Islet + Parathyroid Co-transplant for Type 1 Diabetes

(PARADIGM Trial)

Overseen By Crystal Loucel, MPH, MS, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Peter Stock

Must be taking: Calcineurin inhibitors

Disqualifiers: Obesity, Hypertension, Infections, others

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

Compensation: Varies

Number of Visits: 76

8 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The primary objective is to test the hypothesis that co-transplantation of allogeneic PTG with adult pancreatic islets (derived from same deceased donor) in the IM site in people with Type 1 diabetes with functioning kidney and/or liver transplants is safe, allows islet engraftment, and leads to insulin independence.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking a calcineurin inhibitor-based maintenance immunosuppression, you must continue it. Please consult with the trial team for more details.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should be on certain immunosuppressive medications if they have had a kidney or liver transplant. It's best to discuss your specific medications with the trial team.

What safety data exists for islet and parathyroid co-transplantation in Type 1 Diabetes?

The safety data for islet transplantation, which is a component of the islet and parathyroid co-transplantation, indicates that it is a minimally invasive procedure with some risks associated with immunosuppression, such as infections and malignancies. A study involving autologous regulatory T cells in islet transplantation showed no negative effects related to Treg infusion and only minor complications from immunosuppressive drugs, suggesting that the treatment is safe and feasible. However, there is no specific safety data available for the co-transplantation of islet and parathyroid glands. ^{1 2 3 4 5}

Is the Islet + Parathyroid Co-transplant for Type 1 Diabetes safe for humans?

Research on pancreatic islet transplantation, which is part of the Islet + Parathyroid Co-transplant, shows that it is generally safe, though it requires ongoing medication to prevent the body from rejecting the transplant. Some studies have shown minor complications related to these medications, but no major safety concerns have been reported. ^{1 2 3 4 5}

Is the treatment of co-transplanting parathyroid glands with pancreatic islets promising for type 1 diabetes?

Yes, co-transplanting parathyroid glands with pancreatic islets is promising because it can improve the success of islet transplants. This approach may help the transplanted cells survive better and work more effectively, potentially leading to better blood sugar control for people with type 1 diabetes. ^{6 7 8 9 10}

How is the Islet + Parathyroid Co-transplant treatment different from other treatments for type 1 diabetes?

The Islet + Parathyroid Co-transplant treatment is unique because it combines pancreatic islets with parathyroid tissue, potentially enhancing the survival and function of the transplanted islets, which are responsible for insulin production. This approach aims to improve the engraftment and effectiveness of islet transplants, which traditionally face challenges like immune rejection and limited donor availability. ^{6 7 8 9 10}

What data supports the idea that Islet + Parathyroid Co-transplant for Type 1 Diabetes is an effective treatment?

The available research shows that while islet transplantation has improved over time, it still faces challenges like the need for multiple donor organs and difficulties in monitoring success. Pancreas transplantation is often more successful, especially for patients with low surgical risk. However, islet transplantation is a better option for those with high surgical risk due to other health issues. Both treatments can prevent severe low blood sugar in the long term, which is a significant benefit for people with type 1 diabetes. The 'Edmonton Protocol' improved short-term outcomes for islet transplants, but long-term insulin independence remains low, indicating room for improvement. ^{5 6 11 12 13}

What data supports the effectiveness of the treatment Co-transplantation of PTG with Pancreatic Islets for Type 1 Diabetes?

Pancreatic islet transplantation has shown promise in improving blood sugar control in type 1 diabetes, although achieving long-term insulin independence remains challenging. The Edmonton Protocol improved short-term outcomes, but further advances are needed to maintain the function of transplanted islets over time. ^{5 6 11 12 13}

Who Is on the Research Team?

Peter Stock, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

Adults over 18 with Type 1 diabetes who have had a kidney or liver transplant at least 6 months ago and are on specific immunosuppression drugs. They must not be overweight, have stable organ function without recent rejections, no severe infections or heart issues in the past year, and agree to use contraception.

Inclusion Criteria

My liver tests are normal and I haven't had a rejection episode in the last 6 months.

My body does not produce c-peptide when stimulated.

I had a kidney or liver transplant over 6 months ago and am on specific immune-suppressing drugs.

Exclusion Criteria

My kidney function is low and I've had a rejection episode before a transplant.

I haven't had serious fungal infections like aspergillus, histoplasmosis, or coccidioidomycosis in the last year.

My cholesterol and triglycerides levels are high and untreated.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Transplantation

Co-transplantation of allogeneic parathyroid glands with adult pancreatic islets in the intramuscular site

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after transplantation, including assessments of glycemic control and beta cell function

1-2 years

Multiple visits (in-person) at Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2

What Are the Treatments Tested in This Trial?

Interventions

• Co-transplantation of PTG with Pancreatic Islets

Trial Overview The trial is testing if putting parathyroid glands (PTG) together with pancreatic islets from the same donor into people with Type 1 diabetes is safe and can help them stop needing insulin shots by allowing the transplanted cells to work properly.

How Is the Trial Designed?

Group I: PTG with adult pancreatic islet co-transplantation Experimental Treatment 1 Intervention

People with Type 1 (c-peptide negative) diabetes with stable kidney or liver allografts on chronic immunosuppression who receive study intervention, which is co-transplantation of allogeneic parathyroid (PTG) with adult pancreatic islets in people with Type 1 diabetes in the intramuscular (IM) site

Who Is Running the Clinical Trial?

Peter Stock

Lead Sponsor

Trials

1

Recruited

8+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Published Research Related to This Trial

Pancreatic islet transplantation is gaining recognition as a promising treatment for managing blood sugar levels in type 1 diabetes and preventing diabetes after total pancreatectomy in chronic pancreatitis patients.

The review highlights recent advancements in both autologous (using the patient's own islets) and allogenic (donor islets) transplantation, focusing on their metabolic outcomes and the authors' own experiences with autologous transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Islet Cell Transplantation: Graft Stability and Metabolic Outcomes. Ali, KF., Hatipoglu, B.[2020]

Pancreatic islet transplantation is currently the best alternative for restoring insulin secretion in type 1 diabetes, but only 7.5% of patients achieve insulin independence after 5 years, highlighting the need for improved techniques and preservation methods.

Despite the challenges, islet transplantation can significantly reduce severe hypoglycemic episodes and improve glycemic control for selected patients, making it a valuable option for those who can benefit from its effects over 4-5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic islet transplantation. Corrêa-Giannella, ML., Raposo do Amaral, AS.[2021]

Whole vascularized pancreas transplantation can effectively restore insulin secretion and maintain normal blood sugar levels in most patients with type 1 diabetes, potentially improving their quality of life and reducing complications associated with diabetes.

The use of pancreas transplantation for type 2 diabetes remains controversial, but it may be beneficial for patients with severe glycemic dysregulation, as they face similar life-threatening complications as those with type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Type 2 diabetes: is pancreas transplantation an option? Ciancio, G., Burke, GW.[2021]

Pancreas and islet transplantation aim to replicate natural insulin secretion in patients with type 1 diabetes, improving their quality of life and reducing complications, but achieving long-term insulin independence remains a challenge despite 25 years of research.

Islet transplantation is less invasive and can be repeated, but pancreas transplantation is recommended based on specific patient criteria, particularly concerning kidney health, highlighting the need for careful candidate evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreas and islet transplantation. Hakim, N., Papalois, V.[2005]

Pancreas transplantation is the preferred treatment for selected patients with uremia and diabetes, while islet transplantation is still considered experimental in the USA, pending results from ongoing phase III trials.

Pancreas transplants generally offer better outcomes than islet transplants, making them suitable for low-risk surgical patients, whereas high-risk patients should consider islet transplants; both procedures aim to provide long-term prevention of hypoglycemia in type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What defines success in pancreas and islet transplantation-insulin independence or prevention of hypoglycemia? A review. Gruessner, RW., Gruessner, AC.[2018]

Pancreas and islet transplantation can restore insulin secretion in diabetes patients, but they come with significant risks, including the need for immunosuppression and potential complications from major surgery.

Islet transplantation is less invasive than pancreas transplantation and can be repeated to improve outcomes, making it suitable for patients with labile diabetes or those at high surgical risk, especially when combined with kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT). Wojtusciszyn, A., Branchereau, J., Esposito, L., et al.[2020]

Pancreatic islet transplantation (IT) can improve glycaemic control and reduce the fear of hypoglycaemia for individuals with complex Type 1 diabetes, with benefits observed up to 36 months post-transplant.

However, the overall impact on quality of life (QoL) is unclear due to mixed results from studies, limited sample sizes, and the lack of sensitivity in some patient-reported outcome measures, indicating a need for more comprehensive assessments of patient satisfaction and QoL post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review. Speight, J., Reaney, MD., Woodcock, AJ., et al.[2021]

In a first-in-man study involving five patients with type 1 diabetes, the co-infusion of autologous regulatory T cells (Tregs) during allogeneic islet transplantation was found to be safe, with no adverse effects related to the Treg infusion and only minor complications from immunosuppressive drugs.

This study suggests that using Tregs could potentially reduce the need for lifelong immunosuppression in islet transplantation, paving the way for future efficacy studies aimed at enhancing the safety and effectiveness of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation. Bergström, M., Yao, M., Müller, M., et al.[2022]

A 43-year-old woman developed type 1 diabetes within a year after undergoing total pancreatectomy with islet autotransplantation (TPIAT), despite having no signs of autoimmune issues before the surgery.

This case emphasizes the importance of monitoring for de novo type 1 diabetes in TPIAT patients, as the patient showed new autoantibodies and complete loss of beta cell function post-surgery, indicating potential autoimmune activity against the islet graft.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Autoimmune-Mediated β Cell Failure After Total Pancreatectomy With Autologous Islet Transplantation. Bellin, MD., Moran, A., Wilhelm, JJ., et al.[2023]

Pancreas transplantation (PT) is highly effective for patients with type 1 diabetes mellitus (T1DM), showing a graft survival rate of 96.7% over a mean follow-up of 2.3 years, with no recorded patient deaths.

Patients with functioning grafts achieved excellent metabolic control, with average glycosylated hemoglobin levels of 5.5% and median fasting glucose levels of 95 mg/dL, comparable to non-diabetic individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreas Transplantation: Small-Center Experience in Type 1 Diabetes Mellitus in a High-Incidence Region. Tondolo, V., Manunza, R., Pellegrino, RA., et al.[2022]

Co-culturing murine islets with human adipose-derived mesenchymal stem cells (Ad-MSCs) for 48 hours significantly improved islet viability, reduced cell death, and enhanced insulin secretion, suggesting a protective effect of Ad-MSCs on islet function.

In mouse models, islet grafts co-transplanted with Ad-MSCs after a 48-hour co-culture period achieved better euglycemia rates compared to islets transplanted alone, indicating that this strategy may enhance islet engraftment and function in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved islet recovery and efficacy through co-culture and co-transplantation of islets with human adipose-derived mesenchymal stem cells. Gamble, A., Pawlick, R., Pepper, AR., et al.[2019]

Endocrine pancreas transplantation, including both whole pancreas and islet grafts, shows promise for treating insulin-dependent diabetes mellitus (IDDM), but both methods remain experimental with significant technical challenges to overcome.

While whole pancreas transplants have had higher success rates, islet grafts could offer a less invasive alternative if issues like immune destruction and donor organ availability are resolved, and ongoing research into immunoprotection strategies may improve their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives in pancreatic and islet cell transplantation for the therapy of IDDM. Calafiore, R.[2019]

A novel procedure allowed for the successful isolation and infusion of islet cells from a discarded pancreas after an emergency allograft pancreatectomy in a patient with type 1 diabetes and end-stage renal disease, leading to significant recovery in glycemic control.

Three months post-procedure, the patient achieved near-normal blood glucose levels without the need for insulin, demonstrating the potential of islet alloautotransplantation as an effective rescue therapy after pancreas loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation. Nijhoff, MF., Dubbeld, J., van Erkel, AR., et al.[2023]

Citations

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

Pancreatic Islet Cell Transplantation: Graft Stability and Metabolic Outcomes. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Pancreatic islet transplantation. [2021]

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

Type 2 diabetes: is pancreas transplantation an option? [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Pancreas and islet transplantation. [2005]

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

What defines success in pancreas and islet transplantation-insulin independence or prevention of hypoglycemia? A review. [2018]

6. France pubmed.ncbi.nlm.nih.gov

Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT). [2020]

7. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation. [2022]

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

Development of Autoimmune-Mediated β Cell Failure After Total Pancreatectomy With Autologous Islet Transplantation. [2023]

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

Pancreas Transplantation: Small-Center Experience in Type 1 Diabetes Mellitus in a High-Incidence Region. [2022]

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

Improved islet recovery and efficacy through co-culture and co-transplantation of islets with human adipose-derived mesenchymal stem cells. [2019]

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

Perspectives in pancreatic and islet cell transplantation for the therapy of IDDM. [2019]

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

Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation. [2023]