Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Type 1 Diabetes (PARADIGM)

Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Diabetes in the Intra-Muscular Site

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.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Combination product: Co-transplantation of PTG with pancreatic islets

Detailed Description

Single-center, open label, non-randomized safety and efficacy trial to evaluate co-transplantation of allogeneic parathyroid glands (PTG) with adult pancreatic islets (both PTG and pancreatic islets obtained from same deceased donor) in people with Type 1 diabetes in the intramuscular (IM) site with stable function of liver or kidney allografts on chronic immunosuppression.

A total of 8 patients will be enrolled in the study and followed for a minimum of 1 year up to 2 years after the last islet transplant, depending on enrollment date.

• Study Type: Interventional
• Enrollment (Anticipated): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Patricia Brennan, RN, PhD; Phone Number: 415-476-3229; Email: Patricia.Brennan@ucsf.edu
• Study Contact Backup: Name: Rodney Rogers; Phone Number: 415-514-6454; Email: Rodney.Rogers@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California
      • Contact: Patricia Brennan, RN, PhD; Phone Number: 415-476-3229; Email: Patricia.Brennan@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female subjects age 18 or older.
2. Subjects who are able to provide written informed consent and to comply with study procedures.
3. Clinical history compatible with Type 1 diabetes (onset < 40 yrs old and insulin dependent for > 5 yrs at enrollment, c-peptide negative).
4. Recipients should have absent stimulated c-peptide (< 0.3 ng/mL) in response to a (Boost® 6 mL/kg BW to a maximum of 360 mL; another equivalent product), measured at 60 and 90 min after start of consumption.
5. Subjects who are > 6 months post-renal transplant or >6 months post-liver transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic ± Prednisone ≤ 10 mg/day).
6. Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 6 previous months prior to islet transplant, as well as absence of a rejection episode in the 6 months prior to islet transplant
7. Stable liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values < 1.5, or total bilirubin < 1.5 times normal upper limits at time of study entry, as well as absence of a rejection episode in the 6 months prior to islet transplant

Exclusion Criteria:

1. Presence of donor specific anti-HLA antibodies detected by Luminex Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross match
2. Insulin requirement of >1.0 IU/kg/day
3. Weight more than 100 kg or body mass index (BMI) > 30 kg/m2.
4. Primary hyperparathyroidism OR secondary hyperparathyroidism
5. Untreated or unstable proliferative diabetic retinopathy.
6. Blood Pressure: SBP > 180 mmHg or DBP >100 mmHg despite treatment with antihypertensive agents.
7. Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation, as well as presence of a rejection episode in the 6 months prior to islet transplant
8. Elevated liver function tests as defined by: SGOT (AST), SGPT (ALT), alkaline phosphatase values > 1.5, or total bilirubin >1.5 times normal upper limits at time of study entry, as well as presence of a rejection episode in the 6 months prior to islet transplant
9. Proteinuria (albumin/creatinine ratio or ACr > 300mg/g) of new onset since kidney transplantation.
10. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo- Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
11. Active infection including hepatitis B, hepatitis C, HIV, or TB. Quantiferon gold assay will be used to determine TB infection.
12. Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within 1 year prior to study entry.
13. Any history of malignancy following receiving either the kidney or liver transplant, except for completely resected squamous or basal cell carcinoma of the skin
14. Known active alcohol or substance abuse.

15. Severe co-existing cardiac disease, characterized by any one of these conditions:

    1. Recent MI (within past 6 months),
    2. Evidence of ischemia on functional cardiac exam within the last year,
    3. Left ventricular ejection fraction < 30%,
    4. Valvular disease requiring replacement with prosthetic valve.
16. Active infections (except mild skin and nail fungal infections).
17. Active peptic ulcer disease or gastritis, symptomatic gallstones, or portal hypertension.
18. Use of any investigational agents within 4 weeks of enrollment.
19. Administration of live attenuated vaccine(s) within 2 months of enrollment.
20. Any medical condition that, in the opinion of the investigator, will interfere with safe study completion.
21. Positive screen for BK viremia at time of screening.
22. Untreated hyperlipidemia - TC > 200 mg/dL, TGC > 200 mg/dL, LDL > 130 mg/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PTG with adult pancreatic islet co-transplantation; 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	Combination product: Co-transplantation of PTG with pancreatic islets; Co-transplantation of allogeneic parathyroid glands (PTG) with adult pancreatic islets (both PTG and pancreatic islets obtained from same deceased donor) in people with Type 1 diabetes in the intramuscular (IM) site with stable function of liver or kidney allografts on chronic immunosuppression

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.	Minimum of 1 year up to 2 years depending on transplant date
Incidence of post-transplant infections and malignancies	Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.	Minimum of 1 year up to 2 years depending on transplant date
Incidence of de novo sensitization	Safety: Since this study is a pilot non-randomized safety and efficacy trial with patient enrollment limited by budgetary constraints, no direct statistical significance tests can be performed.	Minimum of 1 year up to 2 years depending on transplant date
Incidence of Insulin independence	Efficacy: Incidence of participants no longer using insulin	Minimum of 1 year up to 2 years depending on transplant date

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycemic control	Assessed by measuring HbA1c using high-performance liquid chromatography	Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2
Glycemic lability	Assessed with the Mean Amplitude of Glycemic Excursions (MAGE) test	Day 75, Day 180, Day 270, Year 1
Hypoglylcemic episodes: Clarke Survey Score	The Clarke survey will be used to assess the frequency and severity of hypoglycemic episodes	Day 75, Day 180, Day 270, Year 1
Hypoglylcemic episodes: Hypo Score	The HYPO score will be used to assess the frequency and severity of hypoglycemic episodes	Day 75, Day 180, Day 270, Year 1
Beta cell function as assessed by Mixed Meal Tolerance Test (MMTT)	Results from both MMTT and FSIGT will be used to assess beta cell function	Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2
Beta cell function as assessed by Insulin-Modified Frequently-Sampled Intravenous Glucose ToleranceTest (FSIGT)	Results from both MMTT and FSIGT will be used to assess beta cell function	Day 75, Day 180, Day 270, Year 1, Year 1.5, Year 2

Collaborators and Investigators

• Sponsor: Peter Stock
• Collaborators: California Institute for Regenerative Medicine (CIRM)
• Investigators: Principal Investigator: Peter Stock, MD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2019
• Primary Completion (Anticipated): September 30, 2024
• Study Completion (Anticipated): January 31, 2025

Study Registration Dates

• First Submitted: May 24, 2019
• First Submitted That Met QC Criteria: June 4, 2019
• First Posted (Actual): June 6, 2019

Study Record Updates

• Last Update Posted (Actual): May 17, 2023
• Last Update Submitted That Met QC Criteria: May 15, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: 18-26725

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No