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

Peter Stock

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Type 1 Diabetes

Treatments: Combination Product: Co-transplantation of PTG with pancreatic islets

Study type: Interventional

Funder types: Other

Identifiers

NCT03977662

18-26725

Details and patient eligibility

About

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.

Full 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.

Enrollment: 8 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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. Use of any investigational agents within 4 weeks of enrollment.

18. Administration of live attenuated vaccine(s) within 2 months of enrollment.

19. Any medical condition that, in the opinion of the investigator, will interfere with safe study completion.

20. Positive screen for BK viremia at time of screening.

21. Untreated hyperlipidemia - TC > 200 mg/dL, TGC > 200 mg/dL, LDL > 130 mg/dL

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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8 participants in 1 patient group

PTG with adult pancreatic islet co-transplantation

Experimental group

Description:

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

Treatment:

Combination Product: Co-transplantation of PTG with pancreatic islets