Incretin Effect and Use After Clinical Islet Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Pantoprazole
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: One arm: Sitagliptin + Pantoprazole<br>Intervention Details: Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout. | Drug: Pantoprazole<br>* 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.<br>* Other names: Pantoloc;Drug: Sitagliptin<br>* Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months.<br>* Other names: Januvia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 6 months | 
| 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 | HbA1c was measured using method (manufacturer) at baseline, 3, 6 and 9 months. | 6 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 | Mean daily insulin use was calculated from the three days prior to study visits and performed at baseline, 3, 6, and 9 months. | 6 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. | Baseline and One month | 
| Change From Baseline on Gastrin Level After One Month of Therapy | Gastrin levels were measured at baseline and at one month by method (manufacturer). | Baseline and One month | 
| HbA1c Plasma Laboratory Value for Participants After 6 Months of Therapy | HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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. | 6 months | 
| 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 | Measuring the weight change from baseline at months: 1, 3, 6 and 9. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | After the 3 month washout period | 
| Insulin Dose (U/Day) |  | After the 3 month washout period | 
| 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. | 3 months - washout period | 
| 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. | After the 3 month washout period | 
| 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 | After the 3 month washout period | 
| 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. | 3 months - washout period | 
| 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. | 3 months - washout period | 
| 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. | After the 3 month washout period |