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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to help people with Type 1 diabetes become insulin-independent. By transplanting special cells from the pancreas and parathyroid glands, both from the same donor, researchers aim to make the procedure safer and more effective for those who have already received a kidney or liver transplant. This process is known as Co-transplantation of PTG with Pancreatic Islets. The study will determine if this treatment can help the body accept the new cells and reduce insulin dependence. Suitable candidates for this trial have Type 1 diabetes, have had a stable kidney or liver transplant, and rely on insulin. As a Phase 1, Phase 2 trial, it focuses on understanding how the treatment works and measuring its effectiveness in an initial group, offering participants a chance to be among the first to benefit from this innovative approach.

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.

Is there any evidence suggesting that co-transplantation of PTG with pancreatic islets is likely to be safe?

Research has shown that transplanting parathyroid glands along with adult pancreatic islets holds promise for safety. Studies have found that this combination can enhance the survival and function of the transplanted islets. This is significant because longer islet survival may reduce insulin needs and low blood sugar episodes in people with Type 1 diabetes.

Although specific safety details from current studies are not provided, early clinical trials are testing the treatment. The primary goal at this stage is to ensure safety for participants, with close monitoring for any side effects. So far, efforts focus on preventing serious harm.

In summary, research suggests that this co-transplantation is generally well-tolerated, and ongoing studies aim to confirm its safety for humans. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about the co-transplantation of parathyroid glands (PTG) with pancreatic islets for Type 1 diabetes because it offers a unique approach compared to current treatment options like insulin therapy and islet transplantation alone. This treatment targets the underlying cause of diabetes by potentially restoring the body's ability to produce insulin naturally. By co-transplanting PTG with pancreatic islets into the muscle, this method aims to improve islet survival and function, thanks to the supportive role of PTG in regulating calcium and creating a more favorable environment for the islets. If successful, this could reduce the need for chronic insulin injections and improve the quality of life for people with Type 1 diabetes.

What evidence suggests that co-transplantation of PTG with pancreatic islets might be an effective treatment for Type 1 diabetes?

This trial will evaluate the co-transplantation of parathyroid tissue with pancreatic islets for people with Type 1 diabetes. Research has shown that transplanting parathyroid tissue alongside pancreatic islets can significantly enhance the survival and function of the islet cells. In earlier studies, this method greatly improved the performance of islets transplanted into muscle tissue. The addition of parathyroid glands helps protect the insulin-producing islets, potentially leading to better blood sugar control. Early results suggest that this combination might enable people with Type 1 diabetes to stop needing insulin shots. Although more research is necessary, these initial findings offer promise for improved diabetes treatment. ^{1 3 5 6 7}

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

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

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

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT03977662

Pancreatic Islets and Parathyroid Gland Co-transplantation ... Single-center, open label, non-randomized safety and efficacy trial to evaluate co-transplantation of allogeneic parathyroid glands (PTG) with adult pancreatic ...

2. cirm.ca.gov cirm.ca.gov/our-progress/awards/pancreatic-islets-and-parathyroid-gland-co-transplantation-treatment-diabetes-intra-muscular-site-paradigm/

Pancreatic Islets and Parathyroid Gland Co-transplantation for ... Co-transplantation of parathyroid tissue with pancreatic islets leads to dramatic improvement in islet survival and function after intramuscular transplant.

3. journals.lww.com journals.lww.com/transplantjournal/abstract/2018/07001/reversal_of_diabetes_and_preservation_of.589.aspx

Reversal of Diabetes and Preservation of Pancreatic Islet... Cotransplantation of PTG with both mouse islet and SCIPC in the SQ and IM resulted in complete preservation of islet graft in comparison to significant islet ...

4. alphaclinic.ucsf.edu alphaclinic.ucsf.edu/pancreatic-islets-and-parathyroid-gland-co-transplantation-treatment-diabetes-intra-muscular-site

Pancreatic Islets and Parathyroid Gland Co-transplantation for ... This is a single-center, open-label, non-randomized safety and efficacy trial to evaluate co-transplantation of allogeneic parathyroid glands (PTG) with adult ...

5. smartpatients.com smartpatients.com/trials/NCT03977662

Pancreatic Islets and Parathyroid Gland Co-transplantation ... The primary objective is to test the hypothesis that co-transplantation of allogeneic PTG with adult pancreatic islets (derived from same deceased donor) in ...

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/62/NCT03977662/Prot_SAP_002.pdf

Pancreatic Islets and Parathyroid Gland Co-transplantation ... Study Design: Single-center, open label, non-randomized safety and efficacy trial to evaluate co-transplantation of allogeneic parathyroid ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9889686/

Pancreatic islet transplantation in type 1 diabetes: Current ... Based on current data, islet transplantation successfully reduces severe hypoglycemia and insulin requirement. However, graft survival is still not good enough, ...