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Safety and Dosing Study of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure (GLP-2-01)

Primary Purpose

Intestinal Failure, Short Bowel Syndrome

Status
Terminated
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Glucagon-Like Peptide 2
Glucagon like peptide-2
Sponsored by
Alberta Children's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intestinal Failure focused on measuring Infant Nutrition Disorders, Childhood nutrition disorders, malnutrition, post surgical syndromes, necrotising enterocolitis, intestinal atresia, gastroschisis

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Alberta Children's Hospital
  • Stollery Children's Hospital
  • British Columbia Children's Hospital
  • Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Intestinal Failure in children (>1 year)

GLP-2 in Infants (<1 year of age)

Arm Description

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

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.

Outcomes

Primary Outcome Measures

Frequency of Adverse events
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
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.

Secondary Outcome Measures

Changes in the Enteral Caloric intake
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
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
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
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
During the treatment phase, the number of septic episodes, and the type of infecting organisms will be recorded.
Serum Citrulline Levels
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

Full Information

First Posted
April 5, 2012
Last Updated
December 19, 2014
Sponsor
Alberta Children's Hospital
Collaborators
Stollery Children's Hospital, The Hospital for Sick Children, British Columbia Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01573286
Brief Title
Safety and Dosing Study of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure
Acronym
GLP-2-01
Official Title
Phase 1-2 Trial of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure
Study Type
Interventional

2. Study Status

Record Verification Date
December 2014
Overall Recruitment Status
Terminated
Why Stopped
GLP-2 Drug product stability concerns
Study Start Date
January 2012 (undefined)
Primary Completion Date
August 2014 (Actual)
Study Completion Date
August 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Alberta Children's Hospital
Collaborators
Stollery Children's Hospital, The Hospital for Sick Children, British Columbia Children's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intestinal Failure, Short Bowel Syndrome
Keywords
Infant Nutrition Disorders, Childhood nutrition disorders, malnutrition, post surgical syndromes, necrotising enterocolitis, intestinal atresia, gastroschisis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intestinal Failure in children (>1 year)
Arm Type
Experimental
Arm Description
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
Arm Title
GLP-2 in Infants (<1 year of age)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Glucagon-Like Peptide 2
Other Intervention Name(s)
Glucagon-like peptide-2 (Lot: IC-115) Mfg. University of Calgary
Intervention Description
Patients will be treated with 20 ug/kg/day GLP-2, in two doses, given subcutaneously for 3 days (Phase 1). If the treatment is well tolerated, GLP-2 will be continued for a total of 42 days.
Intervention Type
Drug
Intervention Name(s)
Glucagon like peptide-2
Other Intervention Name(s)
Glucagon-like peptide-2 (Lot: IC-115) Mfg. University of Calgary
Intervention Description
Patients will treated with 5, 10 or 20 ug/kg/day of GLP-2, given twice daily by subcutaneous injection. The initial cohort of patients will be treated at 5 ug/kg (n=6), and if this dose is seen to be safe, and levels appropriate, the next group of 6 will be treated at 10 ug/kg/day. If this dose is seen to be safe, and levels appropriate, the final group of 6 will be treated at 20 ug/kg/day. Patients will be given GLP-2 at the assigned dose, subcutaneously for 3 days (Phase 1). If the treatment is well tolerated, GLP-2 will be continued, at the same dose, for a total of 42 days.
Primary Outcome Measure Information:
Title
Frequency of Adverse events
Description
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.
Time Frame
One year
Title
Pharmacokinetics (Peak serum level. Area under the curve
Description
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.
Time Frame
Done on Day 3 and 42
Secondary Outcome Measure Information:
Title
Changes in the Enteral Caloric intake
Description
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.
Time Frame
one year
Title
Nutritional Parameters
Description
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.
Time Frame
one year
Title
Mucosal Morphology
Description
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.
Time Frame
6 weeks
Title
Intrinsic GLP-2 Production
Description
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
Time Frame
One year
Title
Septic Episodes
Description
During the treatment phase, the number of septic episodes, and the type of infecting organisms will be recorded.
Time Frame
6 weeks
Title
Serum Citrulline Levels
Description
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
Time Frame
One year.

10. Eligibility

Sex
All
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Sigalet, MD PhD
Organizational Affiliation
Alberta Children's Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B 6A8
Country
Canada
Facility Name
Stollery Children's Hospital
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2C8
Country
Canada
Facility Name
British Columbia Children's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3V4
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
24368164
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.
Results Reference
background
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
Results Reference
result

Learn more about this trial

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

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