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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by Alberta Children's Hospital
Sponsor:
Collaborators:
Stollery Children's Hospital
The Hospital for Sick Children
British Columbia Children's Hospital
Information provided by (Responsible Party):
David Sigalet MD PhD, Alberta Children's Hospital
ClinicalTrials.gov Identifier:
NCT01573286
First received: April 5, 2012
Last updated: March 10, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Intestinal Failure
Short Bowel Syndrome
Drug: Glucagon-Like Peptide 2
Drug: Glucagon like peptide-2
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1-2 Trial of Glucagon-like Peptide 2 (GLP-2) in Infants and Children With Intestinal Failure

Resource links provided by NLM:


Further study details as provided by Alberta Children's Hospital:

Primary Outcome Measures:
  • Frequency of Adverse events [ Time Frame: One year ] [ Designated as safety issue: Yes ]

    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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: one year ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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. ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 25
Study Start Date: January 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
Drug: Glucagon-Like Peptide 2
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.
Other Name: Glucagon-like peptide-2 (Lot: IC-115) Mfg. University of Calgary
Experimental: 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.
Drug: Glucagon like peptide-2

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.

Other Name: Glucagon-like peptide-2 (Lot: IC-115) Mfg. University of Calgary

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

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01573286

Contacts
Contact: Viona Lam, BScN 403 955 3248 viona.lam@albertahealthservices.ca
Contact: David sigalet, MD PhD 403 955 2271 sigalet@ucalgary.ca

Locations
Canada, Alberta
Alberta Children's Hospital Recruiting
Calgary, Alberta, Canada, T3B 6A8
Contact: Viona Lam, BScN    403 955 3248    viona.lam@albertahealthservices.ca   
Contact: Mary Brindle, MD    403 955 2848    mary.brindle@alberthealthservices.ca   
Sub-Investigator: Dana Boctor, MD         
Sub-Investigator: Mary Brindle, MD         
Principal Investigator: David Sigalet, MD PhD         
Stollery Children's Hospital Recruiting
Edmonton, Alberta, Canada, T6G 2C8
Contact: Bryan Dicken, MD MSc    780 487 8822    Bryan.Dicken@albertahealthservices.ca   
Principal Investigator: Bryan Dicken, MD MSc         
Sub-Investigator: Linda Casey, MD         
Canada, British Columbia
British Columbia Children's Hospital Recruiting
Vancouver, British Columbia, Canada, V6H 3V4
Contact: Sonia Butterworth, MD FRCSC    604 875 2667    sbutterworth@cw.bc.ca   
Principal Investigator: Sonia Butterworth, MD FRCSC         
Canada, Ontario
Hospital for Sick Children Not yet recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Paul Wales, MD FRCSC    416-813-7654 ext 1490    paul.wales@sickkids.ca   
Principal Investigator: Paul Wales, MD FRCSC         
Sponsors and Collaborators
Alberta Children's Hospital
Stollery Children's Hospital
The Hospital for Sick Children
British Columbia Children's Hospital
Investigators
Principal Investigator: David Sigalet, MD PhD Alberta Children's Hospital
  More Information

Publications:
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 to be presented at DDW2014, Chicago IL

Responsible Party: David Sigalet MD PhD, Professor, Division of Pediatric Surgery, Alberta Children's Hospital
ClinicalTrials.gov Identifier: NCT01573286     History of Changes
Other Study ID Numbers: GLP-2-01, 150979
Study First Received: April 5, 2012
Last Updated: March 10, 2014
Health Authority: Canada: Health Canada

Keywords provided by Alberta Children's Hospital:
Infant Nutrition Disorders
Childhood nutrition disorders
malnutrition
post surgical syndromes
necrotising enterocolitis
intestinal atresia
gastroschisis

Additional relevant MeSH terms:
Syndrome
Short Bowel Syndrome
Disease
Pathologic Processes
Malabsorption Syndromes
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Postoperative Complications
Glucagon
Glucagon-Like Peptide 1
Gastrointestinal Agents
Therapeutic Uses
Pharmacologic Actions
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Incretins

ClinicalTrials.gov processed this record on September 18, 2014