Trial Outcomes & Findings for Incretin Effect and Use After Clinical Islet Transplantation (NCT NCT00768651)

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

8 participants

Primary outcome timeframe

6 months

Results posted on

2015-06-18

Participant Flow

Recruitment period took place between March 2010 thru October 2010. Consent took place in the Clinical Islet Transplant Program at the University of Alberta.

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).

Participant milestones

Participant milestones
Measure	Sitagliptin + Pantoprazole Intervention Details: 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, followed by a three-month washout. Sitagliptin: Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months, followed by a three-month washout.
Overall Study STARTED	8
Overall Study COMPLETED	7
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Sitagliptin + Pantoprazole Intervention Details: 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, followed by a three-month washout. Sitagliptin: Starting on Day 1, Sitagliptin 100mg once daily administered orally at the same time each day for a period of 6 months, followed by a three-month washout.
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Incretin Effect and Use After Clinical Islet Transplantation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	One Arm: Sitagliptin + Pantoprazole n=8 Participants 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.
Age, Continuous	54 years n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants
Region of Enrollment Canada	8 participants n=5 Participants
Weight	69 kg STANDARD_DEVIATION 15 • n=5 Participants
BMI	22.6 kg/m^2 STANDARD_DEVIATION 3.4 • n=5 Participants
Diabetes Duration Prior to 1st Transplant	36.1 years n=5 Participants
Number of islet infusions	2 number of islet infusions n=5 Participants
Islet equivalents infused	12,046 equivalents per kg STANDARD_DEVIATION 4,030 • n=5 Participants
Time since first transplant	67 months n=5 Participants
Interval since last transplant	53 months n=5 Participants
Time insulin free	47.8 months n=5 Participants
Tacrolimus daily dose	4.5 mg STANDARD_DEVIATION 1.2 • n=5 Participants
Mycophenolate daily dose	1406 mg STANDARD_DEVIATION 461 • n=5 Participants

PRIMARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	One Arm: Sitagliptin + Pantoprazole n=8 Participants 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.
The Primary Endpoint Will be Insulin Independence After 6 Months of Therapy.	0.25 proportion of participants Interval -0.06 to 0.56

PRIMARY outcome

Timeframe: 6 months

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

HbA1c was measured using method (manufacturer) at baseline, 3, 6 and 9 months.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline and One month

Gastrin levels were measured at baseline and at one month by method (manufacturer).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

HbA1c was measured at baseline, 3, 6, and 9 months using method (manufacturer.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

An intravenous arginine stimulation test (AST) \[Ryan:2002cg\] was performed at baseline, 6, and 9 months to assess Graft function.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 6 months

Measuring the weight change from baseline at months: 1, 3, 6 and 9.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	One Arm: Sitagliptin + Pantoprazole n=7 Participants 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.
Insulin Independence After the 3 Month Washout Period	0 % of insulin indipendent participants

SECONDARY outcome

Timeframe: After the 3 month washout period

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After the 3 month washout period

Measuring of HbA1c using method (manufacturer) at baseline, and months: 1, 3, 6, 9.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

Adverse Events

One Arm: Sitagliptin + Pantoprazole

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	One Arm: Sitagliptin + Pantoprazole n=8 participants at risk 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.
Gastrointestinal disorders Nausea or Diarrhea	25.0% 2/8 • Number of events 2

Additional Information

Peter Senior, MD, PhD - Professor of Medicine, Medical Director-Clinical Islet Transplant Program,

Faculty of Medicine and Dentistry, University of Alberta

Phone: 780-407-1480

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place