Clinical Trial: Safety and Dosing Study of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Phase 1-2 Trial of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure

Brief Summary: 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.

Detailed Summary:

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.

Older children (greater than 1 year of age), requiring PN for >30% calories> one year post surgery will also be eligible; these patients will be dosed at 20 &
Sponsor: Alberta Children's Hospital

Current Primary Outcome:

• Frequency of Adverse events [ Time Frame: 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 [ Time Frame: 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.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Changes in the Enteral Caloric intake [ Time Frame: one year ]
  During active drug administration, changes in the proportion of total enteral calories tolerated (Including discontinuation of parenteral nutrition) will be monitored twice weekly (hospital inpatients) and weekly (for outpatients). Following the phase of active treatment, patients will be followed at 1, 6, and 12 months.
• Nutritional Parameters [ Time Frame: one year ]
  During the phase of active treatment, nutritional parameters; weight gain, maintenance of growth (z scores), Liver function, albumin, protein levels, C-reactive protein, electrolytes, renal function (creatinine levels) will be monitored twice weekly (hospital inpatients) and weekly (for outpatients). Following the phase of active treatment, patients will be followed at 1, 6, and 12 months.
• Mucosal Morphology [ Time Frame: 6 weeks ]
  If procedures requiring sedation or surgery are done during the phase of active drug administration, intestinal biopsies will be requested, to quantify changes in crypt cell proliferation and apoptosis index, and intestinal morphology (villus height and/or crypt depth) between pre-treatment surgical samples, and specimens obtained while under treatment.
• Intrinsic GLP-2 Production [ Time Frame: One year ]
  At the beginning of the active treatment, and during week 5, intrinsic meal stimulated GLP-2 production will be assessed. During followup, these values will be assessed at 1,6 and 12 months post-treatment
• Septic Episodes [ Time Frame: 6 weeks ]
  During the treatment phase, the number of septic episodes, and the type of infecting organisms will be recorded.
• Serum Citrulline Levels [ Time Frame: One year. ]
  Citrulline levels as a measure of intestinal mucosal mass will be assessed at time 0, and on the last day of active treatment. During followup, these values will be assessed at 1,6 and 12 months post-treatment

Original Secondary Outcome:

• Changes in the Enteral Caloric intake [ Time Frame: one year ]
  During active drug administration, changes in the proportion of total enteral calories tolerated (Including discontintuation of parenteral nutrition) will be monitored twice weekly (hospital inpatients) and weekly (for outpatients). Following the phase of active treatment, patients will be followed at 1, 6, and 12 months.
• Nutritional Parameters [ Time Frame: one year ]
  During the phase of active treatment, nutritional parameters; weight gain, maintenance of growth (z scores), Liver function, albumin, protein levels, C-reactive protein, electrolytes, renal function (creatinine levels) will be monitored twice weekly (hospital inpatients) and weekly (for outpatients). Following the phase of active treatment, patients will be followed at 1, 6, and 12 months.
• Mucosal Morphology [ Time Frame: 6 weeks ]
  If procedures requiring sedation or surgery are done during the phase of active drug administration, intestinal biopsies will be requested, to quantify changes in crypt cell proliferation and apoptosis index, and intestinal morphology (villus height and/or crypt depth) between pre-treatment surgical samples, and specimens obtained while under treatment.
• Plasma Citrulline levels and Intrinsic GLP-2 Production [ Time Frame: One year ]
  At the beginning of the active treatment, and during week 5, intrinsic meal stimulated GLP-2 production will be assesed. Citrulline levels as a measure of intestinal mucosal mass will be assessed at time 0, and on the last day of active treament. During followup, these values will be assessed at 1,6 and 12 months post-treatment
• Septic Episodes [ Time Frame: 6 weeks ]
  During the treatment phase, the number of septic episodes, and the type of infecting organisms will be recorded.

Dates:
Date Received: April 5, 2012
Date Started: January 2012
Date Completion: August 2015
Last Updated: December 19, 2014
Last Verified: December 2014