Incretin Effect and Use After Clinical Islet Transplantation

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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: Pantoprazole; Drug: Sitagliptin

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G2C8
      • University of Alberta - Clinical Islet Transplant Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Alberta
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Peter Senior, MD, PhD, University of Alberta

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (ACTUAL): July 1, 2011
• Study Completion (ACTUAL): December 1, 2011

Study Registration Dates

• First Submitted: October 7, 2008
• First Submitted That Met QC Criteria: October 7, 2008
• First Posted (ESTIMATE): October 8, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): June 18, 2015
• Last Update Submitted That Met QC Criteria: May 29, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Sitagliptin Phosphate; Pantoprazole
• Other Study ID Numbers: 7331