Adrenergic Blockers for Type 1 Diabetes Post-Islet Transplant

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: University of Pennsylvania

Must be taking: Insulin, Immunosuppressants

Must not be taking: Anti-diabetics, Investigational agents

Disqualifiers: Obesity, Hypertension, Cardiovascular disease, others

Compensation: Varies

Number of Visits: 3

Duration: 3.5 hours per session, across three sessions

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how certain medications affect individuals with type 1 diabetes who have received islet cell transplants. The researchers aim to understand how the body's nerves and hormones respond to low blood sugar post-transplant. Participants will receive either a medication that blocks nerve signals (such as Phentolamine), a medication that blocks hormone signals (such as Propranolol), or a placebo to assess the impact on blood sugar regulation. This trial is suitable for those who have had type 1 diabetes for over 10 years, received an islet transplant more than 6 months ago, and have stable graft function. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants a chance to contribute to groundbreaking diabetes research.

Will I have to stop taking my current medications?

The trial requires that you do not take any anti-diabetic medication other than insulin within 4 weeks of enrollment. If you are on other medications, you may need to stop them before joining the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that propranolol and phentolamine have been safely used in various medical situations. Propranolol often treats high blood pressure and heart problems, with a long history of safe use. Phentolamine manages sudden increases in blood pressure and is known to be safe for short-term use.

Studies related to type 1 diabetes and islet transplantation indicate that these drugs do not harm the main functions of the transplanted islet cells. They do not interfere with the cells' ability to regulate insulin and glucagon, hormones that manage blood sugar levels.

This trial is in its early stages and primarily aims to understand how the treatment works, rather than confirm its safety. However, the safe use of these drugs in other areas offers some reassurance. Participants should still consult their healthcare provider about any potential risks before joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using adrenergic blockers for Type 1 Diabetes post-islet transplant because these treatments potentially enhance the success of islet transplantation. Phentolamine and propranolol, the two drugs being tested, could help regulate blood glucose levels more effectively by targeting the body's adrenergic system, which plays a role in stress responses that can impact insulin release and glucose uptake. Unlike traditional treatments that mainly focus on insulin therapy, these drugs might improve the islets' function and longevity after transplantation, offering a more sustainable solution for managing Type 1 Diabetes.

What evidence suggests that this trial's treatments could be effective for type 1 diabetes post-islet transplant?

Research has shown that islet transplantation can help people with type 1 diabetes reduce or even eliminate their need for insulin. In some studies, up to 74% of recipients stopped using insulin. This trial will assess different treatments' effects on islet transplantation outcomes. Phentolamine, one treatment under study, might prevent insulin from lowering C-peptide levels, indicating insulin production. This could help the body release more glucagon, a hormone that raises blood sugar, during low blood sugar episodes. In contrast, propranolol, another treatment option in this trial, does not appear to affect how transplanted islets respond to low blood sugar. These findings suggest that phentolamine may improve blood sugar control after islet transplants, while propranolol might not offer the same benefit. ^{1 2 6 7 8}

Who Is on the Research Team?

Michael R Rickels, MD., MS

Principal Investigator

Division of Endocrinology, Diabetes & Metabolism, Perelman School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults aged 21-65 with type 1 diabetes who have had an islet cell transplant at least 6 months ago. They should be using standard immunosuppression, have stable graft function, and not require high doses of insulin. Women must not be pregnant or breastfeeding and willing to use contraception. Exclusions include severe chronic diseases, uncontrolled hypertension, obesity (BMI ≥30), abnormal organ functions, certain medication uses within the last month, and other conditions that could affect safety.

Inclusion Criteria

I am between 21 and 65 years old.

GROUP 1: Subjects able to provide written informed consent and comply with study protocol

I am using standard immunosuppression medication as directed.

Exclusion Criteria

My kidney function is below normal levels.

I take more than 5 mg of prednisone daily or its equivalent.

You have a body mass index (BMI) of 30 or higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo hyperinsulinemic euglycemic-hypoglycemic clamps with administration of α-adrenergic blocker phentolamine, β-adrenergic blocker propranolol, or placebo

3.5 hours per session, across three sessions

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Phentolamine
• Placebo
• Propranolol

Trial Overview The study tests how blocking different parts of the nervous system affects blood sugar control in those who've received a pancreas cell transplant for diabetes. It involves three drugs: phentolamine (α-adrenergic blocker), propranolol (β-adrenergic blocker), and placebo. Participants will undergo glucose clamps under each condition in a randomized double-blind manner to see if these interventions influence their body's response to low blood sugar.

How Is the Trial Designed?

Group I: Group 1-Propranolol Intra-hepatic islet Active Control 1 Intervention

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 II: Group 2 - Extra-hepatic islet Active Control 1 Intervention

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

Group III: Group 3 - Intra-hepatic auto islet Active Control 1 Intervention

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

Group IV: Group 1-Phentolamine Intra-hepatic islet Active Control 1 Intervention

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 V: Group 1- Placebo Intra-hepatic islet Placebo Group 1 Intervention

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.

Phentolamine is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Regitine for:

• Hypertension
• Pheochromocytoma

Approved in Canada as Phentolamine for:

• Hypertension
• Pheochromocytoma

Approved in European Union as Phentolamine for:

• Hypertension
• Pheochromocytoma

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a study of 215 patients with insulin-dependent diabetes, the use of alpha-adrenoblockers led to a reduction in blood sugar levels without needing to increase insulin doses, suggesting they can help manage diabetes more effectively.

In contrast, beta-adrenoblockers worsened diabetes control and did not change growth hormone levels, indicating they are not recommended for patients with diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of alpha and beta receptor blockaders on the degree of glycemia, growth hormone content of blood and catecholamine excretion in insulin-dependent diabetes mellitus]. Alekseeva, GG., Iukhlova, NA.[2016]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11444263/

or β-Adrenergic blockade does not affect transplanted islet ... Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of glucagon secretion in ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03079921

NCT03079921 | Adrenergic System in Islet Transplantation This study is designed to test the hypothesis that α-adrenergic (neural) blockade will abolish insulin-mediated suppression of C-peptide, attenuating α-cell ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11906537/

Islet Cell Replacement and Regeneration for Type 1 Diabetes A recent phase 3 study confirmed that allogeneic islet transplantation is a safe and effective treatment for patients with T1D and unstable ...

4. researchgate.net researchgate.net/publication/364362720_Long-term_Outcomes_With_Islet-Alone_and_Islet-After-Kidney_Transplantation_for_Type_1_Diabetes_in_the_Clinical_Islet_Transplantation_Consortium_The_CIT-08_Study

Long-term Outcomes With Islet-Alone and Islet-After- ... Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining ...

5. researchgate.net researchgate.net/publication/386425705_b-Cell_Secretory_Capacity_Predicts_Metabolic_Outcomes_over_6_Years_following_Human_Islet_Transplantation

β-Cell Secretory Capacity Predicts Metabolic Outcomes ... β-Cell Secretory Capacity Predicts Metabolic Outcomes over 6 Years following Human Islet Transplantation. December 2024; Diabetes. DOI:10.2337/ ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11893597/

Donor after circulatory death in pancreas transplantation This scoping review presents a comprehensive comparative analysis of transplantation outcomes between DCD and donors after brain death (DBD).

7. journals.physiology.org journals.physiology.org/doi/pdf/10.1152/ajpendo.00002.2024

or β-Adrenergic blockade does not affect transplanted islet ... Type 1 diabetes recipients of intrahepatic islet transplantation exhibit glucose-dependent suppression of insulin and activation of.

8. go.drugbank.com go.drugbank.com/drugs/DB00692

Phentolamine: Uses, Interactions, Mechanism of Action Phentolamine is used to prevent or control hypertensive episodes that may occur in a patient with pheochromocytoma due to stress or manipulation.