Incretin Effect and Use After Clinical Islet Transplantation

Phase 2

Completed

Conditions: Type 1 Diabetes

Interventions: Drug: Pantoprazole
Drug: Sitagliptin

Registration Number: NCT00768651

Lead Sponsor: University of Alberta

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Not provided

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:
1. Hypersensitivity to sitagliptin or pantoprazole for any component of the formulation.
2. 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).
3. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
One arm: Sitagliptin + Pantoprazole	Sitagliptin	Intervention Details: Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout.
One arm: Sitagliptin + Pantoprazole	Pantoprazole	Intervention Details: Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout.

Primary Outcome Measures

Name	Time	Method
The Primary Endpoint Will be Insulin Independence After 6 Months of Therapy.	6 months	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	6 months
Number of Participants With HbA1c < 6.0 % After 6 Months of Therapy	6 months	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	6 months
Mean Daily Insulin Use (U/Day) After 6 Months of Therapy	6 months	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	Baseline and One month	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	Baseline and One month	Gastrin levels were measured at baseline and at one month by method (manufacturer).
HbA1c Plasma Laboratory Value for Participants After 6 Months of Therapy	6 months	HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer.
Acute Insulin Responses to Arginine After 6 Months of Therapy	6 months	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	6 months	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	6 months	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.	6 months	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	6 months
Weight Change From Baseline After 6 Months of Therapy	6 months	Measuring the weight change from baseline at months: 1, 3, 6 and 9.

Secondary Outcome Measures

Name	Time	Method
Insulin Independence After the 3 Month Washout Period	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)	After the 3 month washout period
Acute Insulin Response to Arginine After the 3 Month Washout Period	3 months - 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	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.	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. Ther
C-peptide Laboratory Value Before a Mixed Meal Tolerance Test (MMTT) After the 3 Month Washout Period.	3 months - 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.	3 months - 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	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.