Clinical trial NCT03079921: Adrenergic System in Islet Transplantation
Official title: Adrenergic Contribution to Glucose Counterregulation in Islet Transplantation
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: EARLY_PHASE1
Conditions: Type1diabetes
Hypoglycemia
Hypoglycemia Unawareness
Islet Cell Transplantation
Keywords: Islet Graft Function
Islet Cell transplantation
Auto-islet transplantation
Intra-hepatic islets
Extra-hepatic islets
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2017-03-15
Enrollment: 11
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: This study is a within subject and across group mechanistic design.

Islet cell hormonal responses to a hyperinsulinemic euglycemic-hypoglycemic clamp will be assessed in "Group 1" on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo.

Responses in "Group 1" under the placebo condition will be used for comparison to those obtained from hyperinsulinemic euglycemic-hypoglycemic clamp testing on one occasion in subjects in each of "Group 2" and "Group 3".
Primary purpose: BASIC_SCIENCE

Brief summary: To determine the effect of sympathetic neural and hormonal (epinephrine) input on islet cell hormonal responses to insulin-induced hypoglycemia in type 1 diabetic recipients of intrahepatic islet transplantation. We hypothesize that α-adrenergic (neural) blockage will abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion during hypoglycemia, and that β-adrenergic (hormonal) blockage will have no effect. Glucose counterregulatory responses will be measured during hyperinsulinemic euglycemic-hypoglycemic clamps on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. The demonstration of neural rather than hormonal regulation of the transplanted islet cell response to hypoglycemia is critical for understanding the mechanism for protection from hypoglycemia afforded by intrahepatically transplanted.

Detailed description: This study is designed to test the hypothesis that α-adrenergic (neural) blockade will abolish insulin-mediated suppression of C-peptide, attenuating α-cell glucagon secretion during hypoglycemia, and that β-adrenergic (hormonal) blockade will have no effect. Glucose counterregulatory responses will be measured during hyperinsulinemic euglycemic-hypoglycemic clamps on three occasions with randomized, double-blind administration of the α-adrenergic blocker phentolamine, the β-adrenergic blocker propranolol, or placebo. The demonstration of neural rather than hormonal regulation of the transplanted islet cell response to hypoglycemia is critical for understanding the mechanism for protection from hypoglycemia afforded by intrahepatically transplanted islets.

Glucose counterregulation has not been studied in type 1 diabetic recipients of extrahepatic islet transplantation. Comparison of glucose counterregulatory responses measured during hyperinsulinemic euglycemic-hypoglycemic clamps will be compared to those obtained from type 1 diabetic recipients of intrahepatic islet transplantation studied under the placebo condition above.

Glucose counterregulation has not been directly compared between recipients of intrahepatic auto- and allo-islet transplantation. Direct comparison of glucose counterregulatory responses under the same experimental conditions is required to understand whether mechanisms other than the glucagon response may be important to the reported hypoglycemia affecting pancreatectomized recipients of islet auto-transplantation.

Eligibility criteria: Inclusion Criteria:

GROUP 1

1. Male and female subjects age 21 to 65 years of age.
2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
3. Clinical history compatible with type 1 diabetes with onset of disease at \< 40 years of age and insulin-dependent for \> 10 years at the time of islet transplantation \> 6 months before study.
4. Stable islet graft function defined by C-peptide \> 0.5 ng/ml and insulin-independent or insulin-dependent with daily insulin requirement \< 0.2 units/kg•d to maintain HbA1c \< 7.0%.
5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus or mycophenolic acid with azathioprine are permissible if stable for over 3 months. Prednisone is allowable if no more than 5 mg daily.

Exclusion Criteria:

GROUP 1

1. BMI ≥ 30 kg/m2.
2. Insulin requirement of ≥ 0.2 units/kg•day.
3. HbA1c ≥ 7.0%.
4. Uncontrolled hypertension: systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg.
5. History of cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease, or current use of β-blocker therapy.
6. Bronchial asthma.
7. Abnormal kidney function: Estimated glomerular filtration rate (eGFR) \< 60 ml/min/1.73 m2.
8. Abnormal liver function: persistent elevation of liver function tests \> 1.5 times the upper limit of normal.
9. Untreated hypothyroidism, Addison's disease, or Celiac disease.
10. Anemia: baseline hemoglobin concentration \< 11 g/dl in women and \< 12 g/dl in men.
11. Presence of a seizure disorder not related to prior severe hypoglycemia.
12. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
13. For female participants of child-bearing potential: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of study participation. Oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
14. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
15. Use of any investigational agents within 4 weeks of enrollment.
16. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Inclusion Criteria GROUP 2

1. Male and female subjects age 21 to 65 years of age.
2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
3. Clinical history compatible with type 1 diabetes with onset of disease at \< 40 years of age and insulin-dependent for \> 10 years at the time of islet transplantation \> 6 months before study.
4. Stable islet graft function defined by C-peptide \> 0.5 ng/ml and insulin-independent or insulin-dependent with daily insulin requirement \< 0.2 units/kg•d to maintain HbA1c \< 7.0%.
5. Use of standard immunosuppression consisting of tacrolimus with or without sirolimus or mycophenolic acid. Substitutions of tacrolimus with cyclosporine, and of sirolimus or mycophenolic acid with azathioprine are permissible if stable for over 3 months. Prednisone is allowable if no more than 5 mg daily.

Exclusion Criteria:

GROUP 2

1. BMI ≥ 30 kg/m2.
2. Insulin requirement of ≥ 0.2 units/kg•day.
3. HbA1c ≥ 7.0%.
4. Uncontrolled hypertension: systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg.
5. Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
6. Abnormal kidney function: eGFR \< 60 ml/min/1.73 m2.
7. Abnormal liver function: persistent elevation of liver function tests \> 1.5 times the upper limit of normal.
8. Untreated hypothyroidism, Addison's disease, or Celiac disease.
9. Anemia: baseline hemoglobin concentration \< 11 g/dl in women and \< 12 g/dl in men.
10. Presence of a seizure disorder not related to prior severe hypoglycemia.
11. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
12. For female participants of child-bearing potential: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of study participation. Oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
13. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
14. Use of any investigational agents within 4 weeks of enrollment.
15. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Inclusion Criteria GROUP 3

Patients who meet all of the following criteria are eligible for participation in Group 3 of this study:

1. Male and female subjects age 21 to 65 years of age.
2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
3. Clinical history compatible with total pancreatectomy and autologous islet transplantation \> 6 months before study.
4. Stable islet graft function defined by C-peptide \> 0.5 ng/ml and insulin-independent or insulin-dependent with daily insulin requirement \< 0.2 units/kg•d to maintain HbA1c \< 7.0%.

Exclusion Criteria:

GROUP 3

1. BMI ≥ 30 kg/m2.
2. Insulin requirement of ≥ 0.2 units/kg•day.
3. HbA1c ≥ 7.0%.
4. Uncontrolled hypertension: systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg.
5. Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
6. Abnormal kidney function: eGFR \< 60 ml/min/1.73 m2.
7. Abnormal liver function: persistent elevation of liver function tests \> 1.5 times the upper limit of normal.
8. Anemia: baseline hemoglobin concentration \< 11 g/dl in women and \< 12 g/dl in men.
9. Presence of a seizure disorder not related to prior severe hypoglycemia.
10. Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
11. For female participants of child-bearing potential: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of study participation. Oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
12. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
13. Use of any investigational agents within 4 weeks of enrollment.
14. Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study

Primary outcomes:
measure: C-PEPTIDE suppression during hyperinsulinemia euglycemia.
timeFrame: For C-peptide at the 60-90 time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.
measure: GLUCAGON activation during hyperinsulinemia hypoglycemia.
timeFrame: For Glucagon at the 150-180 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.
Secondary outcomes:
measure: EPINEPHRINE during hyperinsulinemia hypoglycemia.
timeFrame: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.
measure: Rates of ENDOGENOUS GLUCOSE PRODUCTION during hyperinsulinemia hypoglycemia.
timeFrame: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.
measure: AUTONOMIC SYMPTOMS during hyperinsulinemia
timeFrame: During metabolic testing; this symptom questionnaire will be asked at the following time points: -15min, -1min, 30min, 60min,75min, 90min,120min, 150min, 165min, 180min.
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism
state: Pennsylvania
Study officials:
affiliation: Division of Endocrinology, Diabetes & Metabolism, Perelman School of Medicine
name: Michael R Rickels, MD., MS
role: PRINCIPAL_INVESTIGATOR
References: