外分泌功能不全的CF受试者。控制吸收不良的有效性、剂量范围的生物安全性和酶浓度的药代动力学是本研究的目标。这项研究分为四个不同的观察和评估阶段：筛查、基线、治疗和随访。治疗期包括门诊护理和住院护理相结合。受试者在每天三(3)餐和两(2)种零食中的每一餐中间服用随机分配的研究药物，持续28天。最初的安全性研究将集中在健康志愿者和CF研究人群。后续研究将评估胰腺外分泌功能不全所致吸收不良患者的疗效。这项研究计划招募总共约140名受试者，服用三种剂量的TheraCLEC-Total和一支服用Creon的受试者(每支受试者大约35名)。预计TheraCLEC-Total将被用于治疗由胰腺外分泌功能不全引起的肠道吸收不良。

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.