Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea

Abstract

Backgruound: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans.

Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness.

Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

Keywords: Clinical trial; Diabetes mellitus; Islets of Langerhans; Swine; Transplantation.

Fig. 1.

Overall flowchart of the clinical trial of porcine islet xenotransplantation. Pancreatic islets will be isolated from designated pathogen-free (DPF)-grade Seoul National University (SNU) miniature pigs and transplanted into the portal vein of each patient’s liver. The major points raised by the Korean Ministry of Food and Drug Safety during the review process were broadly categorized into the source of pigs and the definition of DPF status, islet product release criteria, concerns about zoonosis, the use of immunosuppressants, patient selection and inclusion/exclusion criteria, and the sample archive. GMP, good manufacturing practices.

Fig. 2.

Design of the clinical trial of porcine islet xenotransplantation. Patients will be recruited and selected 6 months before the start of the clinical study. During the 6-month-long intensive deliberation period, patients will be monitored using a continuous glucose monitoring system (CGMS) and multiple doses of insulin or insulin pumps. After consulting a psychiatrist, they will have two deliberation opportunities before providing informed consent. F/U, follow-up; W/U, work-up.

Fig. 3.

Immunosuppression regimen. The first patient will be transplanted with porcine islets using a conventional immunosuppression regimen composed of anti-thymoglobulin induction and cytokine blockers such as tumor necrosis factor-α and interleukin 1β, with sirolimus and tacrolimus as maintenance drugs. The second patient will be transplanted using the above immunosuppression regimen plus B cell-depleting antibody, belimumab, and tacrolimus will be replaced with tofacitinib 4 weeks after transplantation. ATG, anti-thymoglobulin; IV, intravenous; PO, per os (by mouth); DO, day 0; BID, bis in die (twice a day); SQ, subcutaneous.