Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea

Article information

Diabetes Metab J. 2024;.dmj.2023.0260
Publication date (electronic) : 2024 May 21
doi : https://doi.org/10.4093/dmj.2023.0260
1Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
2Tascom, Co. Ltd., Anyang, Korea
3Department of Animal Health, Cheongju University College of Health and Medical Sciences, Cheongju, Korea
4Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea
5Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
6Department of Biomedical Sciences, Seoul National University, Seoul, Korea
7Department of Laboratory Medicine, College of Medicine, Hallym University, Anyang, Korea
8Department of Medical Education, Ewha Womans University College of Medicine, Seoul, Korea
9GenNBio Inc., Seongnam, Korea
Corresponding author: Kwang-Won Kim https://orcid.org/0000-0003-1046-117X Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea E-mail: kwkim@gilhospital.com
*Byung-Joon Kim and Jun-Seop Shin contributed equally to this study as first authors.
Received 2023 August 7; Accepted 2024 January 17.

Abstract

Background

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.

GRAPHICAL ABSTRACT

Highlights

• Porcine islets are seen as a viable alternative to human pancreatic islets for type 1 diabetes.

• Porcine islets survive long-term in non-human primates without zoonosis risks.

• An open-label trial will assess safety and efficacy of porcine islet transplantation in type 1 diabetes.

• Two individuals with poor glycemic control despite intensive insulin will be enrolled.

• The primary goal is porcine islet safety, with a secondary aim to reduce insulin doses and hypoglycemic unawareness.

INTRODUCTION

Diabetes mellitus is a metabolic disorder causing hyperglycemia, resulting from insufficient insulin secretion (type 1 diabetes mellitus) or insulin resistance (type 2 diabetes mellitus) [1]. Patients with type 1 diabetes mellitus facing absolute insulin deficiency, often necessitate insulin treatment, yet some encounter hypoglycemic episodes despite advanced insulin therapy [2]. Islet transplantation, emerging with the Edmonton Protocol in 2000, serves as a viable option for such cases [3]. However, prolonged use of immunosuppressive drugs to prevent rejection and the limited availability of donor pancreases pose significant challenges. To mitigate organ shortages, xenotransplantation, especially using pigs, has been extensively explored for decades [4]. In collaboration with the World Health Organization, The International Xenotransplantation Association (IXA) issued guidelines in 2009 for safe clinical trials of porcine islets, titled “The International Xenotransplantation Association consensus statement on the conditions for undertaking clinical trials of porcine islet products in type 1 diabetes” [5]. A key impediment to the clinical application of porcine islet xenotransplantation is the difficulty in meeting success criteria in non-human primate (NHP) preclinical studies. The 2016 update of the IXA guidelines specifies prerequisites for NHP studies, including maintaining fasting blood glucose levels of <150 mg/dL and non-fasting levels of <200 mg/dL without exogenous insulin or with significantly reduced insulin requirements in at least four out of six consecutive NHPs post-porcine islet transplantation. Follow-up should span a minimum of 6 months in all cases, ideally extending to 12 months in one or two successful cases [6].

Several research groups have reported varying porcine islet graft survival in NHP studies [7,8]. In 2015, our group demonstrated the first proof-of-concept by curing diabetes in five diabetic NHPs through the transplantation of porcine islets, utilizing an immunosuppressive drug (anti-CD154 monoclonal antibody) deemed clinically inapplicable [9]. Subsequently, we presented comparable yet less robust data with a potentially clinically applicable drug, an anti-CD40 monoclonal antibody [10]. Lastly, we reported the maintenance of glycemic control within normal ranges in four out of five diabetic NHPs with significantly reduced exogenous insulin, achieved through a clinically applicable immunosuppressive regimen [11]. Based on these preclinical results in NHPs, we standardized various procedures, including source pig validation, islet product manufacturing, and regulatory frameworks. This groundwork laid the foundation for the development of a relevant clinical trial protocol. Consequently, this study outlines a comprehensive protocol for the inaugural porcine islet xenotransplantation clinical trial. The trial targets patients experiencing labile glycemic control and hypoglycemic unawareness, aligning with IXA guidelines.

METHODS

Overall study design

A clinical trial, titled “A single-center, open-label, sponsor-initiated clinical trial to assess the safety and efficacy of porcine islet transplantation on diabetes patients (Institutional Review Board [IRB] no. GCIRB2023-031),” has received approval. The study flowchart and key considerations at each stage are depicted in Fig. 1. Gachon Hospital will enroll two patients experiencing recurrent hypoglycemic unawareness and brittle diabetes, who will undergo porcine islet xenotransplantation through the portal vein. The administration of commercially available immunosuppressants will follow the prescribed program schedule. Patients will attend regular outpatient clinic visits at Gachon Hospital for postoperative monitoring and blood sampling for a duration of up to 2 years. Monitoring of the patient’s family members, primarily spouses or sexual partners, will also be conducted to investigate the potential occurrence of xenozoonosis. The comprehensive study outline is illustrated in Fig. 2.

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.

Study objectives

The primary aim of this trial will be to evaluate the safety of porcine islet xenotransplantation in patients. This will involve monitoring adverse effects (AEs) and changes in vital signs and laboratory tests throughout the clinical trial period. The secondary objective will be to validate the clinical efficacy of porcine islet xenotransplantation by assessing exogenous insulin injection doses and quantifying the frequency of hypoglycemic unawareness.

Study participants, screening, and informed consent

In this single-center clinical trial, two participants will enroll. The explorative nature of xenotransplantation and the potential for xenozoonosis, such as porcine endogenous retrovirus (PERV) reactivation, has led to a limited number of participants approved during the Investigational New Drug (IND) approval process. The screening period, commencing 6 months before transplantation, aims to identify suitable candidates. Public advertisements and outpatient clinic outreach at the Gachon Intensive Diabetes Care Clinic will be utilized to recruit as many potential diabetic patients as possible. However, only those precisely meeting the inclusion and exclusion criteria will be selected (Table 1). Throughout the screening period, selected patients will undergo a deliberation period. They will be equipped with a continuous glucose monitoring (CGM) system and administered multiple doses of insulin or insulin pump. Comprehensive education will be provided on the objectives of this study, adherence to the program schedule, and the potential benefits and risks of porcine islet xenotransplantation. Notably, patients will have two opportunities to consult with a psychiatrist before providing informed consent, and they retain the freedom to withdraw from the study at any time. In addition to informing patients, their family members will receive information about the purpose of this study, the transplantation procedure, potential benefits and risks of porcine islet xenotransplantation, and their responsibilities. This includes attending continuous monitoring and blood sampling sessions.

Inclusion and exclusion criteria

Preparation of porcine islets and transplantation

The fundamental surgical, islet isolation, and portal vein transplantation techniques for this study mirror those employed in islet allotransplantation. Preceding transplantation, porcine islets sourced from designated pathogen-free (DPF)-free pigs will undergo isolation, commencing 6 days prior to the procedure, continuing until the total islet count (10,000 islet equivalent/kg of the patient body weight) is achieved. Pancreases will be harvested from DPF-free adult pigs aged over 2 years and transported to the good manufacturing practices (GMP)-compliant islet isolation room at Gachon Hospital. The GMP-compliant collagenase-based Ricord’s method will be employed for the isolation of porcine islets. The isolated porcine islets will undergo scrutiny to ensure compliance with rapid islet product release criteria, including Gram-negative status, mycoplasma-free composition, and a low level of endotoxin (<5 mEU/mL). The collected islets will be resuspended in normal saline and subsequently infused into the portal vein of the patient via percutaneous transhepatic approach by a radiologist. A comprehensive report detailing the islet release criteria will be compiled post-transplantation.

Immunosuppression regimen

In this study, we will administer commercially available immunosuppressive agents, building upon a basic regimen derived from the human islet transplantation setting. To manage robust immune responses in the xenotransplantation context, a subset of agents will be introduced alongside the foundational regimen. The initial patient will undergo transplantation with porcine islets utilizing a conventional immunosuppression approach, featuring anti-thymoglobulin induction and cytokine blockers such as tumor necrosis factor-α (humira) and interleukin 1β (anakinra). Maintenance drugs will include sirolimus and tacrolimus. Subsequently, the second patient will receive porcine islets using the same immunosuppression regimen. However, enhancements will include the incorporation of the B cell-depleting antibody, belimumab, and the substitution of tacrolimus with tofacitinib starting 4 weeks post-transplantation (Fig. 3). The rationale behind the immunosuppressive regimen is to initially expose the first patient to a relatively low-risk immunosuppression, followed by the second patient with an add-on strategy incorporating calcineurin inhibitor-sparing and B-cell depleting effects. These regimens have demonstrated efficacy in previous NHP studies without any observed serious AEs [11].

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.

Infection prophylaxis

In this study, scheduled potent systemic immunosuppression necessitates meticulous infection prophylaxis, akin to protocols routinely employed in human solid organ transplantations like kidney transplantation. Alongside systemic antibiotic prophylaxis, we will administer disease-specific regimens targeting cytomegalovirus infection and pneumocystis pneumonia.

Visits, test, data collection, and data analysis

The patient will undergo continuous monitoring through physical activity assessments, laboratory tests, chest X-rays, and abdominal ultrasound examinations. Discharge from the hospital is anticipated 6 days post-transplantation. Throughout the 2-year follow-up period, the patient will undergo a total of 13 routine visits (Supplementary Tables 1 and 2). To proactively guard against potential xenozoonotic diseases, including PERV, blood samples will be systematically collected from the patient on 13 occasions and from close contact individuals thrice. These samples will be securely archived at Gachon Hospital for a span of 2 years and subsequently transferred to a government institute as mandated by the new law, with archival preservation extending up to 30 years.

Primary endpoint (safety)

To assess the safety of porcine islet xenotransplantation, AEs and significant changes in vital signs and laboratory test results will be systematically monitored and documented for up to 2 years post-transplantation. Case report forms (CRFs) will capture symptoms, initial manifestation and resolution dates, severity, causality of procedures or drugs, treatments, and consequences of all AEs. An adverse drug reaction refers to any deleterious and unintended responses caused by drugs at any dose during the clinical trial, where a causative relationship can be established. An AE will be classified as “serious” (serious adverse event [SAE]) if it leads to outcomes such as death, a life-threatening event, initial hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or disability in daily life functions, a congenital anomaly/birth defect, or clinically significant conditions such as drug dependence/abuse and hematologic disorder. All SAEs will be promptly reported to the IRB in accordance with Gachon Hospital regulations. The severity of AEs will be assessed following the common terminology criteria for AEs version 4.03 by the National Cancer Institute, categorized as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening consequences), and grade 5 (death). Any AE potentially linked to xenozoonosis will be considered an SAE, regardless of its severity.

Secondary endpoint (efficacy)

To assess the efficacy of porcine islet xenotransplantation, we will monitor and record daily blood glucose levels, exogenous insulin dosage, frequency of hypoglycemic unawareness, and porcine C-peptide in serum on CRFs. Graft rejection will be determined by the absence of porcine C-peptide in serum and a return to the same or higher concentration of glycosylated hemoglobin as observed pre-transplantation.

Statistical analysis

As this study will enroll only two participants, a comprehensive description—instead of detailed statistical analyses—will be provided for the demographic data and evaluation variables related to the safety and efficacy of porcine islet xenotransplantation for each participant.

DISCUSSION

This article presents a clinical trial protocol for treating diabetes in patients through porcine islet xenotransplantation. The protocol has recently gained approval from the Korean Ministry of Food and Drug Safety (MFDS). The approval was driven by the establishment of a robust regulatory framework, successful fulfillment of preclinical criteria outlined by IXA, and the accumulation of valuable prior clinical experience.

In 2020, the Korean National Assembly sanctioned “The act on the safety and support for advanced regenerative medicine and advanced biopharmaceuticals” [12]. This legislative approval sets the stage for advancing the clinical application of porcine islet xenotransplantation in the treatment of diabetes. Approval for the trial was officially granted on December 5, 2022, following an exhaustive 30-month review. Throughout this review, the MFDS meticulously assessed documents across eight key points: (1) ensuring the validity of data obtained from NHPs in a non-good laboratory practices setting; (2) addressing concerns about zoonosis; (3) evaluating the potential for ectopic distribution of transplanted porcine islets beyond the liver; (4) assessing the risk of tumorigenicity; (5) scrutinizing the source pigs; (6) examining the use of immunosuppressants and their dose reduction strategy; (7) refining patient selection and inclusion/exclusion criteria; and (8) investigating the potential transmission of unknown pathogen(s) within the hospital. Of these concerns, confirming the DPF status of the donor pig herd emerged as the most significant and challenging. A comprehensive analysis identified a total of 146 potential pig pathogens. Various analytical methods, including real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and whole blood culture, were employed to detect these pathogens (Supplementary Table 3). The donor pig herds underwent testing, confirming the absence of 40 different types of bacteria, six fungi, 27 parasites, and 73 viruses—all yielding negative results. Particularly crucial is the confirmation of the absence of porcine cytomegalovirus (PCMV), porcine lymphotropic herpesvirus types 1 and 2 (PLHV-1 and -2), and PERV. This becomes especially pertinent in light of recent findings suggesting a potential association between PCMV reactivation and early graft failure in pig heart transplantation in human patients [13].

Previous clinical trials involving encapsulated or naked porcine islet transplantation in diabetic patients have mitigated certain risks associated with xenotransplantation and have partially confirmed the safety of porcine islets (Supplementary Table 4) [8].

As porcine islet xenotransplantation has not yet been undertaken in Korea and considering the current uncertainty regarding xenozoonosis, including PERV activation, only two patients will be included in the study. The limited number of participants precludes statistical analyses and definitive scientific assessments of the benefits and risks associated with porcine islet transplantation and the safety of porcine islet xenotransplantation. However, the primary endpoint of the study will be achieved. Furthermore, a 2-year follow-up will provide ample data for in-depth analyses of porcine islet functionality.

The ethical considerations of this clinical trial will undergo thorough evaluation. Recent advancements in glycemic control, facilitated by CGM and automatic injections of various insulin formulations, will enhance the potential for numerous diabetic patients to manage their glycemia within acceptable ranges [14]. This technical progress is anticipated to benefit highly motivated and relatively young patients with diabetes, though it will not prevent various complications [15]. Islet transplantation is poised to offer optimal physiological insulin, counter-regulatory hormone, and glucagon production, thereby mitigating the progression of diabetic complications [16]. Strict benefit and risk analyses, meticulous patient selection, and a comprehensive follow-up schedule will be essential to outweigh the potential risks associated with porcine islet transplantation. In summary, the clinical trial on porcine islet xenotransplantation is expected to make a significant contribution to scientific history and instill hope in many patients with diabetes.

SUPPLEMENTARY MATERIALS

Supplementary materials related to this article can be found online at https://doi.org/10.4093/dmj.2023.0260.

Supplementary Table 1.

Clinical study schedule: from participation in the clinical study to hospital admission

dmj-2023-0260-Supplementary-Table-1.pdf
Supplementary Table 2.

Clinical study schedule: follow-up from 1 week after discharge

dmj-2023-0260-Supplementary-Table-2.pdf
Supplementary Table 3.

Designated-pathogen-free list

dmj-2023-0260-Supplementary-Table-3.pdf
Supplementary Table 4.

Clinical experiences of porcine islet xenotransplantation [8]

dmj-2023-0260-Supplementary-Table-4.pdf

Notes

CONFLICTS OF INTEREST

The authors from Tascom, Co. Ltd. and GenNBio have no conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception or design: B.J.K., J.S.S., C.G.P., S.J.K., K.W.K.

Acquisition, analysis or interpretation of data: all authors.

Drafting the work or revisiting: B.J.K., J.S.S.

Final approval of the manuscript: B.J.K., J.S.S., K.W.K.

FUNDING

This work was supported by a grant from the Korea Healthcare Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry for Health and Welfare, Republic of Korea (Grant No. HI13C0954).

Acknowledgements

We are grateful to the members of the Ethics Committees of IXA and TTS, Drs. Richard N. Pierson, Emanuele Cozzi, Francesco L. Ierino, Wayne Paris, Rita Bottino, Mariachiara Tallacchini, and Ian Dittmer. We extend special thanks to Dr. Richard N. Pierson for his outstanding leadership and hard work. We also thank Drs. Sang Il Kim, Ik Jin Yun, and Myoung-Joon Kim for their valuable participation in the on-site review of the clinical protocols.

References

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37 Suppl 1:S81–90.
2. The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the diabetes control and complications trial. Diabetes 1997;46:271–86.
3. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–8.
4. Ekser B, Ezzelarab M, Hara H, van der Windt DJ, Wijkstrom M, Bottino R, et al. Clinical xenotransplantation: the next medical revolution? Lancet 2012;379:672–83.
5. Hering BJ, Cooper DK, Cozzi E, Schuurman HJ, Korbutt GS, Denner J, et al. The International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes: executive summary. Xenotransplantation 2009;16:196–202.
6. Hering BJ, Cozzi E, Spizzo T, Cowan PJ, Rayat GR, Cooper DK, et al. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes: executive summary. Xenotransplantation 2016;23:3–13.
7. Coe TM, Markmann JF, Rickert CG. Current status of porcine islet xenotransplantation. Curr Opin Organ Transplant 2020;25:449–56.
8. Matsumoto S, Tomiya M, Sawamoto O. Current status and future of clinical islet xenotransplantation. J Diabetes 2016;8:483–93.
9. Shin JS, Kim JM, Kim JS, Min BH, Kim YH, Kim HJ, et al. Longterm control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. Am J Transplant 2015;15:2837–50.
10. Shin JS, Kim JM, Min BH, Yoon IH, Kim HJ, Kim JS, et al. Preclinical results in pig-to-non-human primate islet xenotransplantation using anti-CD40 antibody (2C10R4)-based immunosuppression. Xenotransplantation 2018;25e12356.
11. Kim JM, Hong SH, Chung H, Shin JS, Min BH, Kim HJ, et al. Long-term porcine islet graft survival in diabetic non-human primates treated with clinically available immunosuppressants. Xenotransplantation 2021;28e12659.
12. Ministry of Food and Drug Safety. Major content of lower statute of “Act on the safety of and support for advanced regenerative medicine and advanced biopharmaceuticals.” Available from: https://www.mfds.go.kr/eng/brd/m_75/view.do?seq=18&srchFr=&srchTo=&srchWord=&srchTp=&itm_seq_1=0&itm_seq_2=0&multi_itm_seq=0&company_cd=&company_nm=&page=1 (cited 2024 Feb 29).
13. Cooper DK, Yamamoto T, Hara H, Pierson RN 3rd. The first clinical pig heart transplant: was IVIg or pig cytomegalovirus detrimental to the outcome? Xenotransplantation 2022;29e12771.
14. Yoo JH, Kim JH. Advances in continuous glucose monitoring and integrated devices for management of diabetes with insulin-based therapy: improvement in glycemic control. Diabetes Metab J 2023;47:27–41.
15. Berget C, Messer LH, Forlenza GP. A clinical overview of insulin pump therapy for the management of diabetes: past, present, and future of intensive therapy. Diabetes Spectr 2019;32:194–204.
16. Fiorina P, Folli F, Maffi P, Placidi C, Venturini M, Finzi G, et al. Islet transplantation improves vascular diabetic complications in patients with diabetes who underwent kidney transplantation: a comparison between kidney-pancreas and kidney-alone transplantation. Transplantation 2003;75:1296–301.

Article information Continued

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.

Table 1.

Inclusion and exclusion criteria

Inclusion criteria:
 All of the following criteria must be met
  1. Patients who understand research sufficiently and have voluntarily consented to participate in the study
  2. Patients who are at least 19 years old
  3. Patients diagnosed with type 1 diabetes and have had diabetes for at least 5 years
  4. Patients who have a stimulated C-peptide less than 0.3 ng/mL in oral glucose tolerance test or glucagon stimulation test
  5. Patients who have been hospitalized at least twice a year due to unconsciousness caused by hypoglycemia without premonitory symptoms (blood glucose <54 mg/dL) or have visited the emergency room at least twice a year for the same reason
  6. Patients who meet at least one of the following criteria:
   (1) Patients with significant glycemic variability, characterized by repeated severe hyperglycemia and hypoglycemia: Patients whose lability index (LI) calculated by self-measured blood glucose within 6 months before screening is 90th percentile (625 mmol/L, 2 hr/week) or higher or whose MAGE (mean amplitude of glycemic excursions) on continuous glucose monitoring is 90th percentile (236) or higher
   (2) Patients whose daily life is severely affected by symptomatic hypoglycemia that requires emergency room visits or assistance from others: Patients whose Hypo score within 6 months before screening is 90th percentile (351) or higher or whose low blood glucose index (LBGI) on continuous glucose monitoring is 90th percentile (5.2) or higher
Exclusion criteria:
 Any subject who meets any of the following criteria is not eligible to participate in this study
  1. Insulin requirement >1.0 IU/kg/day
  2. Body mass index (BMI) >30 kg/m2
  3. Untreated proliferative diabetic retinopathy
  4. Currently receiving immunosuppressive therapy due to organ transplantation
  5. Renal dysfunction below CKD3b (eGFR [CKD-EPI] <30 mL/min/1.73 m2)
  6. Hypersensitivity to the immunosuppressive agents used concomitantly or their constituents
  7. Smoking, alcohol or drug abuse within the last 6 months, as determined by the investigator
  8. A history of the following comorbidities or the use of the following medications:
   (1) Chronic infectious diseases such as human immunodeficiency virus (HIV), human T-cell lymphotrophic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV), tuberculosis (TB), etc.
   (2) Lymphoproliferative disorders such as lymphoma or leukemia associated with Epstein-Barr virus (EBV)
   (3) Invasive aspergillosis, histoplasmosis, or coccidioidomycosis within 1 year prior to screening
   (4) Recurrent herpes zoster twice or more, or disseminated herpes zoster
   (5) AST or ALT levels exceeding three times the upper limit of normal on a hematological test
   (6) Evidence of moderate to severe hepatobiliary disease (hepatitis, portal hypertension, tumor, biliary abnormality, etc.) confirmed by abdominal ultrasound or liver cirrhosis on imaging tests
   (7) A history of any malignant tumor within the last 5 years
   (8) Severe or end-stage heart failure patients (NYHA class III/IV)
   (9) Uncontrolled cardiovascular disease (patients who have undergone intervention for myocardial infarction or angina within the last 6 months)
   (10) Patients with gastric ulcers (patients who have been diagnosed with ulcers by endoscopy and are being treated within the last month)
   (11) Patients who are at risk of QT prolongation (congenital or acquired QT prolongation) or those who are taking drugs known to increase the exposure of tacrolimus or to prolong the QT interval
   (12) Patients with an absolute neutrophil count <1,000 cell/mm3, absolute lymphocyte count <500 cell/mm3, or hemoglobin <9 g/dL
   (13) Patients with venous thrombosis or thromboembolism, active venous thromboembolism (deep vein thrombosis, pulmonary embolism), or a history of these conditions
   (14) Patients receiving cyclosporine or bosentan
   (15) Patients receiving potassium-preserving diuretics
   (16) Patients taking strong inhibitors of CYP3A4 and/or P-gp (telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin, etc.) or strong inducers of CYP3A4 and/or P-gp (rifampin, rifabutin, etc.), except when antiviral, antibacterial, or antituberculosis agents are required due to the use of immunosuppressants after transplantation
  9. Patients with a history of genetic disorders such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
  10. Female patients who are pregnant, breastfeeding, planning to become pregnant, or unwilling to agree to appropriate contraceptiona during the study period
  11. Participants who have received study drugs or medical devices as study subjects in other studies within the past 12 weeks (however, they may be registered at the clinical discretion of the investigator)
  12. Participants who are judged by a psychiatrist as unsuitable for this study due to serious medical conditions that can reduce compliance with the study or mental disorder

CKD3b, chronic kidney disease 3b; eGFR, estimated glomerular filtration rate; CKD-EPI, chronic kidney disease epidemiology collaboration; AST, alanine aminotransferase; ALT, aspartate aminotransferase; NYHA, New York Heart Association; CYP3A4, cytochrome P450 3A4; P-gp, P-glycoprotein.

a

Hormonal contraceptives, intrauterine devices or systems, double barrier methods (spermicidal agents with condoms and contraceptive vaginal diaphragms, vaginal sponges, or cervical caps), infertility procedures (tubal ligation, bilateral oophorectomy, etc.).