Clinical trial NCT01573286: Safety and Dosing Study of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure
Official title: Phase 1-2 Trial of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Intestinal Failure
Short Bowel Syndrome
Keywords: Infant Nutrition Disorders
Childhood nutrition disorders
malnutrition
post surgical syndromes
necrotising enterocolitis
intestinal atresia
gastroschisis
Lead sponsor: Alberta Children's Hospital
Sponsor class: OTHER
Collaborators: name: Stollery Children's Hospital
name: The Hospital for Sick Children
name: British Columbia Children's Hospital
First posted: 2012-04-09
Enrollment: 13
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 description: 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 μg/kg/day (via twice daily subcutaneous injection) n= 7.

Patients will be followed on the principle of intention to treat after initial randomization. The endpoints will be monitoring for safety, and recording of adverse events and a pharmacokinetic profile at 3 days.

If the hormone is well tolerated these studies will be extended into a phase 2 study, for an additional 39 days; monitoring safety, patient tolerance of enteral nutrition, growth, citrulline levels, nutrient absorptive capacity, liver function and repeat pharmacokinetic studies.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Frequency of Adverse events
timeFrame: One year
measure: Pharmacokinetics (Peak serum level. Area under the curve
timeFrame: Done on Day 3 and 42
Secondary outcomes:
measure: Changes in the Enteral Caloric intake
timeFrame: one year
measure: Nutritional Parameters
timeFrame: one year
measure: Mucosal Morphology
timeFrame: 6 weeks
measure: Intrinsic GLP-2 Production
timeFrame: One year
measure: Septic Episodes
timeFrame: 6 weeks
measure: Serum Citrulline Levels
timeFrame: One year.
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Alberta Children's Hospital
name: David Sigalet, MD PhD
role: STUDY_DIRECTOR
References:
citation: Sigalet DL, de Heuvel E, Wallace L, Bulloch E, Turner J, Wales PW, Nation P, Wizzard PR, Hartmann B, Assad M, Holst JJ. Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs. Regul Pept. 2014 Jan 10;188:70-80. doi: 10.1016/j.regpep.2013.12.006. Epub 2013 Dec 22.
citation: Sigalet DL, Lam V, Karnik V, Brindle M, Boctor D, Casey LW, Dicken B, Butterworth S, Stoffman S,de Heuval E, Wright-wilson G, Wallace L. Safety and Dosing Study of Glucagon-like Peptide 2 (GLP-2) in Children With Intestinal Failure DDW Abstract presented at DDW 2014, Chicago IL