Incretin Effect and Use After Clinical Islet Transplantation

University of Alberta8 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Type 1 Diabetes

Interventions

PantoprazoleDRUG

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.

SitagliptinDRUG

Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria Subjects must meet the following criteria to be enrolled in this study: 1. 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. 2. Insulin independent for 3 months or longer after islet transplant. 3. Early graft dysfunction as defined by: 1. HbA1c \>6% (but less than 7.5%); or 2. fasting glucose \> 7 mmol/L (126 mg/dl); or 3. random glucose \> 10 mmol/L (180 mg/dl), and 4. Total insulin use of \< 10 units/day. 4. C-peptide positive. 5. Able to provide informed consent. Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from the study: 1. Unable to provide informed consent. 2. Prior therapy with sitagliptin or a proton pump inhibitor in the preceding 2 months. 3. 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). 4. 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). 5. Uncontrolled hyperglycemia 6. Any subject that in the opinion of the investigator would not be a good candidate for study participation.

Locations (1)

University of Alberta - Clinical Islet Transplant Program

Edmonton, Alberta, Canada

Outcomes

Primary Outcomes

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).

Time frame: 6 months

Number of Participants Not Using Insulin for at Least One Week After 6 Months of Therapy

Time frame: 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.

Time frame: 6 months

Number of Participants With Fasting Plasma Glucose (FPG) < 7 mmol/l After 6 Months of Therapy

Time frame: 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.

Time frame: 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.

Time frame: Baseline and One month

Data from ClinicalTrials.gov

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Secondary Outcomes

Insulin Independence After the 3 Month Washout Period

Time frame: After the 3 month washout period

Insulin Dose (U/Day)

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: After the 3 month washout period