Back to resultsIncretin Effect and Use After Clinical Islet Transplantation
Primary Purpose
Type 1 Diabetes
Status
Completed
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Pantoprazole
Sitagliptin
Sponsored by
About this trial
This is an interventional treatment trial for Type 1 Diabetes
Eligibility Criteria
Inclusion Criteria
Subjects must meet the following criteria to be enrolled in this study:
- Male or female, aged 18 to 70, inclusive, who is a previous islet transplant recipient (at least 3 months since last islet transplant) and who received their transplant at the University of Alberta.
- Insulin independent for 3 months or longer after islet transplant.
Early graft dysfunction as defined by:
- HbA1c >6% (but less than 7.5%); or
- fasting glucose > 7 mmol/L (126 mg/dl); or
- random glucose > 10 mmol/L (180 mg/dl), and
- Total insulin use of < 10 units/day.
- C-peptide positive.
- Able to provide informed consent.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from the study:
- Unable to provide informed consent.
- Prior therapy with sitagliptin or a proton pump inhibitor in the preceding 2 months.
- Vulnerable populations (i.e. cognitively impaired, pregnant women, residing in institutions, University of Alberta students or employees under the supervision of any of the investigators).
Children, adolescent or patients with a "contraindication" or "warning" listed in the package insert of any of the study drugs:
- Hypersensitivity to sitagliptin or pantoprazole for any component of the formulation.
- Renal disease or renal dysfunction (as suggested by serum creatinine levels ≥ 136 µmol/L (males), ≥ 124 µmol/L (females) or abnormal creatinine clearance; or estimated by Glomerular Filtration Rate (GFR) <50 ml/min/1.73m2).
- Acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).
- Uncontrolled hyperglycemia
- Any subject that in the opinion of the investigator would not be a good candidate for study participation.
Sites / Locations
- University of Alberta - Clinical Islet Transplant Program
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
One arm: Sitagliptin + Pantoprazole
Arm Description
Intervention Details: Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout.
Outcomes
Primary Outcome Measures
The Primary Endpoint Will be Insulin Independence After 6 Months of Therapy.
Insulin independence was defined as no insulin use for at least one week, HbA1c < 6.0%, fasting plasma glucose < 7.0 mmol/l, fasting or stimulated c-peptide ≥ 0.5 ng/ml. In addition capillary blood glucose levels could not be >7.8 mmol/l (fasting) or > 10 mmol/l (post-prandial) on more than three occasions in the preceding week. Mean daily insulin use was calculated from the three days prior to study visits. Blinded continuous glucose monitoring (CGM) was performed using the iPro device and Carelink software (Medtronic, Mississauga, ON, CA).
Number of Participants Not Using Insulin for at Least One Week After 6 Months of Therapy
Number of Participants With HbA1c < 6.0 % After 6 Months of Therapy
HbA1c was measured using method (manufacturer) at baseline, 3, 6 and 9 months.
Number of Participants With Fasting Plasma Glucose (FPG) < 7 mmol/l After 6 Months of Therapy
Mean Daily Insulin Use (U/Day) After 6 Months of Therapy
Mean daily insulin use was calculated from the three days prior to study visits and performed at baseline, 3, 6, and 9 months.
Change From Baseline of GLP-1 Level After One Month of Therapy
Fasting Glucagon-Like Peptide (GLP-1) levels were measured at baseline and one month. Blood samples were collected in p700 vacutainers (Becton Dickinson, Franklin Lakes, NJ) containing a Dipeptidyl peptidase-4 (DPP4) protease inhibitor cocktail to measure total and active GLP-1 in duplicate using a commercially available ELISA (kit manufacturer) and expressed as the ratio of active:total GLP-1.
Change From Baseline on Gastrin Level After One Month of Therapy
Gastrin levels were measured at baseline and at one month by method (manufacturer).
HbA1c Plasma Laboratory Value for Participants After 6 Months of Therapy
HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer.
Acute Insulin Responses to Arginine After 6 Months of Therapy
An intravenous arginine stimulation test (AST) [Ryan:2002cg] was performed at baseline, 6, and 9 months to assess Graft function.
C-peptide Laboratory Value at 90 Minutes After a Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
C-peptide Laboratory Value Before a Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
Glucose Laboratory Value at 90 Minutes After Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy.
Measuring Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Blood Glucose Laboratory Value Before Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Weight Change From Baseline After 6 Months of Therapy
Measuring the weight change from baseline at months: 1, 3, 6 and 9.
Secondary Outcome Measures
Insulin Independence After the 3 Month Washout Period
Insulin independence was defined as no insulin use for at least one week, HbA1c < 6.0%, fasting plasma glucose < 7.0 mmol/l, fasting or stimulated c-peptide ≥ 0.5 ng/ml. In addition capillary blood glucose levels could not be >7.8 mmol/l (fasting) or > 10 mmol/l (post-prandial) on more than three occasions in the preceding week. Mean daily insulin use was calculated from the three days prior to study visits. Blinded continuous glucose monitoring (CGM) was performed using the iPro device and Carelink software (Medtronic, Mississauga, ON, CA).
Insulin Dose (U/Day)
Acute Insulin Response to Arginine After the 3 Month Washout Period
An intravenous Arginine stimulation test (AST) [Ryan:2002cg] was performed at baseline, 6, and 9 months to assess Graft function. The Arginine is a proxy for insulin secretory reserve (Robertson:2004br)(Rickels:2007cg) and correlates with islet mass in the context of islet allo-transplant (Ryan:2002cg), auto-transplant (Teuscher:1998eu) and hemipancreatectomy (Seaquist:1992iv). An increase in Arginine (AIRarg) would have suggested an increase in beta cell mass.
HbA1c Plasma Laboratory Value for Participants After the 3 Month Washout Period
Measuring of HbA1c using method (manufacturer) at baseline, and months: 1, 3, 6, 9.
C-peptide Plasma Laboratory Value at 90 Minutes After a Mixed Meal Tolerance Test (MMTT) at the End of the 3 Month Washout Period.
Measuring of C-peptide before and 90 minutes after a Mixed Meal Tolerance Test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function. Ther
C-peptide Laboratory Value Before a Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period.
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
Glucose Laboratory Value at 90 Minutes After Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period.
Measuring Blood Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Blood Glucose Laboratory Value Before Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period
Measuring Blood Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Full Information
NCT ID
NCT00768651
First Posted
October 7, 2008
Last Updated
May 29, 2015
Sponsor
University of Alberta
Collaborators
Juvenile Diabetes Research Foundation
1. Study Identification
Unique Protocol Identification Number
NCT00768651
Brief Title
Incretin Effect and Use After Clinical Islet Transplantation
Official Title
Pilot Study of Safety and Efficacy of Combined Use of Dipeptidyl-peptidase Inhibitor (Sitagliptin) and Proton Pump Inhibitor (Pantoprazole) to Prevent Beta-cell Apoptosis and Promote Islet Regeneration in Islet Transplant Recipients With Early Graft Dysfunction
Study Type
Interventional
2. Study Status
Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
October 2008 (undefined)
Primary Completion Date
July 2011 (Actual)
Study Completion Date
December 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Alberta
Collaborators
Juvenile Diabetes Research Foundation
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
We aim to study if the administration of medications to increase the secretion of hormones from the intestines can improve glycemic control, reduce insulin use and promote β-cell regeneration/expansion in subjects with type 1 diabetes following islet transplantation who are back using small doses of insulin because of early graft dysfunction. We believe that the results will enable us to understand whether these drugs could be useful in islet transplant recipients, particularly if glycemic control deteriorates.
Detailed Description
This is a single centre non-randomized pilot study. Subjects will be recruited from the current cohort of islet transplant recipients at the University of Alberta.
The primary objective of the study is to evaluate whether the combination of sitagliptin and pantoprazole can restore insulin independence in previously insulin independent islet transplant recipients experiencing early graft dysfunction. The study will also evaluate the safety of the combination drug therapy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)
8. Arms, Groups, and Interventions
Arm Title
One arm: Sitagliptin + Pantoprazole
Arm Type
Experimental
Arm Description
Intervention Details:
Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout.
Intervention Type
Drug
Intervention Name(s)
Pantoprazole
Other Intervention Name(s)
Pantoloc
Intervention Description
Starting on Day 1, Pantoprazole 80 mg daily (40 mg every morning and 40 mg every evening) administered orally at the same time each day for a period of 6 months.
Intervention Type
Drug
Intervention Name(s)
Sitagliptin
Other Intervention Name(s)
Januvia
Intervention Description
Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months.
Primary Outcome Measure Information:
Title
The Primary Endpoint Will be Insulin Independence After 6 Months of Therapy.
Description
Insulin independence was defined as no insulin use for at least one week, HbA1c < 6.0%, fasting plasma glucose < 7.0 mmol/l, fasting or stimulated c-peptide ≥ 0.5 ng/ml. In addition capillary blood glucose levels could not be >7.8 mmol/l (fasting) or > 10 mmol/l (post-prandial) on more than three occasions in the preceding week. Mean daily insulin use was calculated from the three days prior to study visits. Blinded continuous glucose monitoring (CGM) was performed using the iPro device and Carelink software (Medtronic, Mississauga, ON, CA).
Time Frame
6 months
Title
Number of Participants Not Using Insulin for at Least One Week After 6 Months of Therapy
Time Frame
6 months
Title
Number of Participants With HbA1c < 6.0 % After 6 Months of Therapy
Description
HbA1c was measured using method (manufacturer) at baseline, 3, 6 and 9 months.
Time Frame
6 months
Title
Number of Participants With Fasting Plasma Glucose (FPG) < 7 mmol/l After 6 Months of Therapy
Time Frame
6 months
Title
Mean Daily Insulin Use (U/Day) After 6 Months of Therapy
Description
Mean daily insulin use was calculated from the three days prior to study visits and performed at baseline, 3, 6, and 9 months.
Time Frame
6 months
Title
Change From Baseline of GLP-1 Level After One Month of Therapy
Description
Fasting Glucagon-Like Peptide (GLP-1) levels were measured at baseline and one month. Blood samples were collected in p700 vacutainers (Becton Dickinson, Franklin Lakes, NJ) containing a Dipeptidyl peptidase-4 (DPP4) protease inhibitor cocktail to measure total and active GLP-1 in duplicate using a commercially available ELISA (kit manufacturer) and expressed as the ratio of active:total GLP-1.
Time Frame
Baseline and One month
Title
Change From Baseline on Gastrin Level After One Month of Therapy
Description
Gastrin levels were measured at baseline and at one month by method (manufacturer).
Time Frame
Baseline and One month
Title
HbA1c Plasma Laboratory Value for Participants After 6 Months of Therapy
Description
HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer.
Time Frame
6 months
Title
Acute Insulin Responses to Arginine After 6 Months of Therapy
Description
An intravenous arginine stimulation test (AST) [Ryan:2002cg] was performed at baseline, 6, and 9 months to assess Graft function.
Time Frame
6 months
Title
C-peptide Laboratory Value at 90 Minutes After a Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Description
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
6 months
Title
C-peptide Laboratory Value Before a Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Description
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
6 months
Title
Glucose Laboratory Value at 90 Minutes After Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy.
Description
Measuring Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
6 months
Title
Blood Glucose Laboratory Value Before Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Time Frame
6 months
Title
Weight Change From Baseline After 6 Months of Therapy
Description
Measuring the weight change from baseline at months: 1, 3, 6 and 9.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Insulin Independence After the 3 Month Washout Period
Description
Insulin independence was defined as no insulin use for at least one week, HbA1c < 6.0%, fasting plasma glucose < 7.0 mmol/l, fasting or stimulated c-peptide ≥ 0.5 ng/ml. In addition capillary blood glucose levels could not be >7.8 mmol/l (fasting) or > 10 mmol/l (post-prandial) on more than three occasions in the preceding week. Mean daily insulin use was calculated from the three days prior to study visits. Blinded continuous glucose monitoring (CGM) was performed using the iPro device and Carelink software (Medtronic, Mississauga, ON, CA).
Time Frame
After the 3 month washout period
Title
Insulin Dose (U/Day)
Time Frame
After the 3 month washout period
Title
Acute Insulin Response to Arginine After the 3 Month Washout Period
Description
An intravenous Arginine stimulation test (AST) [Ryan:2002cg] was performed at baseline, 6, and 9 months to assess Graft function. The Arginine is a proxy for insulin secretory reserve (Robertson:2004br)(Rickels:2007cg) and correlates with islet mass in the context of islet allo-transplant (Ryan:2002cg), auto-transplant (Teuscher:1998eu) and hemipancreatectomy (Seaquist:1992iv). An increase in Arginine (AIRarg) would have suggested an increase in beta cell mass.
Time Frame
3 months - washout period
Title
HbA1c Plasma Laboratory Value for Participants After the 3 Month Washout Period
Description
Measuring of HbA1c using method (manufacturer) at baseline, and months: 1, 3, 6, 9.
Time Frame
After the 3 month washout period
Title
C-peptide Plasma Laboratory Value at 90 Minutes After a Mixed Meal Tolerance Test (MMTT) at the End of the 3 Month Washout Period.
Description
Measuring of C-peptide before and 90 minutes after a Mixed Meal Tolerance Test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function. Ther
Time Frame
After the 3 month washout period
Title
C-peptide Laboratory Value Before a Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period.
Description
Measuring of C-peptide before and 90 minutes after a mixed meal tolerance test (MMTT) [Ryan:2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
3 months - washout period
Title
Glucose Laboratory Value at 90 Minutes After Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period.
Description
Measuring Blood Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
3 months - washout period
Title
Blood Glucose Laboratory Value Before Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period
Description
Measuring Blood Glucose before and 90 minutes after Mixed Meal Tolerance Test (MMTT) [Ryan: 2005ts] at baseline, 6 and 9 months to assess Graft function.
Time Frame
After the 3 month washout period
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
Subjects must meet the following criteria to be enrolled in this study:
Male or female, aged 18 to 70, inclusive, who is a previous islet transplant recipient (at least 3 months since last islet transplant) and who received their transplant at the University of Alberta.
Insulin independent for 3 months or longer after islet transplant.
Early graft dysfunction as defined by:
HbA1c >6% (but less than 7.5%); or
fasting glucose > 7 mmol/L (126 mg/dl); or
random glucose > 10 mmol/L (180 mg/dl), and
Total insulin use of < 10 units/day.
C-peptide positive.
Able to provide informed consent.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from the study:
Unable to provide informed consent.
Prior therapy with sitagliptin or a proton pump inhibitor in the preceding 2 months.
Vulnerable populations (i.e. cognitively impaired, pregnant women, residing in institutions, University of Alberta students or employees under the supervision of any of the investigators).
Children, adolescent or patients with a "contraindication" or "warning" listed in the package insert of any of the study drugs:
Hypersensitivity to sitagliptin or pantoprazole for any component of the formulation.
Renal disease or renal dysfunction (as suggested by serum creatinine levels ≥ 136 µmol/L (males), ≥ 124 µmol/L (females) or abnormal creatinine clearance; or estimated by Glomerular Filtration Rate (GFR) <50 ml/min/1.73m2).
Acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).
Uncontrolled hyperglycemia
Any subject that in the opinion of the investigator would not be a good candidate for study participation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Senior, MD, PhD
Organizational Affiliation
University of Alberta
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alberta - Clinical Islet Transplant Program
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G2C8
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
27087519
Citation
Senior PA, Koh A, Yau J, Imes S, Dinyari P, Malcolm AJ, Light P, Shapiro AM. Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study. Diabet Med. 2017 Feb;34(2):204-212. doi: 10.1111/dme.13131. Epub 2016 May 22.
Results Reference
derived
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Incretin Effect and Use After Clinical Islet Transplantation
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