Gastrin + Islet Transplant for Type 1 Diabetes

Overseen By Fouad Kandeel, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Must not be taking: Anticoagulants

Disqualifiers: Kidney disease, Cardiovascular disease, Hypertension, Hyperlipidemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical study will evaluate the safety and effectiveness of Gastrin treatment with islet transplantation to help patients with difficult to control type 1 diabetes make insulin again and improve blood sugar control. This study involves two investigational (experimental) products not yet approved by the U.S. Food and Drug Administration (FDA) as a treatment for any disease: 1. Human allogenic islet cells (islet cells from a deceased, unrelated human donor) 2. Gastrin-17 (Gastrin) - a hormone secreted by the gut

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be able to comply with a post-transplant regimen, which includes immunosuppression and other requirements, so it's best to discuss your specific medications with the trial team.

Is the Gastrin + Islet Transplant treatment generally safe for humans?

Clinical islet transplantation has been considered safe, but there are challenges with rejection and technical issues. In a study with stem cell-derived pancreatic cells, most adverse events were related to surgical procedures or immunosuppression side effects, suggesting that while there are risks, they are generally manageable. ^{1 2 3 4 5}

How does the Gastrin + Islet Transplant treatment for Type 1 Diabetes differ from other treatments?

This treatment is unique because it combines allogenic human islet cells with gastrin, which helps increase the number of insulin-producing beta cells from pancreatic duct cells, potentially expanding the beta-cell mass and improving insulin production. This approach addresses the shortage of donor islets and aims to enhance the effectiveness of islet transplantation, which is a limitation of current treatments. ^{6 7 8 9 10}

What data supports the effectiveness of the treatment involving Gastrin and Islet Transplant for Type 1 Diabetes?

Research shows that islet transplantation can help eliminate severe low blood sugar episodes and may lead to insulin independence in some patients with type 1 diabetes. Recent improvements have made long-term outcomes of islet transplantation similar to pancreas transplantation, and it can also stabilize and reverse some diabetes complications. ^{11 12 13 14 15}

Who Is on the Research Team?

Fouad Kandeel, MD, PhD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-68 with type 1 diabetes who have unstable blood glucose, frequent hypoglycemia, or severe episodes leading to hospital visits. Participants must be fully vaccinated against COVID-19 and willing to follow a strict post-transplant regimen including immunosuppression and contraception. Exclusions include active peptic ulcers, untreated psychiatric illness, significant cardiovascular disease, high insulin requirements, certain infections like HIV/HBV/HCV/CMV/syphilis, recent organ transplants, and those without insurance for follow-up care.

Inclusion Criteria

Your blood sugar levels are not stable and you have frequent low blood sugar episodes, are unaware of low blood sugar symptoms, have had severe low blood sugar episodes in the past year, or have erratic blood sugar levels that affect your daily life.

I am committed to following a strict post-transplant care plan, including medication adherence and health monitoring.

I have had Type 1 diabetes for over 5 years with specific C-peptide levels.

Exclusion Criteria

I currently have an active stomach ulcer.

You are actively abusing alcohol, drugs, or smoking cigarettes, unless you have been abstinent for more than 3 months.

I have had an organ or tissue transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Islet Transplantation and Initial Gastrin Treatment

Participants receive a single islet transplant and begin the first round of Gastrin treatment with twice daily injections for 30 days

4 weeks

Frequent visits for monitoring

Second Gastrin Treatment

Participants receive a second round of Gastrin treatment with twice daily injections for 30 days, 6 months after the initial transplant

4 weeks

Frequent visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, with frequent follow-up visits for one year after transplant

12 months

Frequent visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Allogenic Human Islet Cells
• Gastrin-17

Trial Overview The study tests the safety and effectiveness of Gastrin hormone treatment combined with transplantation of human allogenic islet cells in patients with difficult-to-control type 1 diabetes. These experimental treatments aim to help patients produce their own insulin again and improve blood sugar control.

How Is the Trial Designed?

Group I: Single Arm Study Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

University of California, Los Angeles

Collaborator

Trials

1,594

Recruited

10,430,000+

Published Research Related to This Trial

Islet transplantation has become a viable treatment for type 1 diabetes, significantly reducing severe hypoglycemia in about 15% of patients, with recent improvements in long-term outcomes now comparable to pancreas transplantation.

The procedure is gaining wider acceptance, with reimbursement from health insurance providers in several countries, and ongoing efforts aim to enhance its availability and safety, potentially allowing for earlier intervention in newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

State of the art of clinical islet transplantation and novel protocols of immunosuppression. Shapiro, AM.[2021]

Co-transplanting mesenchymal stromal cells (MSCs) with islets significantly improved glucose control in a mouse model of diabetes, particularly when islets were placed under the kidney capsule, indicating a potential strategy to enhance islet transplant outcomes.

The MSCs reduced early islet cell death (apoptosis) and improved islet survival, suggesting that MSCs may provide protective effects during the critical early post-transplant period, although they did not increase beta cell proliferation or differentiate into beta cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. Borg, DJ., Weigelt, M., Wilhelm, C., et al.[2021]

Islet allotransplantation has been performed for about 30 years to treat brittle type 1 diabetes, but its use is still limited to select patients due to challenges like the need for lifelong immunosuppression.

Research is ongoing to improve islet production, engraftment, and long-term function, including strategies like co-transplanting beta cell progenitors to enhance graft survival, with clinical trials anticipated in the near future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Islet transplantation 30 years after the first transplants. Antonioli, B., Galuzzi, M.[2019]

Over the past two decades, advancements in human islet isolation techniques have significantly improved the recovery of functional islets from pancreases, which is crucial for successful islet transplantation.

The use of standardized tissue dissociation enzyme (TDE) blends, specifically a mixture of collagenase and protease, has been key in achieving higher yields of islets, although challenges remain in optimizing these processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human pancreatic tissue dissociation enzymes for islet isolation: Advances and clinical perspectives. Loganathan, G., Balamurugan, AN., Venugopal, S.[2020]

In a study of 35 type 1 diabetic patients who received islet cell transplants from a median of 6 donors, the withdrawal of immunosuppressants led to low rates of allosensitization as measured by the CDC assay (only 6% positivity for class I antibodies).

However, a high rate of allosensitization was observed using the Luminex assay, with 72% of patients testing positive for class I or class II antibodies, particularly associated with lower β-cell purity in the grafts, while the use of steroids helped reduce the positivity for class I antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive factors of allosensitization after immunosuppressant withdrawal in recipients of long-term cultured islet cell grafts. Hilbrands, R., Gillard, P., Van der Torren, CR., et al.[2016]

Allogeneic islet transplantation can help restore insulin independence for diabetes patients, but the limited availability of organ donors poses a significant challenge.

Recent advances in pluripotent stem cell (PSC) technology show promise for generating insulin-producing β cells, but ensuring the safety of these cells before transplantation is critical to prevent tumor formation, with strategies being developed to enhance safety, such as purifying differentiated cells and using engineered suicide genes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies to Improve the Safety of iPSC-Derived β Cells for β Cell Replacement in Diabetes. Pellegrini, S., Zamarian, V., Sordi, V.[2022]

Islet allotransplantation has been largely unsuccessful, with only 4 out of 74 attempts leading to long-term insulin independence, indicating significant challenges in overcoming islet yield and rejection issues.

The success of islet autotransplantation suggests potential for improvement in allotransplantation if rejection can be prevented, but current techniques for islet preparation and immunosuppression need significant advancements to enhance success rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreas and islet transplantation. II. Clinical trials. Sutherland, DE.[2020]

In a phase 1/2 study involving 17 type 1 diabetes patients, implanted pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) showed the ability to engraft and function as insulin-releasing islet cells, with 63% of the implanted devices demonstrating insulin expression after 3-12 months.

The study found that 35.3% of subjects had positive C-peptide levels, indicating insulin production, as early as 6 months post-implant, suggesting that PEC-01 cells could be a promising renewable alternative to traditional pancreatic islet transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Shapiro, AMJ., Thompson, D., Donner, TW., et al.[2022]

Islet transplantation outcomes for type 1 diabetes have improved over time, with insulin independence rates increasing from 27% in 1999-2002 to 44% in 2007-2010, indicating enhanced efficacy of the procedure.

Safety outcomes also improved, as evidenced by a lower rate of islet reinfusion (48% in 2007-2010 compared to 60-65% in earlier years) and a reduction in adverse events, suggesting a more favorable risk profile for recent transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improvement in outcomes of clinical islet transplantation: 1999-2010. Barton, FB., Rickels, MR., Alejandro, R., et al.[2022]

Xenotransplantation of pig islets has shown promise in preclinical studies involving 181 nonhuman primates, demonstrating the feasibility of using pig islets for treating type 1 diabetes.

Recent advancements have led to prolonged insulin independence in diabetic recipients through various islet products and immunotherapeutic strategies, indicating a potential pathway for future clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pig-to-nonhuman primate islet xenotransplantation. Hering, BJ., Walawalkar, N.[2021]

The combination of epidermal growth factor (EGF) and gastrin significantly increases beta-cell mass in adult human pancreatic islets, with a remarkable 118% increase in beta-cell numbers observed in cultures after 4 weeks.

This combination therapy not only enhances beta-cell proliferation in vitro but also improves insulin content and secretory responses in vivo when human islets are implanted in mice, suggesting a promising approach for expanding insulin-producing cells for diabetes treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. Suarez-Pinzon, WL., Lakey, JR., Brand, SJ., et al.[2022]

Combination treatment with glucagon-like peptide-1 (GLP-1) and gastrin significantly expanded the beta-cell mass in human pancreatic islets implanted in diabetic mice, leading to improved blood glucose levels.

The increase in insulin-producing cells was primarily due to pancreatic duct cells transforming into insulin-positive cells, demonstrating a potential mechanism for enhancing beta-cell mass in islet transplantation for type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice. Suarez-Pinzon, WL., Lakey, JR., Rabinovitch, A.[2022]

Combination therapy with epidermal growth factor (EGF) and gastrin significantly prolonged the survival of transplanted islet grafts in diabetic NOD mice, increasing median survival time to 60 days compared to shorter durations with EGF alone (36 days) or gastrin alone (19 days).

The combination treatment also resulted in a higher number of insulin-stained beta-cells in the islet grafts and reduced the number of immune cells attacking the beta cells, indicating that EGF and gastrin can inhibit autoimmune responses and improve islet transplantation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapy with epidermal growth factor and gastrin delays autoimmune diabetes recurrence in nonobese diabetic mice transplanted with syngeneic islets. Suarez-Pinzon, WL., Rabinovitch, A.[2008]

Streptozotocin-induced diabetes in rats significantly reduced fasting gastrin levels, indicating a state of hypogastrinemia, with levels dropping from 256 pg/ml in controls to 107 pg/ml in diabetics.

Islet transplantation successfully restored gastrin levels to normal within one month, demonstrating that islet cells play a crucial role in regulating gastrin production and maintaining homeostasis in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypogastrinemia in streptozotocin diabetes with islet transplantation--reconstitution. Fabri, PJ., Weber, CJ., Gower, WR., et al.[2019]

A combination therapy involving induced mixed chimerism and administration of gastrin and epidermal growth factor (EGF) was shown to reverse late-stage Type 1 diabetes (T1D) in a mouse model, suggesting a potential new treatment approach.

This therapy promotes both the regeneration and replication of insulin-producing β cells, which could provide a long-term cure for T1D, potentially replacing the need for islet transplantation in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mixed chimerism and growth factors augment β cell regeneration and reverse late-stage type 1 diabetes. Wang, M., Racine, JJ., Song, X., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

State of the art of clinical islet transplantation and novel protocols of immunosuppression. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

Mesenchymal stromal cells improve transplanted islet survival and islet function in a syngeneic mouse model. [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Islet transplantation 30 years after the first transplants. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Human pancreatic tissue dissociation enzymes for islet isolation: Advances and clinical perspectives. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Predictive factors of allosensitization after immunosuppressant withdrawal in recipients of long-term cultured islet cell grafts. [2016]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Strategies to Improve the Safety of iPSC-Derived β Cells for β Cell Replacement in Diabetes. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Pancreas and islet transplantation. II. Clinical trials. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Improvement in outcomes of clinical islet transplantation: 1999-2010. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Pig-to-nonhuman primate islet xenotransplantation. [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Combination therapy with glucagon-like peptide-1 and gastrin induces beta-cell neogenesis from pancreatic duct cells in human islets transplanted in immunodeficient diabetic mice. [2022]

13. United States pubmed.ncbi.nlm.nih.gov

Combination therapy with epidermal growth factor and gastrin delays autoimmune diabetes recurrence in nonobese diabetic mice transplanted with syngeneic islets. [2008]

14. United States pubmed.ncbi.nlm.nih.gov

Hypogastrinemia in streptozotocin diabetes with islet transplantation--reconstitution. [2019]

15. United States pubmed.ncbi.nlm.nih.gov

Mixed chimerism and growth factors augment β cell regeneration and reverse late-stage type 1 diabetes. [2021]