Incretin Effect and Use After Clinical Islet Transplantation

NCT00768651 | Completed Phase 2 Results

• 1 other identifier: 7331
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 1 Diabetes

Outcome Measures

Primary Outcomes (14)

• 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 Outcomes (8)

• Insulin Independence After the 3 Month Washout Period

  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

  3 months - washout period

• HbA1c Plasma Laboratory Value for Participants After the 3 Month Washout Period

  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.

  After the 3 month washout period

Study Arms (1)

One arm: Sitagliptin + Pantoprazole

EXPERIMENTAL

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

Drug: Pantoprazole; Drug: Sitagliptin

Interventions

Pantoprazole DRUG

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.

Also known as: Pantoloc

One arm: Sitagliptin + Pantoprazole

Sitagliptin DRUG

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

Also known as: Januvia

One arm: Sitagliptin + Pantoprazole

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Alberta: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (1)

University of Alberta - Clinical Islet Transplant Program

Edmonton, Alberta, T6G2C8, Canada

Location

Related Publications (1)

• 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.

  PMID: 27087519 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Pantoprazole; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Triazoles; Azoles; Pyrazines

Limitations and Caveats

The major weaknesses of the study are the small sample size and the lack of a control group.

Results Point of Contact

• Title: Peter Senior, MD, PhD - Professor of Medicine, Medical Director-Clinical Islet Transplant Program,
• Organization: Faculty of Medicine and Dentistry, University of Alberta

peters@islet.ca

780-407-1480

Study Officials

• Peter Senior, MD, PhD

  University of Alberta

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 7, 2008
• First Posted: October 8, 2008
• Study Start: October 1, 2008
• Primary Completion: July 1, 2011
• Study Completion: December 1, 2011
• Last Updated: June 18, 2015
• Results First Posted: June 18, 2015

Record last verified: 2015-05

Locations

CA (1)