| Outcome Measures: |
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 Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal., Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion|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 Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal., Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 365±14 after the last islet infusion | 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)., Day 75±5 after the 1st and 2nd islet infusion|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)., Day 365±14 after last islet infusion|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., HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion|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., Day 365±14 after the 1st islet infusion|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., Day 365±14 after the last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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., Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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, Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion|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), Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | Other: 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., At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion|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., At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,|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., Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion|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., At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,
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| Locations: |
The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation, Chicago, Illinois, 60637, United States|Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes., Praha, 14021, Czechia|Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele, Milan, 20132, Italy|S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, Milan, 20162, Italy|Transplant Institute - Sahlgrenska University Hospital, Göteborg, 41345, Sweden|Department of Nephrology and Transplantation; Skane University Hospital, Malmö, 20502, Sweden|Department of Transplantation Surgery; The Karolinska University Hospital, Stockholm, 14186, Sweden|Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital, Uppsala, 75185, Sweden|Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, United Kingdom
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