Islet Transplantation in Diabetes Mellitus Type 1
Conditions
Keywords
Pancreatic islet transplantation, Diabetes Mellitus Type 1, Islet transplantation graft survival & function
Brief summary
The objective of this clinical trial was: \- to assess whether Reparixin leads to improved transplant outcome as measured by glycaemic control following intra-hepatic infusion of pancreatic islets in patients with Type 1 diabetes (T1D). The safety of Reparixin in the specific clinical setting was also evaluated. Background: The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after organ transplantation. Reparixin is the first low molecular weight blocker of CXCL8 biological activity in clinical development. Thus, the use of reparixin may emerge as a potential key component in the sequentially integrated approach to immunomodulation and control of non specific inflammatory events surrounding the early phases of pancreatic islet transplantation in T1D patients.
Detailed description
Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. Several strategies are being evaluated, including anti-TNFα, aimed to prevent early inflammatory events that limit islet engraftment. Among possible mechanisms CXCL8 could play a crucial role in triggering the inflammatory reaction and might represent a relevant therapeutic target to prevent early graft failure. Preliminary data obtained in transplanted patients recruited in the ongoing pilot trial coupled with the safety shown in human phase 1 and 2 studies provide a sound rationale for further development of reparixin in islet transplantation and prompted the conduct of this phase 3 clinical, multicentre, randomised, double-blind, parallel assignment study aimed at assessing the efficacy and safety of reparixin in preventing graft dysfunction after islet transplantation in T1D subjects. At least 42 patients receiving pancreatic islet transplant were involved. Patients might receive up to 2 islet transplants, with the second transplant on average 6 months after the first one. Patients were randomly (2:1) assigned to receive either reparixin or placebo (control group). The Investigational Product was administered as an added on treatment to the immunosuppressant regimen.
Interventions
DRUGReparixin
Continuous i.v. infusion into a central vein for 7 days, starting approximately 12 hrs (6-18 hrs) before each pancreatic islet infusion.The Investigational Product (IP) were to be administered as an add-on treatment for the immunosuppressant regimen.
DRUGPlacebo
Continuous infusion at a volume/rate matching active treatment.The placebo was to be administered as well as an add-on treatment for the immunosuppressant regimen.
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Ages 18-70 years, inclusive. * Patients eligible for a pancreatic islet transplantation program * Planned intrahepatic islet transplantation alone from a non-living donor with brain death. * Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations. * Patients who have 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, including recipients of previous pancreatic islet transplantation. * Recipients of islet from a non-heart beating donor. * Pre-transplant average daily insulin requirement \>1 IU/kg/day. * Pre-transplant (the more recent value obtained within the 4 months prior to enrolment) HbA1c \>11%. * Patients with inadequate renal reserve as per calculated creatinine clearance (CLcr) \< 60 mL/min according to the Cockcroft-Gault formula (1976). * Patients with hepatic dysfunction as defined by increased ALT (alanine aminotranferase) / AST (aspartate aminotransferase) \> 3 x upper limit of normal (ULN) and increased total bilirubin \> 3mg/dL \[\>51.3 µmol/L\]). * 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 12 weeks of enrolment, including anti-inflammatory strategies (e.g. anti-TNFα, anti-IL-1 RA). * Hypersensitivity to: 1. ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID). 2. 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). Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg | Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion | The MMTT was to be performed ideally after an overnight fast. The test was to be initiated before 10 a.m. The Boost Original complete nutritional drink (Nestlé Nutrition) was used for the MMTT. Subjects were given 6 mL/kg of Boost preparation up to a maximum of 360 mL, to be drunk within 5 min. Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Change from baseline is assessed as absolute decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week. |
| Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | C-peptide levels not normalized by the number of islet equivalent (IEQ)/kg were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame. |
| Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Insulin levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame. |
| β-cell Function as Assessed by β-score in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | The β-score ranges from 0 (no graft function) to 8 (interpreted as an index of excellent graft function), and gives 0-2 points each for glucose, HbA1C, stimulated C-peptide and insulin requirement. Both for the total and partial scores the higher the score, the better the outcome. Fasting plasma glucose (mg/dL): ≤99 (Score 2); 100 - 124 (Score 1); ≥125 (Score 0); HbA1c (%): ≤6.1(Score 2); 6.2 - 6.9 (Score 1); ≥ 7.0 (Score 0); Daily average (previous week) insulin (IU/kg/day): --- (Score 2); 0.01 - 0.24 (score 1); ≥ 0.25 (Score 0) Stimulated C-peptide (ng/mL): ≥ 0.9; 0.3 - 0.89; ≤0.3 |
| β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | TEF selects the two pivotal components of the β-score (DIR and A1C) and links them together through a simple description of how insulin supply influences the patient's glycemic control. TEF was evaluated by the following equation: TEF = a.DIR + b.HbA1c + c where DIR = daily insulin requirement (average in the previous week); a = -1; b = 1/-5.43; c = -a.DIR (pre-transplant) - b.HbA1c (pre-transplant) |
| Percentage of Insulin-independent Patients at Day 75 | Day 75±5 after the 1st and 2nd islet infusion | For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by: * a glycated hemoglobin (HbA1c) level of less than 7%; * a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period); * a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period). |
| Percentage of Insulin-independent Patients at Day 365 | Day 365±14 after last islet infusion | For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by: * a glycated hemoglobin (HbA1c) level of less than 7%; * a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period); * a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period). |
| Percentage of Patients Who Achieve and Maintain an HbA1c <7.0% (or a Reduction in HbA1c > 2%) AND Are Free of Severe Hypoglycaemic Events After Transplant in the Efficacy Population 1 | HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion | For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. |
| Percentage of Patients Who Did Not Receive a 2nd Islet Infusion | Day 365±14 after the 1st islet infusion | This endpoint describes subjects who were not allocated to a 2nd islet infusion because they were insulin independent after the 1st islet infusion. |
| Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1 | Day 365±14 after the last islet infusion | The cumulative number of severe hypoglycaemic events after last transplant was assessed. For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, 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 \<54 mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. |
| Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Change from baseline is assessed as percentage decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week. |
| Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Change from baseline in Glycated haemoglobin (HbA1c) was assessed as absolute decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: \<5.7% Normal; 5.7-6.4% prediabetes; \>6.5 diabetes. |
| Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion | Change from baseline in Glycated haemoglobin (HbA1c) was assessed as percentage decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: \<5.7% Normal; 5.7-6.4% prediabetes; \>6.5 diabetes. |
| Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Glucose levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion | Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded. |
| Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, | Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded. |
| Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, | Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex. |
| Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion | Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex. |
Countries
Czechia, Italy, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 51 subjects were randomised into the trial. Three of these subjects did not have a transplant and never received randomised medication. Hence, a total of 48 subjects took trial medication and were included in the Safety Population.
Participants by arm
| Arm | Count |
|---|---|
| Reparixin Group Continuous iv infusion
Reparixin: Continuous i.v. infusion into a central vein for 7 days, starting approximately 12 hrs (6-18 hrs) before each pancreatic islet infusion.The Investigational Product (IP) were to be administered as an add-on treatment for the immunosuppressant regimen. | 29 |
| Placebo Group Continuous iv infusion
Placebo: Continuous infusion at a volume/rate matching active treatment.The placebo was to be administered as well as an add-on treatment for the immunosuppressant regimen. | 19 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | forbidden medication | 1 | 1 |
| Overall Study | Graft loss | 1 | 1 |
| Overall Study | Patient didn't proceed to 1st Islet Inf | 1 | 1 |
Baseline characteristics
| Characteristic | Reparixin Group | Placebo Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 18 Participants | 46 Participants |
| Age, Continuous | 47.3 years STANDARD_DEVIATION 11.3 | 42.6 years STANDARD_DEVIATION 10.8 | 45.5 years STANDARD_DEVIATION 11.2 |
| Region of Enrollment Czechia | 5 participants | 3 participants | 8 participants |
| Region of Enrollment Italy | 7 participants | 5 participants | 12 participants |
| Region of Enrollment Sweden | 7 participants | 6 participants | 13 participants |
| Region of Enrollment United Kingdom | 2 participants | 1 participants | 3 participants |
| Region of Enrollment United States | 8 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 17 Participants | 12 Participants | 29 Participants |
| Sex: Female, Male Male | 12 Participants | 7 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 19 |
| other Total, other adverse events | 29 / 29 | 18 / 19 |
| serious Total, serious adverse events | 17 / 29 | 12 / 19 |
Outcome results
Primary
Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg
The MMTT was to be performed ideally after an overnight fast. The test was to be initiated before 10 a.m. The Boost Original complete nutritional drink (Nestlé Nutrition) was used for the MMTT. Subjects were given 6 mL/kg of Boost preparation up to a maximum of 360 mL, to be drunk within 5 min. Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal.
Time frame: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 365±14 after the last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin Group | Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg | 0.234 ng/mL/min | Standard Deviation 0.243 |
| Placebo Group | Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg | 0.207 ng/mL/min | Standard Deviation 0.127 |
p-value: 0.711599.75% CI: [-0.184, 0.232]ANOVA
Primary
Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg
The MMTT was to be performed ideally after an overnight fast. The test was to be initiated before 10 a.m. The Boost Original complete nutritional drink (Nestlé Nutrition) was used for the MMTT. Subjects were given 6 mL/kg of Boost preparation up to a maximum of 360 mL, to be drunk within 5 min. Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal.
Time frame: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin Group | Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg | 0.247 ng/mL/min | Standard Deviation 0.218 |
| Placebo Group | Area Under the Curve (AUC) for the Serum C-peptide Level During the First 2 Hours of an MMTT (Mixed Meal Tolerance Test), Normalized by the Number of Islet Equivalent (IEQ)/kg | 0.321 ng/mL/min | Standard Deviation 0.208 |
p-value: 0.986399.75% CI: [-0.205, 0.207]ANOVA
Secondary
Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1
Change from baseline is assessed as absolute decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | transplant 1 | -0.231 IU/kg/day | Standard Deviation 0.204 |
| Reparixin Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | transplant 2 | -0.389 IU/kg/day | Standard Deviation 0.163 |
| Reparixin Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | last transplant | -0.302 IU/kg/day | Standard Deviation 0.167 |
| Placebo Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | transplant 1 | -0.220 IU/kg/day | Standard Deviation 0.203 |
| Placebo Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | transplant 2 | -0.463 IU/kg/day | Standard Deviation 0.168 |
| Placebo Group | Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | last transplant | -0.375 IU/kg/day | Standard Deviation 0.208 |
Comparison: This is is the analytic statistics for Day 75 (Transplant 1)p-value: 0.695295% CI: [-0.13, 0.088]ANCOVA
Comparison: This is is the analytic statistics for Day 75 (Transplant 2)p-value: 0.55695% CI: [-0.068, 0.124]ANCOVA
Comparison: This is the analytic statics for Day 365 (last Transplant)p-value: 0.253795% CI: [-0.042, 0.154]ANCOVA
Secondary
Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1
Change from baseline in Glycated haemoglobin (HbA1c) was assessed as absolute decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: \<5.7% Normal; 5.7-6.4% prediabetes; \>6.5 diabetes.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 1 | -1.58 percent of HbA1c | Standard Deviation 0.87 |
| Reparixin Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 2 | -2.04 percent of HbA1c | Standard Deviation 1.1 |
| Reparixin Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Last Transplant | -1.30 percent of HbA1c | Standard Deviation 1.14 |
| Placebo Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 1 | -2.18 percent of HbA1c | Standard Deviation 1.23 |
| Placebo Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 2 | -2.81 percent of HbA1c | Standard Deviation 1.37 |
| Placebo Group | Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Last Transplant | -1.87 percent of HbA1c | Standard Deviation 1.26 |
Comparison: This is the analytic statics for Day 75 (Transplant 1)p-value: 0.325395% CI: [-0.21, 0.63]ANCOVA
Comparison: This is the analytic statics for Day 75 (Transplant 2)p-value: 0.606995% CI: [-0.46, 0.78]least square mean difference
Comparison: This is the analytic statics for Day 365 (last Transplant)p-value: 0.643795% CI: [-0.56, 0.93]ANCOVA
Secondary
Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1
C-peptide levels not normalized by the number of islet equivalent (IEQ)/kg were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 365 - Last transplant | 1.06 ng/mL | Standard Deviation 1.02 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 0.50 ng/mL | Standard Deviation 0.46 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 3.33 ng/mL | Standard Deviation 1.98 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 0.71 ng/mL | Standard Deviation 0.77 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 365 - Last transplant | 1.65 ng/mL | Standard Deviation 1.66 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 1.18 ng/mL | Standard Deviation 1.32 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 3.30 ng/mL | Standard Deviation 2.15 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 1.66 ng/mL | Standard Deviation 1.8 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 365 - Last transplant | 2.37 ng/mL | Standard Deviation 2.38 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 1.81 ng/mL | Standard Deviation 1.64 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 365 - Last transplant | 0.76 ng/mL | Standard Deviation 0.65 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 1.72 ng/mL | Standard Deviation 1.34 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 365 - Last transplant | 2.47 ng/mL | Standard Deviation 2.27 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 0.93 ng/mL | Standard Deviation 0.69 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 2.98 ng/mL | Standard Deviation 2.15 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 1.42 ng/mL | Standard Deviation 1.36 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 2.11 ng/mL | Standard Deviation 1.74 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 2.13 ng/mL | Standard Deviation 1.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 3.12 ng/mL | Standard Deviation 1.68 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 3.65 ng/mL | Standard Deviation 2.09 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 3.56 ng/mL | Standard Deviation 1.96 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 2.90 ng/mL | Standard Deviation 1.28 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 365 - Last transplant | 1.14 ng/mL | Standard Deviation 0.62 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 365 - Last transplant | 1.32 ng/mL | Standard Deviation 0.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 365 - Last transplant | 2.17 ng/mL | Standard Deviation 1.5 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 365 - Last transplant | 2.88 ng/mL | Standard Deviation 181 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 365 - Last transplant | 3.13 ng/mL | Standard Deviation 1.84 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 2.55 ng/mL | Standard Deviation 1.19 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 0.51 ng/mL | Standard Deviation 0.44 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 0.67 ng/mL | Standard Deviation 0.71 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 0.89 ng/mL | Standard Deviation 0.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 1.46 ng/mL | Standard Deviation 1.43 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 1.80 ng/mL | Standard Deviation 1.57 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 2.04 ng/mL | Standard Deviation 1.64 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 1.27 ng/mL | Standard Deviation 0.5 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 1.73 ng/mL | Standard Deviation 0.78 |
Secondary
Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1
Glucose levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 120.6 mg/dL | Standard Deviation 51.7 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 146.0 mg/dL | Standard Deviation 56 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 191.6 mg/dL | Standard Deviation 66.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 236.9 mg/dL | Standard Deviation 86 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 254.0 mg/dL | Standard Deviation 110.1 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 264.1 mg/dL | Standard Deviation 116.7 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 103.8 mg/dL | Standard Deviation 19.8 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 130.0 mg/dL | Standard Deviation 22.3 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 166.7 mg/dL | Standard Deviation 33.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 189.1 mg/dL | Standard Deviation 57.9 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 191.8 mg/dL | Standard Deviation 72.8 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 188.0 mg/dL | Standard Deviation 88.1 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 365 - Last transplant | 112.2 mg/dL | Standard Deviation 37.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 365 - Last transplant | 139.5 mg/dL | Standard Deviation 43.1 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 365 - Last transplant | 180.1 mg/dL | Standard Deviation 53.9 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 365 - Last transplant | 221.2 mg/dL | Standard Deviation 81.2 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 365 - Last transplant | 235.7 mg/dL | Standard Deviation 112.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 239.9 mg/dL | Standard Deviation 127.6 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 365 - Last transplant | 146.7 mg/dL | Standard Deviation 68.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 118.9 mg/dL | Standard Deviation 40.2 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 172.0 mg/dL | Standard Deviation 70.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 132.5 mg/dL | Standard Deviation 27.6 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 205.5 mg/dL | Standard Deviation 104.3 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 168.1 mg/dL | Standard Deviation 50 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 175.1 mg/dL | Standard Deviation 99.7 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 219.1 mg/dL | Standard Deviation 65.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 365 - Last transplant | 182.7 mg/dL | Standard Deviation 80.2 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 245.0 mg/dL | Standard Deviation 84.7 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 171.7 mg/dL | Standard Deviation 104.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 246.0 mg/dL | Standard Deviation 84.4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 90 min - day 365 - Last transplant | 222.0 mg/dL | Standard Deviation 122.6 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 112.8 mg/dL | Standard Deviation 18.6 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | Basal - day 365 - Last transplant | 125.1 mg/dL | Standard Deviation 64.5 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 134.8 mg/dL | Standard Deviation 26.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 60 min - day 365 - Last transplant | 213.6 mg/dL | Standard Deviation 106.2 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 157.8 mg/dL | Standard Deviation 32.6 |
Secondary
Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1
Insulin levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 16.5 µU/mL | Standard Deviation 43.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 13.5 µU/mL | Standard Deviation 16.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 21.0 µU/mL | Standard Deviation 27.7 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 25.6 µU/mL | Standard Deviation 32.9 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 23.9 µU/mL | Standard Deviation 27.4 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 21.3 µU/mL | Standard Deviation 28.2 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 8.4 µU/mL | Standard Deviation 10.3 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 16.0 µU/mL | Standard Deviation 16 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 28.4 µU/mL | Standard Deviation 30 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 33.7 µU/mL | Standard Deviation 23.4 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 36.3 µU/mL | Standard Deviation 23.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 29.7 µU/mL | Standard Deviation 19.2 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 365 - Last transplant | 7.5 µU/mL | Standard Deviation 7.6 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 365 - Last transplant | 13.8 µU/mL | Standard Deviation 17 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 365 - Last transplant | 19.4 µU/mL | Standard Deviation 19.2 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 365 - Last transplant | 28.5 µU/mL | Standard Deviation 30.1 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 365 - Last transplant | 25.8 µU/mL | Standard Deviation 23.5 |
| Reparixin Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 19.9 µU/mL | Standard Deviation 18.4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 365 - Last transplant | 10.8 µU/mL | Standard Deviation 9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 1 | 15.2 µU/mL | Standard Deviation 39.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 2 | 37.8 µU/mL | Standard Deviation 20.4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 1 | 11.8 µU/mL | Standard Deviation 13.2 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 365 - Transplant 2 | 27.1 µU/mL | Standard Deviation 11.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 1 | 15.8 µU/mL | Standard Deviation 16.9 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 2 | 31.2 µU/mL | Standard Deviation 20.6 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 75 - Transplant 1 | 23.0 µU/mL | Standard Deviation 24.4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 365 - Last transplant | 20.7 µU/mL | Standard Deviation 13.1 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 75 - Transplant 1 | 22.3 µU/mL | Standard Deviation 18.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 2 | 25.3 µU/mL | Standard Deviation 10.4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 120 min - day 75 - Transplant 1 | 23.1 µU/mL | Standard Deviation 18.1 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 90 min - day 365 - Last transplant | 26.1 µU/mL | Standard Deviation 17.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 75 - Transplant 2 | 9.0 µU/mL | Standard Deviation 3.8 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | Basal - day 365 - Last transplant | 6.2 µU/mL | Standard Deviation 4 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 15 min - day 75 - Transplant 2 | 17.5 µU/mL | Standard Deviation 12.1 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 60 min - day 365 - Last transplant | 25.6 µU/mL | Standard Deviation 14.3 |
| Placebo Group | Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 30 min - day 75 - Transplant 2 | 31.1 µU/mL | Standard Deviation 17.8 |
Secondary
Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1
The cumulative number of severe hypoglycaemic events after last transplant was assessed. For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, 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 \<54 mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time frame: Day 365±14 after the last islet infusion
Population: Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin Group | Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1 | 2.88 number of events | Standard Deviation 8.23 |
| Placebo Group | Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1 | 3.50 number of events | Standard Deviation 7.65 |
Secondary
Percentage of Insulin-independent Patients at Day 365
For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by: * a glycated hemoglobin (HbA1c) level of less than 7%; * a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period); * a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period).
Time frame: Day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin Group | Percentage of Insulin-independent Patients at Day 365 | 32.0 percentage of participants |
| Placebo Group | Percentage of Insulin-independent Patients at Day 365 | 31.3 percentage of participants |
p-value: 0.91395% CI: [0.17, 4.93]Regression, Logistic
Secondary
Percentage of Insulin-independent Patients at Day 75
For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by: * a glycated hemoglobin (HbA1c) level of less than 7%; * a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period); * a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period).
Time frame: Day 75±5 after the 1st and 2nd islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin Group | Percentage of Insulin-independent Patients at Day 75 | transplant 1 | 18.5 Percentage of participants |
| Reparixin Group | Percentage of Insulin-independent Patients at Day 75 | transplant 2 | 27.8 Percentage of participants |
| Placebo Group | Percentage of Insulin-independent Patients at Day 75 | transplant 1 | 5.6 Percentage of participants |
| Placebo Group | Percentage of Insulin-independent Patients at Day 75 | transplant 2 | 53.3 Percentage of participants |
Comparison: Analytical statistics are reported for Day 75 after transplant 2p-value: 0.134695% CI: [0.03, 1.63]Regression, Logistic
Secondary
Percentage of Patients Who Achieve and Maintain an HbA1c <7.0% (or a Reduction in HbA1c > 2%) AND Are Free of Severe Hypoglycaemic Events After Transplant in the Efficacy Population 1
For the purpose of this study, a severe hypoglycaemic 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 (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time frame: HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (one or two).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin Group | Percentage of Patients Who Achieve and Maintain an HbA1c <7.0% (or a Reduction in HbA1c > 2%) AND Are Free of Severe Hypoglycaemic Events After Transplant in the Efficacy Population 1 | 40.0 Percentage of participants |
| Placebo Group | Percentage of Patients Who Achieve and Maintain an HbA1c <7.0% (or a Reduction in HbA1c > 2%) AND Are Free of Severe Hypoglycaemic Events After Transplant in the Efficacy Population 1 | 50.0 Percentage of participants |
p-value: 0.546795% CI: [0.16, 2.66]Regression, Logistic
Secondary
Percentage of Patients Who Did Not Receive a 2nd Islet Infusion
This endpoint describes subjects who were not allocated to a 2nd islet infusion because they were insulin independent after the 1st islet infusion.
Time frame: Day 365±14 after the 1st islet infusion
Population: Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin Group | Percentage of Patients Who Did Not Receive a 2nd Islet Infusion | 14.8 percentage of participants |
| Placebo Group | Percentage of Patients Who Did Not Receive a 2nd Islet Infusion | 0.0 percentage of participants |
p-value: 0.1383Fisher Exact
Secondary
Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1
Change from baseline is assessed as percentage decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Transplant 1 | -42.5 Percentage change | Standard Deviation 54.1 |
| Reparixin Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Transplant 2 | -74.0 Percentage change | Standard Deviation 28.6 |
| Reparixin Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Last transplant | -59.4 Percentage change | Standard Deviation 35.8 |
| Placebo Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Last transplant | -63.7 Percentage change | Standard Deviation 33.7 |
| Placebo Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Transplant 1 | -35.0 Percentage change | Standard Deviation 35.3 |
| Placebo Group | Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | Transplant 2 | -27.7 Percentage change | Standard Deviation 26.3 |
Comparison: This is the analytic statics for Day 75 (Transplant 1)p-value: 0.59195% CI: [-35.2, 20.3]ANCOVA
Comparison: This is the analytic statics for Day 75 (Transplant 2)p-value: 0.596695% CI: [-11.8, 20.2]ANCOVA
Comparison: This is the analytic statics for Day 365 (last Transplant)p-value: 0.500595% CI: [-12.1, 24.4]ANCOVA
Secondary
Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1
Change from baseline in Glycated haemoglobin (HbA1c) was assessed as percentage decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: \<5.7% Normal; 5.7-6.4% prediabetes; \>6.5 diabetes.
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 1 | -18.9 Percent change of Hb1Ac % | Standard Deviation 9.5 |
| Reparixin Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 2 | -24.4 Percent change of Hb1Ac % | Standard Deviation 11.6 |
| Reparixin Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Last Transplant | -15.7 Percent change of Hb1Ac % | Standard Deviation 13.1 |
| Placebo Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 1 | -24.0 Percent change of Hb1Ac % | Standard Deviation 10.6 |
| Placebo Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Transplant 2 | -30.5 Percent change of Hb1Ac % | Standard Deviation 11.7 |
| Placebo Group | Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | Last Transplant | -20.9 Percent change of Hb1Ac % | Standard Deviation 12.9 |
Comparison: This is the analytic statistics for Day 75 (Transplant 1)p-value: 0.42995% CI: [-3, 6.9]ANCOVA
Comparison: This is the analytic statistics for Day 75 (Transplant 2)p-value: 0.785395% CI: [-6.3, 8.3]ANCOVA
Comparison: This is the analytic statistics for Day 365 (last Transplant)p-value: 0.658395% CI: [-6.6, 10.4]ANCOVA
Secondary
β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1
TEF selects the two pivotal components of the β-score (DIR and A1C) and links them together through a simple description of how insulin supply influences the patient's glycemic control. TEF was evaluated by the following equation: TEF = a.DIR + b.HbA1c + c where DIR = daily insulin requirement (average in the previous week); a = -1; b = 1/-5.43; c = -a.DIR (pre-transplant) - b.HbA1c (pre-transplant)
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 75 - Transplant 1 | 0.523 U/kg/24 h | Standard Deviation 0.26 |
| Reparixin Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 75 - Transplant 2 | 0.764 U/kg/24 h | Standard Deviation 0.24 |
| Reparixin Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 365 - Last transplant | 0.539 U/kg/24 h | Standard Deviation 0.32 |
| Placebo Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 75 - Transplant 1 | 0.621 U/kg/24 h | Standard Deviation 0.332 |
| Placebo Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 75 - Transplant 2 | 0.981 U/kg/24 h | Standard Deviation 0.275 |
| Placebo Group | β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | day 365 - Last transplant | 0.719 U/kg/24 h | Standard Deviation 0.359 |
Comparison: This is the analytic statistics for Day 75 (Transplant 1)p-value: 0.244495% CI: [-0.286, 0.075]ANOVA
Comparison: This is the analytic statistics for Day 75 (Transplant 2)p-value: 0.032895% CI: [-0.417, -0.019]ANOVA
Comparison: This is the analytic statistics for Day 365 (last Transplant)p-value: 0.105995% CI: [-0.393, 0.039]ANOVA
Secondary
β-cell Function as Assessed by β-score in Efficacy Population 1
The β-score ranges from 0 (no graft function) to 8 (interpreted as an index of excellent graft function), and gives 0-2 points each for glucose, HbA1C, stimulated C-peptide and insulin requirement. Both for the total and partial scores the higher the score, the better the outcome. Fasting plasma glucose (mg/dL): ≤99 (Score 2); 100 - 124 (Score 1); ≥125 (Score 0); HbA1c (%): ≤6.1(Score 2); 6.2 - 6.9 (Score 1); ≥ 7.0 (Score 0); Daily average (previous week) insulin (IU/kg/day): --- (Score 2); 0.01 - 0.24 (score 1); ≥ 0.25 (Score 0) Stimulated C-peptide (ng/mL): ≥ 0.9; 0.3 - 0.89; ≤0.3
Time frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Reparixin Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 75 - Transplant 1 | 4.19 score on a scale | Standard Deviation 2.37 |
| Reparixin Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 75 - Transplant 2 | 5.53 score on a scale | Standard Deviation 1.42 |
| Reparixin Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 365 - Last transplant | 4.63 score on a scale | Standard Deviation 2.5 |
| Placebo Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 75 - Transplant 1 | 4.06 score on a scale | Standard Deviation 2.29 |
| Placebo Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 75 - Transplant 2 | 5.67 score on a scale | Standard Deviation 2.06 |
| Placebo Group | β-cell Function as Assessed by β-score in Efficacy Population 1 | day 365 - Last transplant | 5.13 score on a scale | Standard Deviation 2.42 |
Comparison: This is the analytic statistics for Day 75 (Transplant 1)p-value: 0.994995% CI: [-1.28, 1.28]ANOVA
Comparison: This is the analytic statistics for Day 75 (Transplant 2)p-value: 0.875395% CI: [-1.18, 1.38]ANOVA
Comparison: This is the analytic statistics for Day 365 (last Transplant)p-value: 0.395595% CI: [-1.97, 0.8]ANOVA
Other Pre-specified
Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1
Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded.
Time frame: Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - negative | 72.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - positive | 15.4 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - negative | 84.6 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 20.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 80.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - positive | 29.4 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - negative | 70.6 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 33.3 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 66.7 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - positive | 28.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 26.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - negative | 73.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - positive | 31.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - positive | 27.8 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - positive | 26.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - negative | 72.2 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - negative | 68.8 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 23.5 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 73.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 76.5 Percentage of participants |
Other Pre-specified
Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1
Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded.
Time frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - positive | 7.7 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - negative | 92.3 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 16.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 84.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - positive | 5.9 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - negative | 94.1 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 16.7 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 83.3 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - positive | 20.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - negative | 80.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 93.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - positive | 5.6 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - negative | 93.8 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 1 - negative | 94.4 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - negative | 80.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 12.5 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 6.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 87.5 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | day 365 - Last transplant - positive | 20.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 | pre-transplant 2 - positive | 6.3 Percentage of participants |
Other Pre-specified
Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1
Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex.
Time frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 1 - positive | 48.1 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 1 - negative | 51.9 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 69.2 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 30.8 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 2 - positive | 66.7 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 2 - negative | 33.3 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 66.7 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 33.3 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 365 - Last transplant - positive | 56.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 365 - Last transplant - negative | 44.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 46.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 1 - positive | 52.9 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 2 - negative | 37.5 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 1 - negative | 47.1 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 365 - Last transplant - negative | 50.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 64.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 53.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 35.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | day 365 - Last transplant - positive | 50.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 | pre-transplant 2 - positive | 62.5 Percentage of participants |
Other Pre-specified
Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1
Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex.
Time frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,
Population: The Efficacy Population 1 consisted of all subjects who were randomised, received the IP (either Reparixin or placebo), and had a transplant (either one or two).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 1 - positive | 22.2 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 1 - negative | 77.8 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 28.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 72.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 2 - positive | 22.2 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 2 - negative | 77.8 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 27.8 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 72.2 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 365 - Last transplant - positive | 20.0 Percentage of participants |
| Reparixin Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 365 - Last transplant - negative | 80.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 2 - negative | 85.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 1 - positive | 14.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 2 - negative | 86.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 1 - negative | 85.7 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 365 - Last transplant - negative | 80.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 1 - positive | 20.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 2 - positive | 14.3 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 75 - Transplant 1 - negative | 80.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | day 365 - Last transplant - positive | 20.0 Percentage of participants |
| Placebo Group | Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 | pre-transplant 2 - positive | 13.3 Percentage of participants |