Phase 1-2 Trial of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 13
- 试验地点
- 4
- 主要终点
- Frequency of Adverse events
研究概览
简要总结
This protocol outlines a randomized,open label trial examining the safety, pharmacology and efficacy of Glucagon like peptide 2 (GLP-2) in infants and children with intestinal failure. The investigators hypothesize that GLP-2 given subcutaneously in these patients will be well tolerated, and have similar metabolism to what has been shown in adults. The investigators also expect to show an improvement in the tolerance of enteral nutrition, and a decreased requirement for intravenous feeding.
详细描述
GLP-2 (1-33) is a naturally occurring peptide which is important in controlling the function of the intestine. In previous studies our group has shown that serum levels of GLP-2 correlate with intestinal function in human neonates. Low levels of GLP-2 are predictive of intestinal malabsorption and the development of the so called "Short Bowel Syndrome". GLP-2 has been shown to be specifically trophic for the GI tract, especially for the small intestine.
This proposal outlines a Phase 1 and 2 trial using subcutaneous administration, twice daily of GLP-2 in human infants and children with Intestinal Failure, typically from Short Bowel Syndrome, using varying doses, assigned in a prospective, randomized protocol, with open label monitoring.
The investigational plan is to begin with the Phase 1 trial, administering GLP 2 at varying doses (infants assigned to doses of 5,10, or 20 μg/kg/day, children greater than 1 year dosed at 20 μg/kg/day, given via twice daily subcutaneous injection).
Eligible subjects will be infants (less than 12 months corrected gestational age) with either major resection (remaining small intestine less than 40% of predicted length for gestational age), or demonstrated intestinal failure after intestinal resection/abdominal surgery/gastroschisis (Requirement for parenteral nutrition greater than 50% of total calories, more than 45 days after the last surgery).
Infants will be allocated sequentially to a group (n = 6 per group) treated with GLP-2 at 5,10, or 20 μg/kg/day.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Infants (< 1 year corrected gestational age) Infants with congenital anomalies, or intestinal resection, leaving them with anatomic short bowel syndrome (total remaining small intestine less than 40 % of predicted for gestational age) will be eligible for treatment in the immediate post-operative period.
- •Infants with intestinal resection or repaired gastroschisis who have demonstrated dependence on parenteral nutrition at 45 days post operation with the requirement for >50% of calories by PN (independent of the length of remnant small intestine).
- •Children (> 1 year corrected gestational age) Children with a requirement for >30% of calories by PN more than 1 year (365) days post surgery will be eligible.
排除标准
- •Significant extra-intestinal disease (e.g., grade IV intraventricular hemorrhage, severe hypoxic encephalopathy);
- •Significant cardiovascular, hemodynamic or respiratory instability, as noted by 1) the requirement for dopamine > 4 mcg/kg/min, 2) high frequency ventilatory support, 3) extracorporeal membrane oxygenation.
- •Hepatic disease defined as direct bilirubin > 100 umol/L (5.2 mg/dL)
- •Renal disease defined as BUN > 80 or creatinine > 90 μmol/L (1.5 mg/dL)
- •Inborn errors of metabolism necessitating protein restriction or other special diet;
- •Ongoing sepsis syndrome, as noted by refractory hypotension, thrombocytopenia, acidosis, and/or bacteremia.
- •Primary motility defect such as intestinal pseudo-obstruction.
- •Absorptive defects (such as microvillus inclusion disease)
- •Females who are post-pubertal must agree to comply with measures to prevent pregnancy during the study phase.
- •Coagulopathy which precludes the use of subcutaneous injections.
- •Allergy to GLP-2 or any of the constituent of the GLP-2 IC-115 preparation.
研究组 & 干预措施
Intestinal Failure in children (>1 year)
Children requiring parenteral nutrition for >30% of calories more than 1 year (365) days post surgery will be eligible for treatment with Glucagon-like peptide 2 (20 ug/kg/day) for 6 weeks
干预措施: Glucagon-Like Peptide 2 (Drug)
GLP-2 in Infants (<1 year of age)
Infants under one year of age with congenital anomalies, or intestinal resection, leaving them with anatomic short bowel syndrome (total remaining small intestine less than 40 % of predicted for gestational age) or with intestinal resection or repaired gastroschisis who have demonstrated dependence on parenteral nutrition at 45 days post operation with the requirement for >50% of calories by PN (independent of the length of remnant small intestine) will be eligible for treatment with Glucagon-like peptide 2, at a dose of 5, 10 or 20 ug/kg/day.
干预措施: Glucagon like peptide-2 (Drug)
结局指标
主要结局
Frequency of Adverse events
时间窗: One year
During active drug administration, patients will be monitored daily for serious adverse events. Patients will also be monitored (daily, if inpatients, bi weekly if outpatients) for clinically significant changes in safety data, vital signs, physical examination,and injection site reactions. Laboratory values of liver function and renal function will be monitored weekly for inpatients and bi weekly for outpatients. Following discontinuation of the treatment, patients will be monitored at 1 ,6 and 12 months post completion of the therapy.
Pharmacokinetics (Peak serum level. Area under the curve
时间窗: Done on Day 3 and 42
On days 3 and 42 of the trial, GLP-2 levels will be drawn at time 0 (before injection), 45,90 and 180 minutes post injection. Results will be analyzed for peak levels, and AUC.
次要结局
- Intrinsic GLP-2 Production(One year)
- Septic Episodes(6 weeks)
- Nutritional Parameters(one year)
- Mucosal Morphology(6 weeks)
- Serum Citrulline Levels(One year.)
- Changes in the Enteral Caloric intake(one year)
研究者
David Sigalet MD PhD
Adjunct Professor, Division of Pediatric Surgery
Alberta Children's Hospital