Type 1 Diabetes
Conditions
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.
Interventions
DRUGPantoprazole
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.
DRUGSitagliptin
Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months.
Sponsors
Juvenile Diabetes Research Foundation
University of Alberta
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weight Change From Baseline After 6 Months of Therapy | 6 months | Measuring the weight change from baseline at months: 1, 3, 6 and 9. |
| 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 | — |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Countries
Canada
Participant flow
Recruitment details
Recruitment period took place between March 2010 thru October 2010. Consent took place in the Clinical Islet Transplant Program at the University of Alberta.
Pre-assignment details
Patients signed Informed Consent after a consultation with the PI. Then they proceeded through the evaluation phase of the study. During this phase, some patients were excluded based on the protocol's inclusion and exclusion criteria (i.e. lab reports or procedure that did not meet protocol standards).
Participants by arm
| Arm | Count |
|---|---|
| One Arm: Sitagliptin + Pantoprazole Intervention Details:
Sitagliptin 100 mg daily and Pantoprazole 40 mg bid for 6 months, followed by a three-month washout:
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.
Sitagliptin: Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | One Arm: Sitagliptin + Pantoprazole |
|---|---|
| Age, Continuous | 54 years |
| BMI | 22.6 kg/m^2 STANDARD_DEVIATION 3.4 |
| Diabetes Duration Prior to 1st Transplant | 36.1 years |
| Interval since last transplant | 53 months |
| Islet equivalents infused | 814,061 equivalents total |
| Mycophenolate daily dose | 1406 mg STANDARD_DEVIATION 461 |
| Number of islet infusions | 2 number of islet infusions |
| Region of Enrollment Canada | 8 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 7 Participants |
| Tacrolimus daily dose | 4.5 mg STANDARD_DEVIATION 1.2 |
| Time insulin free | 47.8 months |
| Time since first transplant | 67 months |
| Weight | 69 kg STANDARD_DEVIATION 15 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
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.
Time frame: 6 months
Primary
Blood Glucose Laboratory Value Before Mixed Meal Tolerance Test (MMTT) After 6 Months of Therapy
Time frame: 6 months
Primary
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
Primary
Change From Baseline on Gastrin Level After One Month of Therapy
Gastrin levels were measured at baseline and at one month by method (manufacturer).
Time frame: Baseline and One month
Primary
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.
Time frame: 6 months
Primary
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.
Time frame: 6 months
Primary
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.
Time frame: 6 months
Primary
HbA1c Plasma Laboratory Value for Participants After 6 Months of Therapy
HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer.
Time frame: 6 months
Primary
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
Primary
Number of Participants Not Using Insulin for at Least One Week After 6 Months of Therapy
Time frame: 6 months
Primary
Number of Participants With Fasting Plasma Glucose (FPG) < 7 mmol/l After 6 Months of Therapy
Time frame: 6 months
Primary
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
Primary
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
Population: Per Protocol Set of participants: The participants of subjects in full analysis set who were: compliant with the protocol, compliant with pre-specified exposure to the treatment regimen, and available for measurements of primary variables.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| One Arm: Sitagliptin + Pantoprazole | The Primary Endpoint Will be Insulin Independence After 6 Months of Therapy. | 0.25 proportion of participants |
Comparison: The sample size of 8 was determined to provide a 95% confidence interval expected width of 0.62 for the proportion of subjects who become insulin independent with treatment. Four of eight subjects (50%) would have to achieve insulin independence in order to reject the null hypothesis with 85% power and one sided alpha of 0.025. Statistical significance was set at 5%. Mean values were computed using Student's t-test while medians were compared using Wilcoxon's test.p-value: <0.05t-test, 2 sided
Primary
Weight Change From Baseline After 6 Months of Therapy
Measuring the weight change from baseline at months: 1, 3, 6 and 9.
Time frame: 6 months
Secondary
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
Secondary
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
Secondary
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
Secondary
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
Secondary
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
Secondary
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
Secondary
Insulin Dose (U/Day)
Time frame: After the 3 month washout period
Secondary
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).
Time frame: After the 3 month washout period
Population: Per Protocol Set of participants; The subset of participants in full analysis set who were: compliant with the protocol, compliant with pre-specified exposure to the treatment regimen, and available for measurements of primary and secondary variables.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| One Arm: Sitagliptin + Pantoprazole | Insulin Independence After the 3 Month Washout Period | 0 % of insulin indipendent participants |