Adrenergic System in Islet Transplantation

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

EARLY_PHASE1

Total Enrollment

11 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-01-20

Study Completion Date

2025-12-31

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Type1diabetes Hypoglycemia Hypoglycemia Unawareness Islet Cell Transplantation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

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 Study Purpose

BASIC_SCIENCE

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Conditions of testing for "Group 1" (intra-hepatic islet recipients) will remain double-blind for each subject until their completion of all testing visits, unless for safety concerns, either the PI or Medical Monitor request an unblinding. Groups "2" and "3" will have no masking.

Study Groups

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Group 1-Propranolol Intra-hepatic islet

The dose of propranolol will be 0.48 μg/kilogram•minute, which will provide a total dose of 0.10 mg/kg. It will be administered 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

Group Type ACTIVE_COMPARATOR

Propranolol

Intervention Type DRUG

Physiologic receptor blockade (β2-receptor).

Group 1-Phentolamine Intra-hepatic islet

The dose of phentolamine will be 0.95 μg/kg•min, which will provide a total dose of 0.20 mg/kg. It will be administered 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

Group Type ACTIVE_COMPARATOR

Phentolamine

Intervention Type DRUG

Physiologic receptor blockade (α1-receptor).

Group 1- Placebo Intra-hepatic islet

Placebo in 100mL NSS. Infuse Intravenously at 0.0095 ML/KG/MIN. 1 x only via intravenous infusion over 3.5 hours, starting 30 min before conduct of a hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

100mL bag of Normal Saline Solution (NSS).

Group 2 - Extra-hepatic islet

Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only.

Group Type NO_INTERVENTION

No interventions assigned to this group

Group 3 - Intra-hepatic auto islet

Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only.

Group Type NO_INTERVENTION

No interventions assigned to this group

Interventions

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Phentolamine

Physiologic receptor blockade (α1-receptor).

Intervention Type DRUG

Propranolol

Physiologic receptor blockade (β2-receptor).

Intervention Type DRUG

Placebo

100mL bag of Normal Saline Solution (NSS).

Intervention Type DRUG

Other Intervention Names

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Regitine Inderal Saline Sodium Chloride Solution

Eligibility Criteria

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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.

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.

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 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

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

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

Minimum Eligible Age

21 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Michael R. Rickels, MD, MS

Michael R. Rickels, M.D., M.S. Associate Professor of Medicine Division of Endocrinology, Diabetes & Metabolism Director, Translational Research Program Institute for Diabetes, Obesity & Metabolism University of Pennsylvania Perelman School of Medicine

Responsibility Role PRINCIPAL_INVESTIGATOR