A 90 day, Phase 3, Open Labeled Exploratory Study of RELiZORB to Evaluate Safety, Tolerability, and Nutrient Absorption in Children with Short Bowel Syndrome who are Dependent on Parenteral Nutrition

项目摘要/摘要 短肠综合征(SBS)通常是由于大量小肠的丢失而造成的 消化吸收。治疗包括高卡路里饮食和静脉喂养(即非肠道喂养 营养或PN)，以及其他。由于肠道长度或功能的减少，许多患者不能脱离PN。 接受长期PN的患者经常出现严重的代谢并发症、脓毒症、肝胆管疾病 包括胆汁淤积和纤维化，并可进展为肝功能衰竭。全肠道喂养(肠内营养) 无肠外营养是预防上述并发症的最佳方法。 肠内应用长链甘油三酯治疗SBS患者，尤其是肝病患者 功能障碍，由于胆汁酸吸收不良导致胶束形成减少而不能很好地耐受 和脂肪消化。膳食脂肪以前不能被胆汁酸乳化，也不能被脂肪酶作用。 从病人身上排出的是大便。转向其他形式的脂肪，如中链甘油三酯(MCT) 胆汁酸或胰腺功能不全患者不需要胶束吸收可能耐受性更好 但并不是最理想的，因为它们增加了肠道的渗透负荷。这可能会增加排便的机会。 此外，MCT不含必需脂肪酸(FAs)。提供必要的FA的能力 例如以不需要形成胶束来吸收的形式存在于肠溶配方中的那些， 将允许SBS患者和不再依赖PN的患者获得足够的营养和 继续保持与他们通过肠外获得大部分营养时相同的增长轨迹。 RELiZORB是一种与肠道喂养管组串联连接的酵素盒，旨在模仿 胰腺脂肪酶的功能。据推测，通过使用这种外部脂肪酶装置，肠内营养将被 随着肠内自主性的增加，吸收更好，对PN的依赖减少。这款产品消除了 需要肠道乳化，并消除了包括脂肪酶在内的药物的风险，允许在 饮食进入肠道的时间。该设备已被证明可以消化大多数肠内配方奶粉中90%的脂肪。 这是一项3期开放标签单中心临床试验，以确定安全性、耐受性和 含肠内营养的RELiZORB酶制剂在儿科患者每日90天的生物利用度 SBS受试者，年龄2-18岁，PN依赖。从基线到PN卡路里的变化， 每周评估，将根据曲线下面积作为平均百分比增加或减少进行评估 呈现出95%的可信区间。治疗-紧急不良事件的数量(百分比)，分级 2或以上，以及生命体征异常的发生率、大便数量/次数的变化、造口 输出量，需要减少肠内喂养，尿液颜色，血液学和生化参数的变化将 被列成表格。生长Z评分、72小时粪便脂肪和脂肪吸收系数、血浆FAS、Pn的变化 此外，还将介绍容量、肠内/口腔营养以及脱离PN的能力。

Project Summary/Abstract Short bowel syndrome (SBS) is often due to the loss of large amounts of small intestine that compromises digestive absorption. The treatments include a high-calorie diet and feeding through the vein (i.e., parenteral nutrition or PN), among others. Many patients cannot wean from PN due to reduced intestinal length or function. Patients on long-term PN frequently experience serious metabolic complications, sepsis, hepatic biliary disorders including cholestasis, and fibrosis and can progress to liver failure. Full intestinal feeding (enteral nutrition) without PN is the optimal way to prevent the above complications. Enterally administered long chain triglycerides in patients with SBS, especially those with hepatic dysfunction, are not well tolerated due to bile acid malabsorption, which leads to decreased micelle formation and fat digestion. The dietary fat is unable to be emulsified by the bile acids and acted on by lipases before exiting the patient as stool. Switching to other forms of fat such as medium-chain triglycerides (MCTs) that do not require micelles for absorption may be better tolerated in patients with bile acid or pancreatic insufficiency but are not optimal as they increase the osmotic load in the intestine. This may increase the chance of stool dumping; moreover, MCTs do not contain essential fatty acids (FAs). The ability to provide the essential FAs such as those present in enteral formulas in a form that does not require the formation of micelles for absorption, would allow patients with SBS and those who are no longer PN dependent to receive adequate nutrition and continue to maintain the same growth trajectory as when they received the majority of their nutrition parenterally. RELiZORB is an enzyme cartridge connected in-line with enteral feed tubing sets designed to mimic the function of pancreatic lipase. It is hypothesized that by using this external lipase device, enteral nutrition will be better absorbed, and PN dependence reduced as enteral autonomy is increased. This product eliminates the need for intestinal emulsification and eliminates the risk of drugs, including lipases, allowing absorption at the time the diet enters the gut. The device has been shown to digest >90% of fat in most enteral formulas. This is a phase 3, open label single center clinical trial to determine the safety, tolerability, and bioavailability of the RELiZORB enzyme cartridge with enteral nutrition when used daily for 90 days in pediatric subjects with SBS, aged 2 years – 18 years, who are PN dependent. The change in PN calories from baseline, assessed weekly, will be evaluated by area under the curve as a mean percentage increase or decrease and presented with a 95% confidence interval. The number (percent) of treatment-emergent adverse events, grade 2 or above, as well as the incidence of abnormalities in vital signs, changes in stool amount/frequency, ostomy output, the need to decrease enteral feeds, changes in urine color, hematology and biochemistry parameters will be tabulated. Changes in growth z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma FAs, PN volume, enteral/oral nutrition, and ability to wean from PN will also be described.