Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
Conditions
Keywords
Islet transplantation, Type 1 diabetes mellitus
Brief summary
Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).
Detailed description
Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.
Interventions
DRUGReparixin
Reparixin + immunosuppression
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Ages 18-65 years, inclusive. * Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for \>5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (\<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice. * Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) \> 60 mL/min according to the Cockcroft-Gault formula (1976). * Planned intrahepatic islet transplantation alone from a non-living donor with brain death. * Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight. * Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations. * Patients given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
Exclusion criteria
* Recipients of any previous transplant, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA. * Recipients of islet from a non-heart beating donor. * A body mass index \>30 kg/m2 or patient weight \<45 kg. * Pre-transplant average daily insulin requirement \>1 IU/kg/day. * Pre-transplant HbA1c \>11%. * Patients with hepatic dysfunction as defined by increased ALT/AST \> 3 x ULN and increased total bilirubin \> 3mg/dL \[\>51.3 micromol/L\]). * Patients who receive treatment for a medical condition requiring chronic use of systemic steroids. * Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant. * Use of any investigational agent within 4 weeks of enrolment. * Hypersensitivity to: * ibuprofen or to more than one non steroidal anti-inflammatory drug * medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib. * Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males). Sites will comply with any additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 | day 75 +/- 5 post-transplant | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Achieve Insulin-independence After the Transplant 2 | up to 1 year after transplant 2 | 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. |
| Total Time of Insulin Independence After the Transplant | up to 1 year after transplant 2 | 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. |
| Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Months 1, 3, 6, 12 post-transplant | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). |
| Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Months 1, 3, 6, 12 post-transplant | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). |
| Absolute Change in Fasted HbA1c From Pre-transplant Levels | Months 1, 3, 6, 12 post-transplant | The absolute change between the time-point value and baseline value. |
| Percentage Change in Fasted HbA1c From Pre-transplant Levels | Months 1, 3, 6, 12 post-transplant | The absolute percentage between the time-point value and baseline value. |
| The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | Months 1, 3, 6, 12 post-transplant | Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as hypoglycemia unawareness. |
| Number of Participants With Adverse Events by Severity and With Serious Adverse Events | up to 1 year after transplant | 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. |
| 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 | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant | 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. |
| 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 | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant | 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. |
| The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | up to one year after the transplant | 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). |
| 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 | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant | 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). |
| The Percentage of Patients Free of Severe Hypoglycaemic Events | Months 1, 3, 6, 12 post-transplant | 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. |
| Beta-cell Function as Assessed by Beta-score | Months 1, 3, 6, 12 post-transplant | 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. |
| Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2 | The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets. |
| Serum Level of Alanine Amino Transferase (ALT) | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant | ALT is commonly measured clinically as part of liver function tests. |
| Serum Level of Aspartate Amino Transferase (AST) | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant | AST is commonly measured clinically as part of liver function tests. |
| Change From Pre-transplant in Cytokine Levels - CXCL8 | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 | 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). |
| Change From Pre-transplant in Cytokine Levels - CXCL1 | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 | 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). |
| Change From Pre-transplant in Cytokine Levels - IL-6 | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 | 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). |
| 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 | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant | 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. |
Countries
Germany, Italy
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 immunosoppression regimen see the other arm description.
Reparixin: Reparixin + immunosuppression | 6 |
| 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. | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | graft loss | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | No Experimental Intervention | Reparixin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 6 Participants | 9 Participants |
| Age, Continuous | 48.0 years STANDARD_DEVIATION 7 | 46.2 years STANDARD_DEVIATION 8.8 | 46.8 years STANDARD_DEVIATION 7.9 |
| Region of Enrollment Italy | 3 participants | 6 participants | 9 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 6 / 6 | 3 / 3 |
| serious Total, serious adverse events | 3 / 6 | 1 / 3 |
Outcome results
Primary
The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5
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).
Time frame: day 75 +/- 5 post-transplant
Population: Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin | The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 | 0 percentage of patients |
| No Experimental Intervention | The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 | 0 percentage of patients |
Other Pre-specified
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 12 (transplant 2) | -0.7 IU/kg/day | Standard Deviation 0.4 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 1) | -0.3 IU/kg/day | Standard Deviation 0.3 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 3 (transplant 1) | -0.3 IU/kg/day | Standard Deviation 0.2 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 6 (transplant 1) | -0.2 IU/kg/day | Standard Deviation 0 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 2) | -0.6 IU/kg/day | Standard Deviation 0.2 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 3 (transplant 2) | -0.6 IU/kg/day | Standard Deviation 0.3 |
| Reparixin | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 6 (transplant 2) | -0.5 IU/kg/day | Standard Deviation 0.4 |
| No Experimental Intervention | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 1) | 0.1 IU/kg/day | Standard Deviation 0.1 |
Other Pre-specified
Absolute Change in Fasted HbA1c From Pre-transplant Levels
The absolute change between the time-point value and baseline value.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 12 (transplant 2) | -3.65 Percentage of Hb | Standard Deviation 0.92 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 1) | -1.53 Percentage of Hb | Standard Deviation 0.49 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 3 (transplant 1) | -2.90 Percentage of Hb | Standard Deviation 0.74 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 6 (transplant 1) | -1.87 Percentage of Hb | Standard Deviation 0.6 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 2) | -3.15 Percentage of Hb | Standard Deviation 0.57 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 3 (transplant 2) | -3.10 Percentage of Hb | Standard Deviation 0.76 |
| Reparixin | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 6 (transplant 2) | -3.05 Percentage of Hb | Standard Deviation 1.03 |
| No Experimental Intervention | Absolute Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 1) | -0.87 Percentage of Hb | Standard Deviation 0.4 |
Other Pre-specified
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
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).
Time frame: -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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| No Experimental Intervention | 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) | 0.044 (mg*hr/dL)/IEQ/kg | Standard Deviation 0.004 |
Other Pre-specified
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
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.
Time frame: -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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| No Experimental Intervention | 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) | 0.200 mg*hr/dL | Standard Deviation 0 |
Other Pre-specified
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
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.
Time frame: -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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| No Experimental Intervention | 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 | 308.3 mg*hr/dL | Standard Deviation 105.4 |
Other Pre-specified
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
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.
Time frame: -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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 |
| Reparixin | 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 16.4 |
| No Experimental Intervention | 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) | 7.58 μU*hr/mL | Standard Deviation 2.91 |
Other Pre-specified
Beta-cell Function as Assessed by Beta-score
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 6, transplant 2 | 4.75 score on a scale | Standard Deviation 2.63 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 1, transplant 1 | 1.83 score on a scale | Standard Deviation 1.17 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 3, transplant 1 | 3.75 score on a scale | Standard Deviation 1.26 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 6, transplant 1 | 1.67 score on a scale | Standard Deviation 1.53 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 12, transplant 2 | 6.50 score on a scale | Standard Deviation 0.71 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 1, transplant 2 | 5.25 score on a scale | Standard Deviation 1.5 |
| Reparixin | Beta-cell Function as Assessed by Beta-score | Month 3, transplant 2 | 4.75 score on a scale | Standard Deviation 1.89 |
| No Experimental Intervention | Beta-cell Function as Assessed by Beta-score | Month 1, transplant 1 | 1.33 score on a scale | Standard Deviation 1.53 |
Other Pre-specified
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio
The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 12 (transplant 2) | 1.320 ratio | Standard Deviation 0.212 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 1 (transplant 1) | 111.9 ratio | Standard Deviation 64.1 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 3 (transplant 1) | 176.6 ratio | Standard Deviation 105 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 6 (transplant 1) | 121.1 ratio | Standard Deviation 30 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 1 (transplant 2) | 1.143 ratio | Standard Deviation 0.278 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 3 (transplant 2) | 1.133 ratio | Standard Deviation 0.336 |
| Reparixin | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 6 (transplant 2) | 1.100 ratio | Standard Deviation 0.407 |
| No Experimental Intervention | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | Month 1 (transplant 1) | 13.6 ratio | Standard Deviation 49.6 |
Other Pre-specified
Change From Pre-transplant in Cytokine Levels - CXCL1
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).
Time frame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
Population: Safety population: all patients who were randomized into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 12 hours post-transplant | 11.8 pg/mL | Standard Deviation 72.4 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 6 hours post-transplant | -12.5 pg/mL | Standard Deviation 51.8 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 120 hours post-transplant | 8.7 pg/mL | Standard Deviation 16.1 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 24 hours post-transplant | 1.4 pg/mL | Standard Deviation 61.9 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 168 hours post-transplant | -10.7 pg/mL | Standard Deviation 65 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL1 | 72 hours post-transplant | 63.7 pg/mL | Standard Deviation 40.7 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 168 hours post-transplant | -16.3 pg/mL | Standard Deviation 88.7 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 6 hours post-transplant | -31.9 pg/mL | Standard Deviation 31 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 12 hours post-transplant | -16.8 pg/mL | Standard Deviation 16.2 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 24 hours post-transplant | -65.6 pg/mL | Standard Deviation 127 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 72 hours post-transplant | -51.9 pg/mL | Standard Deviation 157.7 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL1 | 120 hours post-transplant | -60.2 pg/mL | Standard Deviation 130.6 |
Other Pre-specified
Change From Pre-transplant in Cytokine Levels - CXCL8
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).
Time frame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
Population: Safety population: all patients who were randomized into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 6 hours post-transplant | 11.0 pg/mL | Standard Deviation 14.4 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 12 hours post-transplant | 43.8 pg/mL | Standard Deviation 45.5 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 24 hours post-transplant | 10.6 pg/mL | Standard Deviation 21.8 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 72 hours post-transplant | 17.3 pg/mL | Standard Deviation 12 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 120 hours post-transplant | 1.2 pg/mL | Standard Deviation 8 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - CXCL8 | 168 hours post-transplant | -6.8 pg/mL | Standard Deviation 5 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 120 hours post-transplant | -2.2 pg/mL | Standard Deviation 5.4 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 6 hours post-transplant | 22.1 pg/mL | Standard Deviation 19 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 72 hours post-transplant | 2.6 pg/mL | Standard Deviation 8.5 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 12 hours post-transplant | 32.9 pg/mL | Standard Deviation 43.3 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 168 hours post-transplant | -2.8 pg/mL | Standard Deviation 1.7 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - CXCL8 | 24 hours post-transplant | 11.3 pg/mL | Standard Deviation 2.1 |
Other Pre-specified
Change From Pre-transplant in Cytokine Levels - IL-6
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).
Time frame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
Population: Safety population: all patients who were randomized into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 6 hours post-transplant | 0.5 pg/mL | Standard Deviation 4 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 12 hours post-transplant | 15.5 pg/mL | Standard Deviation 20.6 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 24 hours post-transplant | 7.6 pg/mL | Standard Deviation 10.7 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 72 hours post-transplant | 16.3 pg/mL | Standard Deviation 13.5 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 120 hours post-transplant | 0.8 pg/mL | Standard Deviation 5.2 |
| Reparixin | Change From Pre-transplant in Cytokine Levels - IL-6 | 168 hours post-transplant | -2.6 pg/mL | Standard Deviation 3.2 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 120 hours post-transplant | -5.6 pg/mL | Standard Deviation 14.1 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 6 hours post-transplant | 12.1 pg/mL | Standard Deviation 10.6 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 72 hours post-transplant | 3.1 pg/mL | Standard Deviation 13.3 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 12 hours post-transplant | 23.4 pg/mL | Standard Deviation 27.9 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 168 hours post-transplant | -5.5 pg/mL | Standard Deviation 8.6 |
| No Experimental Intervention | Change From Pre-transplant in Cytokine Levels - IL-6 | 24 hours post-transplant | 2.3 pg/mL | Standard Deviation 7.5 |
Other Pre-specified
Number of Participants With Adverse Events by Severity and With Serious Adverse Events
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.
Time frame: up to 1 year after transplant
Population: Safety Population: all patients who were randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE mild | 5 participants |
| Reparixin | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE moderate | 6 participants |
| Reparixin | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE severe | 3 participants |
| Reparixin | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | SAE | 3 participants |
| No Experimental Intervention | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | SAE | 1 participants |
| No Experimental Intervention | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE mild | 2 participants |
| No Experimental Intervention | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE severe | 1 participants |
| No Experimental Intervention | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | TEAE moderate | 2 participants |
Other Pre-specified
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 12 (transplant 2) | -100.0 Percentage change | Standard Deviation 0 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 1) | -41.9 Percentage change | Standard Deviation 39.9 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 3 (transplant 1) | -50.3 Percentage change | Standard Deviation 24.4 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 6 (transplant 1) | -32.0 Percentage change | Standard Deviation 8.9 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 2) | -90.8 Percentage change | Standard Deviation 11.3 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 3 (transplant 2) | -88.7 Percentage change | Standard Deviation 17.8 |
| Reparixin | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 6 (transplant 2) | -81.8 Percentage change | Standard Deviation 36.5 |
| No Experimental Intervention | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Month 1 (transplant 1) | 16.4 Percentage change | Standard Deviation 20.2 |
Other Pre-specified
Percentage Change in Fasted HbA1c From Pre-transplant Levels
The absolute percentage between the time-point value and baseline value.
Time frame: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 12 (transplant 2) | -37.4 Percentage change | Standard Deviation 9.2 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 1) | -16.7 Percentage change | Standard Deviation 4.5 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 3 (transplant 2) | -32.2 Percentage change | Standard Deviation 7.4 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 3 (transplant 1) | -30.3 Percentage change | Standard Deviation 7.9 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 6 (transplant 1) | -19.7 Percentage change | Standard Deviation 7.2 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 2) | -32.8 Percentage change | Standard Deviation 5.9 |
| Reparixin | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 6 (transplant 2) | -31.6 Percentage change | Standard Deviation 10.1 |
| No Experimental Intervention | Percentage Change in Fasted HbA1c From Pre-transplant Levels | Month 1 (transplant 1) | -11.2 Percentage change | Standard Deviation 5.4 |
Other Pre-specified
Serum Level of Alanine Amino Transferase (ALT)
ALT is commonly measured clinically as part of liver function tests.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Month 3 (transplant 2) | 21.0 U/L | Standard Deviation 3.6 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 1 post-transplant 2 | 24.8 U/L | Standard Deviation 10.8 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 2 post-transplant 2 | 22.8 U/L | Standard Deviation 9.3 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 3 post-transplant 2 | 22.8 U/L | Standard Deviation 7.5 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 4 post-transplant 2 | 28.8 U/L | Standard Deviation 10.8 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 5 post-transplant 2 | 31.8 U/L | Standard Deviation 11.7 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 6 post-transplant 2 | 31.8 U/L | Standard Deviation 13 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 7 post-transplant 2 | 35.3 U/L | Standard Deviation 12.1 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Month 1 (transplant 2) | 28.0 U/L | Standard Deviation 12.5 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Pre-transplant 1 | 23.0 U/L | Standard Deviation 9 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 1 post-transplant 1 | 27.5 U/L | Standard Deviation 8.7 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 2 post-transplant 1 | 26.3 U/L | Standard Deviation 9.3 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 3 post-transplant 1 | 29.7 U/L | Standard Deviation 9.7 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 4 post-transplant 1 | 38.5 U/L | Standard Deviation 9 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 5 post-transplant 1 | 63.7 U/L | Standard Deviation 21.9 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 6 post-transplant 1 | 86.0 U/L | Standard Deviation 34 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Day 7 post-transplant 1 | 114.6 U/L | Standard Deviation 56.4 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Month 1 (transplant 1) | 25.8 U/L | Standard Deviation 7.7 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Month 3 (transplant 1) | 25.0 U/L | Standard Deviation 8.7 |
| Reparixin | Serum Level of Alanine Amino Transferase (ALT) | Pre-transplant 2 | 18.5 U/L | Standard Deviation 7.9 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Pre-transplant 1 | 28.7 U/L | Standard Deviation 22.9 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Month 1 (transplant 1) | 29.7 U/L | Standard Deviation 28.9 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 1 post-transplant 1 | 24.7 U/L | Standard Deviation 18.6 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 5 post-transplant 1 | 98.0 U/L | Standard Deviation 33.2 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 2 post-transplant 1 | 36.3 U/L | Standard Deviation 29.7 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 7 post-transplant 1 | 108.3 U/L | Standard Deviation 45.7 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 3 post-transplant 1 | 46.3 U/L | Standard Deviation 34.9 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 6 post-transplant 1 | 108.3 U/L | Standard Deviation 34.4 |
| No Experimental Intervention | Serum Level of Alanine Amino Transferase (ALT) | Day 4 post-transplant 1 | 64.7 U/L | Standard Deviation 23 |
Other Pre-specified
Serum Level of Aspartate Amino Transferase (AST)
AST is commonly measured clinically as part of liver function tests.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Pre-transplant 1 | 22.3 U/L | Standard Deviation 14.6 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Pre-transplant 2 | 17.0 U/L | Standard Deviation 6.2 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 1 post-transplant 2 | 33.0 U/L | Standard Deviation 18.7 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 2 post-transplant 2 | 21.0 U/L | Standard Deviation 7 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 3 post-transplant 2 | 21.5 U/L | Standard Deviation 5.8 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 4 post-transplant 2 | 26.8 U/L | Standard Deviation 9.7 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 6 post-transplant 2 | 23.0 U/L | Standard Deviation 8.8 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 7 post-transplant 2 | 25.3 U/L | Standard Deviation 10.4 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Month 1 (transplant 2) | 17.3 U/L | Standard Deviation 3.3 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Month 3 (transplant 2) | 13.7 U/L | Standard Deviation 5 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 1 post-transplant 1 | 30.5 U/L | Standard Deviation 12.1 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 2 post-transplant 1 | 22.3 U/L | Standard Deviation 9.2 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 3 post-transplant 1 | 24.7 U/L | Standard Deviation 12.8 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 4 post-transplant 1 | 31.8 U/L | Standard Deviation 9.3 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Month 3 (transplant 1) | 15.8 U/L | Standard Deviation 5 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 5 post-transplant 1 | 60.2 U/L | Standard Deviation 28.7 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 6 post-transplant 1 | 64.2 U/L | Standard Deviation 22.1 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 7 post-transplant 1 | 82.0 U/L | Standard Deviation 43.4 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Day 5 post-transplant 2 | 28.5 U/L | Standard Deviation 7.5 |
| Reparixin | Serum Level of Aspartate Amino Transferase (AST) | Month 1 (transplant 1) | 15.5 U/L | Standard Deviation 3.6 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Pre-transplant 1 | 20.0 U/L | Standard Deviation 7.5 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 6 post-transplant 1 | 64.3 U/L | Standard Deviation 29.4 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 1 post-transplant 1 | 18.7 U/L | Standard Deviation 7.4 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Month 1 (transplant 1) | 17.7 U/L | Standard Deviation 10 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 2 post-transplant 1 | 27.3 U/L | Standard Deviation 12.5 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 5 post-transplant 1 | 74.3 U/L | Standard Deviation 26.6 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 3 post-transplant 1 | 31.7 U/L | Standard Deviation 13.4 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 7 post-transplant 1 | 55.0 U/L | Standard Deviation 29.7 |
| No Experimental Intervention | Serum Level of Aspartate Amino Transferase (AST) | Day 4 post-transplant 1 | 49.0 U/L | Standard Deviation 35.5 |
Other Pre-specified
The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant
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).
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | transplant 1 | 0 percentage of patients |
| Reparixin | The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | transplant 2 | 50 percentage of patients |
| No Experimental Intervention | The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | transplant 1 | 0 percentage of patients |
Other Pre-specified
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness
Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as hypoglycemia unawareness.
Time frame: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 12 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 1 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 3 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 6 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 1 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 3 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 6 (transplant 2) | 100 Percentage of patients |
| No Experimental Intervention | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | month 1 (transplant 1) | 100 Percentage of patients |
Other Pre-specified
The Percentage of Patients Free of Severe Hypoglycaemic Events
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 12 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 1 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 3 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 6 (transplant 1) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 1 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 3 (transplant 2) | 100 Percentage of patients |
| Reparixin | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 6 (transplant 2) | 100 Percentage of patients |
| No Experimental Intervention | The Percentage of Patients Free of Severe Hypoglycaemic Events | month 1 (transplant 1) | 100 Percentage of patients |
Other Pre-specified
Time to Achieve Insulin-independence After the Transplant 2
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time to Achieve Insulin-independence After the Transplant 2 | 66.3 days | Standard Deviation 73.7 |
Other Pre-specified
Total Time of Insulin Independence After the Transplant
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Total Time of Insulin Independence After the Transplant | 276.0 total number of days | Standard Deviation 96.2 |