**4. Phase 3 trial of allogeneic islet transplantation**

#### **4.1 Islet alone transplantation**

In the United States, allogeneic islet cells are regulated by the FDA as a drug, and expected to be approved under the biological license [18]. In 2016, a licenseenabling multicenter phase 3 clinical trial was reported (**Table 1**) [27]. For this study, well-defined islet products were manufactured under Current Good Manufacturing Practices and Current Good Tissue Practices [30]. The collaborative

### *Allogeneic Islet Transplantation and Future DOI: http://dx.doi.org/10.5772/intechopen.111812*

islet transplantation (CIT) consortium created the protocol for manufacturing islet products. Under CIT protocol, 324 pancreata were processed, and 170 products (52.5%) met the product release criteria. Patients received 75 of 170 successfully manufactured islet products were transplanted. For immunosuppression, they used anti-thymocyte globulin and etanercept for induction for the first transplant, with basiliximab replacing anti-thymocyte globulin at subsequent transplant (**Table 2**). Sirolimus and low-dose tacrolimus were used for maintenance immunosuppression. Twenty-two patients received one transplantation, 25 patients received two transplantation and one patient received three transplantation. The primary endpoint was the achievement of HbA1c < 7% and freedom from severe hypoglycemic events from day 28 to day 365 after the first transplantation. The primary endpoint was successfully met by 87.5% of patients, and it was concluded that islet transplantation should be considered for patients with type 1 diabetic patients and impaired awareness of hypoglycemia in whom other less invasive current treatments have been ineffective in preventing severe hypoglycemic events.

In 2018, improved health-related quality of life in phase 3 islet transplantation in type 1 diabetes complicated by severe hypoglycemia was reported [31]. The Diabetes Distress Scale (DDS), the hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D) were applied before and after islet transplantation at days 75, 365, and 730. DDS measured emotional burden, physicianrelated distress, regimen-related distress, interpersonal distress, and total score. HFS measured hypoglycemic avoidance behavior, worry about hypoglycemia, and total score.

After transplantation, all items of both DDS and HFS significantly improved in every measure point. This indicated allogeneic islet transplantation can improve the QOL related to diabetes and hypoglycemia from day 75 to day 730.

SF-36 measured physical functioning scale, role physical scale, bodily pain scale, general health scale, vitality scale, social functioning scale, physical component summary (PSC), and mental component summary (MSC) (**Table 3**).



#### **Table 3.**

*Summary of SF 36 [31].*

After transplantation, at day 365 and 730, PCS was significantly improved, and at day 75, MCS was significantly improved. In each item, the physical functioning scale was significantly improved after transplantation at day 75 and 365, role physical scale, general health scale, and vitality scale, were significantly improved at all points, role emotional scale was significantly improved after transplantation at day 365. On the other hand, there was no significant change in the bodily pain scale, social functioning scale, and mental health scale.

EuroQoL measured health preference weight, usual activities, anxiety/depression, mobility, pain/discomfort, self-care, and a visual analog scale of overall health (VAS) (**Table 4**). EuroQoL demonstrated that after transplantation at 365 day VAS was significantly improved, and at 730 VAS and usual activities were significantly improved.



#### **Table 4.**

*Summary of EuroQOL [31].*

However, all other measurements had no significant improvements. Allogeneic islet transplantation dramatically improved hypoglycemia-related QOL.

#### **4.2 Islet after kidney transplantation**

In 2021, a phase 3 trial of human islets after kidney transplantation in type 1 diabetes was reported (**Table 1**) [19]. This was an open-label, single-arm study involving subjects with type 1 diabetes who had previously received kidney transplantation conducted at 10 centers in North America. The primary endpoint was achieving HbA1c level equal to or less than 6.5%, or reduction in HbA1c of at least 1 point from baseline to day 365, and freedom from severe hypoglycemic events from day 28 to day 365 after the initial islet transplant. For immunosuppression, induction immunosuppression consisted of rabbit anti-thymocyte globulin (ATG) and etanercept for the first transplant, with basiliximab replacing ATG for subsequent transplant and in a single case of suspected sensitivity to ATG (**Table 2**). The calcineurin-based maintenance immunosuppression regimen used for the renal transplant was continued after the islet transplant. Up to 10 mg of prednisone was allowed as part of maintenance immunosuppression.

Twenty-four patients who experienced kidney transplantation received allogeneic islet transplantation. Elven patients received single transplantation, 11 patients received two transplantations, and 2 patients received 3 transplantations. After islet transplantation at 365 days, 15 patients (62.5%) met primary endpoints. They also measured DDS and HFS before and after islet transplantation at day 75, 365, 730, and 1095. Both DDS and HFS demonstrated improved QOL after islet transplantation in type 1 diabetic patients who previously received kidney transplantation at all time points. This study also indicated that islet transplantation is effective treatment for patients with type 1 diabetes and unstable glucose control despite intensive insulin treatment, supporting the indication for islet transplantation in the post-renal transplant setting.

More general QOL was assessed with Euro QOL Visual Analog Scale (VAS). EuroQOL VAS from baseline to day 75, day 365, day 730, and day 1095 following islet transplantation were statistically analyzed. The P-values at day 75 were 0.1016 at day 75, 0.0002 at day 365, 0.0952 at day 730, and 0.0327 at day 1095.

In 2022, long-term outcomes with islet-alone transplantation and islet-after-kidney transplantation for type 1 diabetes in the clinical islet transplantation consortium were reported [32]. Islet alone (n = 48) and islet-after-kidney (n = 24) transplant recipients were followed up to 8 years after allogeneic islet transplantation. The primary endpoint is duration of sustained islet allograft function as determined by evidence from MMTT of c-peptide production at each anniversary of the final transplant. A c-peptide level greater than or equal to 0.3 ng/mL at 0, 60, or 90 minutes will be considered evidence of islet allograft function.

Among them, 26 islet patients and 8 patients for islet-after-kidney patients completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced graft failure, respectively.

### **5. Efforts to improve the efficacy of allogeneic islet transplantation**

Phase 3 clinical trial of allogeneic islet transplantation demonstrated the benefit of the islet transplantation, on the other hand, the success rate of production was 52.5%. Improving the success rate is critically important to utilize precious human donor pancreas.

Baylor Research Institute group demonstrated seven consecutive successful clinical islet isolations using the pancreatic ductal injection technique [33]. The average islet yield was 588,566 ± 64,319 islet equivalent (IEQ ), and 6 islet products were implanted into 3 type 1 diabetic patients. All three patients achieved insulin free. They demonstrated that ductal injection immediately after pancreas procurement could enhance the delivery of collagenase resulting in the high success rate of islet isolation [34]. The group also analyzed the 100 human islet isolation, then revealed that in addition to the ductal injection, pancreas procurement by the islet isolation team, two-layer pancreas preservation, and short cold ischemic period had a significant impact to improve the success rate of islet isolation [35]. Among them, the two-layer pancreas preservation was created by Dr. Takashi Kawamura and Dr. Yoshikazu Kuroda (**Figure 1**) [36]. The two-layer method consists of an organ preservation solution and perfluorocarbon. During the preservation by the two-layer method, oxygen is continuously supplied through the perfluorocarbon, and the pancreas can be oxygenized. This method provided the longest preservation period before whole pancreas transplantation using canine model [37] and high islet yield [38]. The first clinical trial of the two-layer preservation before pancreas transplantation and islet isolation was both conducted at the University of Minnesota [39, 40]. Oxygen charged two-layer method was developed to eliminate bringing an oxygen tank for continuous oxygenation [41]. The two-layer pancreas preservation was used for clinical islet transplantation using a non-heartbeating donor (**Table 1**) [17] and the first successful living donor islet transplantation (**Table 1**) [16].

Even improving the efficacy of islet transplantation is important, as long as donor source is human, it is not possible to treat all type 1 diabetic patients who need islet transplantation.

*Allogeneic Islet Transplantation and Future DOI: http://dx.doi.org/10.5772/intechopen.111812*

#### **Figure 1.**

*Two-layer preservation method consists of perfluorocarbon (PFC) and organ preservation solution (for example University of Wisconsin (UW) solution). PFC is unsolvable in the water therefore, PFC and organ preservation solution clearly created the two-layer. The procured pancreas locates between the PFC and organ preservation solution. Oxygen has been provided to PFC for the original two-layer method. For oxygen static charged two-layer method, before using the two-layer preservation method, PFC was fully oxygenated. Fully oxygenated PFC could reserve adequate oxygen concentration for up to 18 hours. During preservation by the two-layer method, pancreas has been oxygenated and maintained high energy status. The two-layer pancreas preservation enabled the longest preservation period before canine whole pancreas transplantation and improved islet yield after human islet isolation.*
