Trial Outcomes & Findings for Reparixin in Pancreatic Islet Transplantation (NCT NCT01220856)

NCT ID: NCT01220856

Last Updated: 2021-03-11

Results Overview

Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: * HbA1c level of less than 7%; * glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period); * glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 9 participants
• Primary outcome timeframe: day 75 +/- 5 post-transplant
• Results posted on: 2021-03-11

Participant Flow

A total of 9 patients were enrolled into the study; 6 were randomized to reparixin and 3 to the control group. All in the control group and 2 in the reparixin group were withdrawn after Transplant 1 due to graft loss. 4 in the reparixin group received Transplant 2. Thereafter, 1 was withdrawn due to graft loss. 1 was lost to follow-up.

Participant milestones

Measure	Reparixin Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Overall Study STARTED	6	3
Overall Study COMPLETED	2	0
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Measure	Reparixin Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Overall Study graft loss	3	3
Overall Study Lost to Follow-up	1	0

Baseline Characteristics

Reparixin in Pancreatic Islet Transplantation

Baseline characteristics by cohort

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.	Total n=9 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	46.2 years STANDARD_DEVIATION 8.8 • n=5 Participants	48.0 years STANDARD_DEVIATION 7.0 • n=7 Participants	46.8 years STANDARD_DEVIATION 7.9 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment Italy	6 participants n=5 Participants	3 participants n=7 Participants	9 participants n=5 Participants

PRIMARY outcome

Timeframe: day 75 +/- 5 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:

• HbA1c level of less than 7%;
• glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
• glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5	0 percentage of patients	0 percentage of patients

OTHER_PRE_SPECIFIED outcome

Timeframe: up to one year after the transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:

• HbA1c level of less than 7%;
• glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
• glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant transplant 1	0 percentage of patients	0 percentage of patients
The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant transplant 2	50 percentage of patients	—

OTHER_PRE_SPECIFIED outcome

Timeframe: up to 1 year after transplant 2

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date.

Outcome measures

Measure	Reparixin n=3 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Time to Achieve Insulin-independence After the Transplant 2	66.3 days Standard Deviation 73.7	—

OTHER_PRE_SPECIFIED outcome

Timeframe: up to 1 year after transplant 2

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence.

Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.

Outcome measures

Measure	Reparixin n=2 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Total Time of Insulin Independence After the Transplant	276.0 total number of days Standard Deviation 96.2	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Daily insulin requirement was calculated as the average requirement over the previous week (seven days).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 1 (transplant 1)	-0.3 IU/kg/day Standard Deviation 0.3	0.1 IU/kg/day Standard Deviation 0.1
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 3 (transplant 1)	-0.3 IU/kg/day Standard Deviation 0.2	—
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 6 (transplant 1)	-0.2 IU/kg/day Standard Deviation 0.0	—
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 1 (transplant 2)	-0.6 IU/kg/day Standard Deviation 0.2	—
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 3 (transplant 2)	-0.6 IU/kg/day Standard Deviation 0.3	—
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 6 (transplant 2)	-0.5 IU/kg/day Standard Deviation 0.4	—
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 12 (transplant 2)	-0.7 IU/kg/day Standard Deviation 0.4	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Daily insulin requirement was calculated as the average requirement over the previous week (seven days).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 1 (transplant 1)	-41.9 Percentage change Standard Deviation 39.9	16.4 Percentage change Standard Deviation 20.2
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 3 (transplant 1)	-50.3 Percentage change Standard Deviation 24.4	—
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 6 (transplant 1)	-32.0 Percentage change Standard Deviation 8.9	—
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 1 (transplant 2)	-90.8 Percentage change Standard Deviation 11.3	—
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 3 (transplant 2)	-88.7 Percentage change Standard Deviation 17.8	—
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 6 (transplant 2)	-81.8 Percentage change Standard Deviation 36.5	—
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels Month 12 (transplant 2)	-100.0 Percentage change Standard Deviation 0.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

The absolute change between the time-point value and baseline value.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 1 (transplant 1)	-1.53 Percentage of Hb Standard Deviation 0.49	-0.87 Percentage of Hb Standard Deviation 0.40
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 3 (transplant 1)	-2.90 Percentage of Hb Standard Deviation 0.74	—
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 6 (transplant 1)	-1.87 Percentage of Hb Standard Deviation 0.60	—
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 1 (transplant 2)	-3.15 Percentage of Hb Standard Deviation 0.57	—
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 3 (transplant 2)	-3.10 Percentage of Hb Standard Deviation 0.76	—
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 6 (transplant 2)	-3.05 Percentage of Hb Standard Deviation 1.03	—
Absolute Change in Fasted HbA1c From Pre-transplant Levels Month 12 (transplant 2)	-3.65 Percentage of Hb Standard Deviation 0.92	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

The absolute percentage between the time-point value and baseline value.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 1 (transplant 1)	-16.7 Percentage change Standard Deviation 4.5	-11.2 Percentage change Standard Deviation 5.4
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 3 (transplant 1)	-30.3 Percentage change Standard Deviation 7.9	—
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 6 (transplant 1)	-19.7 Percentage change Standard Deviation 7.2	—
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 1 (transplant 2)	-32.8 Percentage change Standard Deviation 5.9	—
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 3 (transplant 2)	-32.2 Percentage change Standard Deviation 7.4	—
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 6 (transplant 2)	-31.6 Percentage change Standard Deviation 10.1	—
Percentage Change in Fasted HbA1c From Pre-transplant Levels Month 12 (transplant 2)	-37.4 Percentage change Standard Deviation 9.2	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness".

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 1 (transplant 1)	100 Percentage of patients	100 Percentage of patients
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 3 (transplant 1)	100 Percentage of patients	—
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 6 (transplant 1)	100 Percentage of patients	—
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 1 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 3 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 6 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness month 12 (transplant 2)	100 Percentage of patients	—

OTHER_PRE_SPECIFIED outcome

Timeframe: up to 1 year after transplant

Population: Safety Population: all patients who were randomized into the study.

Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant.

A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Number of Participants With Adverse Events by Severity and With Serious Adverse Events TEAE mild	5 participants	2 participants
Number of Participants With Adverse Events by Severity and With Serious Adverse Events TEAE moderate	6 participants	2 participants
Number of Participants With Adverse Events by Severity and With Serious Adverse Events TEAE severe	3 participants	1 participants
Number of Participants With Adverse Events by Severity and With Serious Adverse Events SAE	3 participants	1 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 12, last transplant	123.7 mg*hr/dL Standard Deviation 18.3	—
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1, transplant 1	318.9 mg*hr/dL Standard Deviation 155.1	308.3 mg*hr/dL Standard Deviation 105.4
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3, transplant 1	235.0 mg*hr/dL Standard Deviation 77.6	—
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6, transplant 1	277.2 mg*hr/dL Standard Deviation 59.9	—
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1, transplant 2	162.5 mg*hr/dL Standard Deviation 36.3	—
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3, transplant 2	171.2 mg*hr/dL Standard Deviation 58.1	—
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6, transplant 2	184.1 mg*hr/dL Standard Deviation 74.4	—

OTHER_PRE_SPECIFIED outcome

Timeframe: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1 (transplant 1)	0.951 mg*hr/dL Standard Deviation 0.875	0.200 mg*hr/dL Standard Deviation 0.000
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3 (transplant 1)	1.789 mg*hr/dL Standard Deviation 1.059	—
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6 (transplant 1)	1.426 mg*hr/dL Standard Deviation 1.114	—
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1 (transplant 2)	3.302 mg*hr/dL Standard Deviation 1.661	—
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3 (transplant 2)	2.488 mg*hr/dL Standard Deviation 2.038	—
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6 (transplant 2)	2.531 mg*hr/dL Standard Deviation 1.831	—
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 12 (last transplant)	4.042 mg*hr/dL Standard Deviation 1.683	—

OTHER_PRE_SPECIFIED outcome

Timeframe: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.

AUC was calculated using the trapezoidal rule.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1 (transplant 1)	19.08 μU*hr/mL Standard Deviation 15.72	7.58 μU*hr/mL Standard Deviation 2.91
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3 (transplant 1)	28.25 μU*hr/mL Standard Deviation 33.43	—
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6 (transplant 1)	13.41 μU*hr/mL Standard Deviation 7.81	—
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 1 (transplant 2)	20.99 μU*hr/mL Standard Deviation 11.89	—
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 3 (transplant 2)	22.85 μU*hr/mL Standard Deviation 23.07	—
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 6 (transplant 2)	19.97 μU*hr/mL Standard Deviation 16.40	—
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant Month 12 (transplant 2)	36.04 μU*hr/mL Standard Deviation 13.83	—

OTHER_PRE_SPECIFIED outcome

Timeframe: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated.

AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 Month 1 (transplant 1)	0.193 (mg*hr/dL)/IEQ/kg Standard Deviation 0.158	0.044 (mg*hr/dL)/IEQ/kg Standard Deviation 0.004
AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 Month 3 (transplant 1)	0.366 (mg*hr/dL)/IEQ/kg Standard Deviation 0.158	—
AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 Month 6 (transplant 1)	0.341 (mg*hr/dL)/IEQ/kg Standard Deviation 0.265	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
The Percentage of Patients Free of Severe Hypoglycaemic Events month 1 (transplant 1)	100 Percentage of patients	100 Percentage of patients
The Percentage of Patients Free of Severe Hypoglycaemic Events month 3 (transplant 1)	100 Percentage of patients	—
The Percentage of Patients Free of Severe Hypoglycaemic Events month 12 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Severe Hypoglycaemic Events month 6 (transplant 1)	100 Percentage of patients	—
The Percentage of Patients Free of Severe Hypoglycaemic Events month 1 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Severe Hypoglycaemic Events month 3 (transplant 2)	100 Percentage of patients	—
The Percentage of Patients Free of Severe Hypoglycaemic Events month 6 (transplant 2)	100 Percentage of patients	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Months 1, 3, 6, 12 post-transplant

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function.

Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Beta-cell Function as Assessed by Beta-score Month 1, transplant 1	1.83 score on a scale Standard Deviation 1.17	1.33 score on a scale Standard Deviation 1.53
Beta-cell Function as Assessed by Beta-score Month 3, transplant 1	3.75 score on a scale Standard Deviation 1.26	—
Beta-cell Function as Assessed by Beta-score Month 6, transplant 1	1.67 score on a scale Standard Deviation 1.53	—
Beta-cell Function as Assessed by Beta-score Month 1, transplant 2	5.25 score on a scale Standard Deviation 1.50	—
Beta-cell Function as Assessed by Beta-score Month 3, transplant 2	4.75 score on a scale Standard Deviation 1.89	—
Beta-cell Function as Assessed by Beta-score Month 6, transplant 2	4.75 score on a scale Standard Deviation 2.63	—
Beta-cell Function as Assessed by Beta-score Month 12, transplant 2	6.50 score on a scale Standard Deviation 0.71	—

OTHER_PRE_SPECIFIED outcome

Timeframe: At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2

Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 1 (transplant 1)	111.9 ratio Standard Deviation 64.1	13.6 ratio Standard Deviation 49.6
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 3 (transplant 1)	176.6 ratio Standard Deviation 105.0	—
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 6 (transplant 1)	121.1 ratio Standard Deviation 30.0	—
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 1 (transplant 2)	1.143 ratio Standard Deviation 0.278	—
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 3 (transplant 2)	1.133 ratio Standard Deviation 0.336	—
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 6 (transplant 2)	1.100 ratio Standard Deviation 0.407	—
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio Month 12 (transplant 2)	1.320 ratio Standard Deviation 0.212	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-transplant and at days 1-7 and months 1 and 3 post-transplant

Population: Safety population: all patients who were randomized into the study.

ALT is commonly measured clinically as part of liver function tests.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Serum Level of Alanine Amino Transferase (ALT) Pre-transplant 1	23.0 U/L Standard Deviation 9.0	28.7 U/L Standard Deviation 22.9
Serum Level of Alanine Amino Transferase (ALT) Day 1 post-transplant 1	27.5 U/L Standard Deviation 8.7	24.7 U/L Standard Deviation 18.6
Serum Level of Alanine Amino Transferase (ALT) Day 2 post-transplant 1	26.3 U/L Standard Deviation 9.3	36.3 U/L Standard Deviation 29.7
Serum Level of Alanine Amino Transferase (ALT) Day 3 post-transplant 1	29.7 U/L Standard Deviation 9.7	46.3 U/L Standard Deviation 34.9
Serum Level of Alanine Amino Transferase (ALT) Day 4 post-transplant 1	38.5 U/L Standard Deviation 9.0	64.7 U/L Standard Deviation 23.0
Serum Level of Alanine Amino Transferase (ALT) Day 5 post-transplant 1	63.7 U/L Standard Deviation 21.9	98.0 U/L Standard Deviation 33.2
Serum Level of Alanine Amino Transferase (ALT) Day 6 post-transplant 1	86.0 U/L Standard Deviation 34.0	108.3 U/L Standard Deviation 34.4
Serum Level of Alanine Amino Transferase (ALT) Day 7 post-transplant 1	114.6 U/L Standard Deviation 56.4	108.3 U/L Standard Deviation 45.7
Serum Level of Alanine Amino Transferase (ALT) Month 1 (transplant 1)	25.8 U/L Standard Deviation 7.7	29.7 U/L Standard Deviation 28.9
Serum Level of Alanine Amino Transferase (ALT) Month 3 (transplant 1)	25.0 U/L Standard Deviation 8.7	—
Serum Level of Alanine Amino Transferase (ALT) Pre-transplant 2	18.5 U/L Standard Deviation 7.9	—
Serum Level of Alanine Amino Transferase (ALT) Day 1 post-transplant 2	24.8 U/L Standard Deviation 10.8	—
Serum Level of Alanine Amino Transferase (ALT) Day 2 post-transplant 2	22.8 U/L Standard Deviation 9.3	—
Serum Level of Alanine Amino Transferase (ALT) Day 3 post-transplant 2	22.8 U/L Standard Deviation 7.5	—
Serum Level of Alanine Amino Transferase (ALT) Day 4 post-transplant 2	28.8 U/L Standard Deviation 10.8	—
Serum Level of Alanine Amino Transferase (ALT) Day 5 post-transplant 2	31.8 U/L Standard Deviation 11.7	—
Serum Level of Alanine Amino Transferase (ALT) Day 6 post-transplant 2	31.8 U/L Standard Deviation 13.0	—
Serum Level of Alanine Amino Transferase (ALT) Day 7 post-transplant 2	35.3 U/L Standard Deviation 12.1	—
Serum Level of Alanine Amino Transferase (ALT) Month 1 (transplant 2)	28.0 U/L Standard Deviation 12.5	—
Serum Level of Alanine Amino Transferase (ALT) Month 3 (transplant 2)	21.0 U/L Standard Deviation 3.6	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Pre-transplant and at days 1-7 and months 1 and 3 post-transplant

Population: Safety population: all patients who were randomized into the study.

AST is commonly measured clinically as part of liver function tests.

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Serum Level of Aspartate Amino Transferase (AST) Day 5 post-transplant 1	60.2 U/L Standard Deviation 28.7	74.3 U/L Standard Deviation 26.6
Serum Level of Aspartate Amino Transferase (AST) Pre-transplant 1	22.3 U/L Standard Deviation 14.6	20.0 U/L Standard Deviation 7.5
Serum Level of Aspartate Amino Transferase (AST) Day 1 post-transplant 1	30.5 U/L Standard Deviation 12.1	18.7 U/L Standard Deviation 7.4
Serum Level of Aspartate Amino Transferase (AST) Day 2 post-transplant 1	22.3 U/L Standard Deviation 9.2	27.3 U/L Standard Deviation 12.5
Serum Level of Aspartate Amino Transferase (AST) Day 3 post-transplant 1	24.7 U/L Standard Deviation 12.8	31.7 U/L Standard Deviation 13.4
Serum Level of Aspartate Amino Transferase (AST) Day 4 post-transplant 1	31.8 U/L Standard Deviation 9.3	49.0 U/L Standard Deviation 35.5
Serum Level of Aspartate Amino Transferase (AST) Day 6 post-transplant 1	64.2 U/L Standard Deviation 22.1	64.3 U/L Standard Deviation 29.4
Serum Level of Aspartate Amino Transferase (AST) Day 7 post-transplant 1	82.0 U/L Standard Deviation 43.4	55.0 U/L Standard Deviation 29.7
Serum Level of Aspartate Amino Transferase (AST) Month 1 (transplant 1)	15.5 U/L Standard Deviation 3.6	17.7 U/L Standard Deviation 10.0
Serum Level of Aspartate Amino Transferase (AST) Month 3 (transplant 1)	15.8 U/L Standard Deviation 5.0	—
Serum Level of Aspartate Amino Transferase (AST) Pre-transplant 2	17.0 U/L Standard Deviation 6.2	—
Serum Level of Aspartate Amino Transferase (AST) Day 1 post-transplant 2	33.0 U/L Standard Deviation 18.7	—
Serum Level of Aspartate Amino Transferase (AST) Day 2 post-transplant 2	21.0 U/L Standard Deviation 7.0	—
Serum Level of Aspartate Amino Transferase (AST) Day 3 post-transplant 2	21.5 U/L Standard Deviation 5.8	—
Serum Level of Aspartate Amino Transferase (AST) Day 4 post-transplant 2	26.8 U/L Standard Deviation 9.7	—
Serum Level of Aspartate Amino Transferase (AST) Day 5 post-transplant 2	28.5 U/L Standard Deviation 7.5	—
Serum Level of Aspartate Amino Transferase (AST) Day 6 post-transplant 2	23.0 U/L Standard Deviation 8.8	—
Serum Level of Aspartate Amino Transferase (AST) Day 7 post-transplant 2	25.3 U/L Standard Deviation 10.4	—
Serum Level of Aspartate Amino Transferase (AST) Month 1 (transplant 2)	17.3 U/L Standard Deviation 3.3	—
Serum Level of Aspartate Amino Transferase (AST) Month 3 (transplant 2)	13.7 U/L Standard Deviation 5.0	—

OTHER_PRE_SPECIFIED outcome

Timeframe: 6, 12, 24, 72, 120, and 168 hours post-transplant 1

Population: Safety population: all patients who were randomized into the study.

Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Change From Pre-transplant in Cytokine Levels - CXCL8 6 hours post-transplant	11.0 pg/mL Standard Deviation 14.4	22.1 pg/mL Standard Deviation 19.0
Change From Pre-transplant in Cytokine Levels - CXCL8 12 hours post-transplant	43.8 pg/mL Standard Deviation 45.5	32.9 pg/mL Standard Deviation 43.3
Change From Pre-transplant in Cytokine Levels - CXCL8 24 hours post-transplant	10.6 pg/mL Standard Deviation 21.8	11.3 pg/mL Standard Deviation 2.1
Change From Pre-transplant in Cytokine Levels - CXCL8 72 hours post-transplant	17.3 pg/mL Standard Deviation 12.0	2.6 pg/mL Standard Deviation 8.5
Change From Pre-transplant in Cytokine Levels - CXCL8 120 hours post-transplant	1.2 pg/mL Standard Deviation 8.0	-2.2 pg/mL Standard Deviation 5.4
Change From Pre-transplant in Cytokine Levels - CXCL8 168 hours post-transplant	-6.8 pg/mL Standard Deviation 5.0	-2.8 pg/mL Standard Deviation 1.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 6, 12, 24, 72, 120, and 168 hours post-transplant 1

Population: Safety population: all patients who were randomized into the study.

Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Change From Pre-transplant in Cytokine Levels - CXCL1 6 hours post-transplant	-12.5 pg/mL Standard Deviation 51.8	-31.9 pg/mL Standard Deviation 31.0
Change From Pre-transplant in Cytokine Levels - CXCL1 12 hours post-transplant	11.8 pg/mL Standard Deviation 72.4	-16.8 pg/mL Standard Deviation 16.2
Change From Pre-transplant in Cytokine Levels - CXCL1 24 hours post-transplant	1.4 pg/mL Standard Deviation 61.9	-65.6 pg/mL Standard Deviation 127.0
Change From Pre-transplant in Cytokine Levels - CXCL1 72 hours post-transplant	63.7 pg/mL Standard Deviation 40.7	-51.9 pg/mL Standard Deviation 157.7
Change From Pre-transplant in Cytokine Levels - CXCL1 120 hours post-transplant	8.7 pg/mL Standard Deviation 16.1	-60.2 pg/mL Standard Deviation 130.6
Change From Pre-transplant in Cytokine Levels - CXCL1 168 hours post-transplant	-10.7 pg/mL Standard Deviation 65.0	-16.3 pg/mL Standard Deviation 88.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 6, 12, 24, 72, 120, and 168 hours post-transplant 1

Population: Safety population: all patients who were randomized into the study.

Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

Outcome measures

Measure	Reparixin n=6 Participants Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 Participants Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Change From Pre-transplant in Cytokine Levels - IL-6 6 hours post-transplant	0.5 pg/mL Standard Deviation 4.0	12.1 pg/mL Standard Deviation 10.6
Change From Pre-transplant in Cytokine Levels - IL-6 12 hours post-transplant	15.5 pg/mL Standard Deviation 20.6	23.4 pg/mL Standard Deviation 27.9
Change From Pre-transplant in Cytokine Levels - IL-6 24 hours post-transplant	7.6 pg/mL Standard Deviation 10.7	2.3 pg/mL Standard Deviation 7.5
Change From Pre-transplant in Cytokine Levels - IL-6 72 hours post-transplant	16.3 pg/mL Standard Deviation 13.5	3.1 pg/mL Standard Deviation 13.3
Change From Pre-transplant in Cytokine Levels - IL-6 120 hours post-transplant	0.8 pg/mL Standard Deviation 5.2	-5.6 pg/mL Standard Deviation 14.1
Change From Pre-transplant in Cytokine Levels - IL-6 168 hours post-transplant	-2.6 pg/mL Standard Deviation 3.2	-5.5 pg/mL Standard Deviation 8.6

Adverse Events

Reparixin

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

No Experimental Intervention

Serious events: 1 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Measure	Reparixin n=6 participants at risk Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 participants at risk Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Blood and lymphatic system disorders Anemia	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Diarrhea	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Gastrointestinal hemorrhage	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Nausea	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Peritoneal hemorrhage	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Vomiting	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Injury, poisoning and procedural complications Drug administration error	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Metabolism and nutrition disorders Diabetic ketoacidosis	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Renal and urinary disorders Renal impairment	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Vascular disorders Hemorrhage	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).

Other adverse events

Measure	Reparixin n=6 participants at risk Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	No Experimental Intervention n=3 participants at risk Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Blood and lymphatic system disorders Anaemia	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Endocrine disorders Hypothyroidism	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Abdominal pain	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Diarrhoea	66.7% 4/6 • Number of events 5 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Nausea	83.3% 5/6 • Number of events 5 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Stomatitis	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Gastrointestinal disorders Vomiting	50.0% 3/6 • Number of events 3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
General disorders Infusion site pain	50.0% 3/6 • Number of events 3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
General disorders Oedema	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Hepatobiliary disorders Hepatic haemorrhage	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Investigations Blood bicarbonate decreased	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Investigations Blood creatinine increased	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Investigations Body temperature increased	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Investigations C-reactive protein increased	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Investigations Fibrin degradation product increased	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Metabolism and nutrition disorders Hypocalcaemia	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Metabolism and nutrition disorders Hypokalaemia	16.7% 1/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Nervous system disorders Headache	50.0% 3/6 • Number of events 3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Nervous system disorders Neuralgia	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Skin and subcutaneous tissue disorders Acne	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Skin and subcutaneous tissue disorders Erythema	66.7% 4/6 • Number of events 6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Skin and subcutaneous tissue disorders Rash	0.00% 0/6 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	33.3% 1/3 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Vascular disorders Hypertension	16.7% 1/6 • Number of events 1 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).
Vascular disorders Hypotension	33.3% 2/6 • Number of events 2 • Through study completion, till follow-up (up to 1 year after the second islet infusion).	0.00% 0/3 • Through study completion, till follow-up (up to 1 year after the second islet infusion).

Additional Information

Luisa Daffonchio, PhD

Dompé SpA

Phone: +39 583831

Email: daffonchio@dompe.it

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place