Type1diabetesEarly Phase 1NCT03079921
Adrenergic System in Islet Transplantation
A Early Phase 1 study testing Phentolamine and Propranolol in people with Type1diabetes and Hypoglycemia, run by University of Pennsylvania at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 65 years
- Conditions the study is for
- Type1diabetes, Hypoglycemia, Hypoglycemia Unawareness
- What is being tested?
- Phentolamine and Propranolol
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Jan 2017to 31 Dec 2025
- Phase
- Early Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- GROUP 1
- Male and female subjects age 21 to 65 years of age.
- Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
- 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.
- 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%.
- 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.
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- Male and female subjects age 21 to 65 years of age.
- Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
- 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.
- 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%.
- 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:
- Male and female subjects age 21 to 65 years of age.
- Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.
- Clinical history compatible with total pancreatectomy and autologous islet transplantation > 6 months before study.
- 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%.
Who cannot join
- GROUP 1
- BMI ≥ 30 kg/m2.
- Insulin requirement of ≥ 0.2 units/kg•day.
- HbA1c ≥ 7.0%.
- Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
- History of cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease, or current use of β-blocker therapy.
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- Bronchial asthma.
- Abnormal kidney function: Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2.
- Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
- Untreated hypothyroidism, Addison's disease, or Celiac disease.
- Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
- Presence of a seizure disorder not related to prior severe hypoglycemia.
- Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
- 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.
- Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
- Use of any investigational agents within 4 weeks of enrollment.
- Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study
- GROUP 2
- BMI ≥ 30 kg/m2.
- Insulin requirement of ≥ 0.2 units/kg•day.
- HbA1c ≥ 7.0%.
- Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
- Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
- Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.
- Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
- Untreated hypothyroidism, Addison's disease, or Celiac disease.
- Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
- Presence of a seizure disorder not related to prior severe hypoglycemia.
- Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
- 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.
- Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
- Use of any investigational agents within 4 weeks of enrollment.
- Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study
- GROUP 3
- BMI ≥ 30 kg/m2.
- Insulin requirement of ≥ 0.2 units/kg•day.
- HbA1c ≥ 7.0%.
- Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg.
- Active cardiovascular disease, including coronary artery, cerebrovascular or peripheral vascular disease.
- Abnormal kidney function: eGFR < 60 ml/min/1.73 m2.
- Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of normal.
- Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men.
- Presence of a seizure disorder not related to prior severe hypoglycemia.
- Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose of hydrocortisone.
- 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.
- Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
- Use of any investigational agents within 4 weeks of enrollment.
- Any medical condition that, in the opinion of the PI, will interfere with the safe completion of the study
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Pennsylvania - Institute for Diabetes, Obesity and Metabolism
Philadelphia, Pennsylvania, 19104
About this study
Official title: Adrenergic Contribution to Glucose Counterregulation in Islet Transplantation
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.
Read the 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.
- Being tested
- Phentolamine, Propranolol, Placebo
- Keywords
- Islet Graft Function, Islet Cell transplantation, Auto-islet transplantation, Intra-hepatic islets, Extra-hepatic islets
- Medical subject headings
- Hypoglycemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhentolamineDrug
Also called Regitine
Physiologic receptor blockade (α1-receptor).
PropranololDrug
Also called Inderal
Physiologic receptor blockade (β2-receptor).
PlaceboDrug
Also called Saline, Sodium Chloride Solution
100mL bag of Normal Saline Solution (NSS).
| Study group | Role | What they receive |
|---|---|---|
| Group 1-Propranolol Intra-hepatic islet | Active comparator | 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. Receives: Drug: Propranolol |
| Group 1-Phentolamine Intra-hepatic islet | Active comparator | 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. Receives: Drug: Phentolamine |
| Group 1- Placebo Intra-hepatic islet | Placebo comparator | 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. Receives: Drug: Placebo |
| Group 2 - Extra-hepatic islet | No intervention | Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only. |
| Group 3 - Intra-hepatic auto islet | No intervention | Hyperinsulinemic euglycemic (90 min) followed by hypoglycemia (90 min) clamp only. |
What is being measured
The primary outcome is the main question the study is designed to answer.
C-PEPTIDE Suppression During Hyperinsulinemia Euglycemia.
The primary outcome measures will be the levels of C-peptide during hyperinsulinemia euglycemia.
Measured: For C-peptide at the 60-90 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.
GLUCAGON Activation During Hyperinsulinemia Hypoglycemia.
The primary outcome measures will be the levels of glucagon during hyperinsulinemia hypoglycemia.
Measured: For Glucagon at the 150-180 minute time-point during the hyperinsulinemic euglycemic-hypoglycemic clamp.
Secondary outcomes (3)
EPINEPHRINE During Hyperinsulinemia Hypoglycemia.
Secondary outcome measures will include levels of epinephrine during hyperinsulinemia hypoglycemia.
Measured: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.
Rates of ENDOGENOUS GLUCOSE PRODUCTION During Hyperinsulinemia Hypoglycemia.
Secondary outcome measures will include rates of endogenous glucose production during hyperinsulinemia hypoglycemia
Measured: During metabolic testing in the 150-180 minute time-point of the hyperinsulinemic euglycemic-hypoglycemic clamp.
AUTONOMIC SYMPTOMS During Hyperinsulinemia Hypoglycemia
A questionnaire was administered every 15-30 min during the study to quantitate autonomic symptoms as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: anxiety, palpitations, sweating, tremor, hunger, and tingling. (6 symptoms)
Total scores range 0 - 30, where higher scores indicate greater autonomic symptoms.
Measured: The autonomic symptom score was calculated as the mean of scores at the two hypoglycemic time points during the clamp (165 and 180 minutes).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Mar 2017
- Study start20 Jan 2017
- Primary completion30 Apr 2019
- Study completion31 Dec 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Type1diabetesStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- 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".
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Responsible party
- Principal investigator, Michael R. Rickels, MD, MS, University of Pennsylvania
- Investigators
- Michael R Rickels, MD., MS, Principal investigator, Division of Endocrinology, Diabetes & Metabolism, Perelman School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03079921
- Sponsor's protocol ID
- 826386
- Other IDs
- 2R01DK091331-06
- Status last verified
- Apr 2026
- First submitted
- 28 Feb 2017
- Last updated
- 27 Apr 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: It is not yet known if there will be any further plan to make IPD available besides the Informed Consent.