Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2011-006201-10 | EudraCT Number |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Reparixin group | Experimental | Continuous iv infusion |
|
| Placebo group | Placebo Comparator | Continuous iv infusion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Reparixin | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
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:
Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).
Additional exclusion criteria specific for US centre.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Lorenzo PIEMONTI, MD | Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele | Principal Investigator |
| Torbjörn LUNDGREN, MD, PhD | Department of Transplantation Surgery; The Karolinska University Hospital | Principal Investigator |
| Gunnar TUFVESON, Professor | Department of Surgery; Uppsala University Hospital | Principal Investigator |
| Ehab RAFAEL, MD, PhD | Department of Nephrology and Transplantation; Skane University Hospital | Principal Investigator |
| James SHAW, Professor | Institute of Transplantation, Newcastle upon Tyne Hospitals - Freeman Hospital | Principal Investigator |
| Frantisek SAUDEK, MD, DrSc | Institute for Clinical and Experimental Medicine (IKEM), Department of Diabetes. | Principal Investigator |
| Piotr WITKOWSKI, MD, PhD | The University of Chicago Medical Center, Department of Surgery | Principal Investigator |
| Federico BERTUZZI, MD | S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation | Chicago | Illinois | 60637 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39735417 | Derived | Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res. 2024 Dec 20;2024:5151171. doi: 10.1155/jdr/5151171. eCollection 2024. | |
| 33908301 | Derived | Bachul PJ, Golab K, Basto L, Zangan S, Pyda JS, Perez-Gutierrez A, Borek P, Wang LJ, Tibudan M, Tran DK, Anteby R, Generette GS, Chrzanowski J, Fendler W, Perea L, Jayant K, Lucander A, Thomas C, Philipson L, Millis JM, Fung J, Witkowski P. Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation. Cell Transplant. 2021 Jan-Dec;30:9636897211001774. doi: 10.1177/09636897211001774. |
Not provided
Not provided
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.
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
safety population: A total of 48 subjects (29 Reparixin, 19 placebo) received trial medication and therefore were included in the Safety Population.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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). | Posted | Mean | Standard Deviation | ng/mL/min | Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion |
|
Not provided
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Development & Operations | Dompé farmaceutici s.p.a. | +39 02 583831 | clinical.trials@dompe.com |
Not provided
| ID | Term |
|---|---|
| D003922 | Diabetes Mellitus, Type 1 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C490707 | reparixin |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Placebo | Drug | 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. |
|
| 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:
| 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 |
| 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, |
| Bengt GUSTAFSSON, MD, PhD | Transplant Institute - Sahlgrenska University Hospital | Principal Investigator |
| Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes. | Prague | 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 | Gothenburg | 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 |
| 32019854 | Derived | Maffi P, Lundgren T, Tufveson G, Rafael E, Shaw JAM, Liew A, Saudek F, Witkowski P, Golab K, Bertuzzi F, Gustafsson B, Daffonchio L, Ruffini PA, Piemonti L; REP0211 Study Group. Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes. Diabetes Care. 2020 Apr;43(4):710-718. doi: 10.2337/dc19-1480. Epub 2020 Feb 4. |
| Adverse Event |
|
| Patient didn't proceed to 1st Islet Inf |
|
| 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| 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. |
| OG001 | 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. |
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | ng/mL/min | 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:
| 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). | Posted | Number | Percentage of participants | Day 75±5 after the 1st and 2nd islet infusion |
|
|
|
|
| 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:
| 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). | Posted | Number | percentage of participants | Day 365±14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Number | Percentage of participants | HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Number | percentage of participants | Day 365±14 after the 1st islet infusion |
|
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | number of events | Day 365±14 after the last islet infusion |
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | IU/kg/day | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | Percentage change | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | percent of HbA1c | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | Percent change of Hb1Ac % | Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | mg/dL | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | ng/mL | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
| 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. | 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). | Posted | Mean | Standard Deviation | µU/mL | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
| 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 | 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). | Posted | Mean | Standard Deviation | score on a scale | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
|
| 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) | 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). | Posted | Mean | Standard Deviation | U/kg/24 h | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion |
|
|
|
|
| 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. | 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). | Posted | Number | Percentage of participants | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion |
|
|
|
| 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. | 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). | Posted | Number | Percentage of participants | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, |
|
|
|
| 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. | 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). | Posted | Number | Percentage of participants | Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion |
|
|
|
| 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. | 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). | Posted | Number | Percentage of participants | At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, |
|
|
|
| 0 |
| 29 |
| 17 |
| 29 |
| 29 |
| 29 |
| EG001 | 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. | 0 | 19 | 12 | 19 | 18 | 19 |
| Leukopenia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Intra-abdominal haemmorrhage | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Implant site haemorrhage | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Multiple organ dysfunction syndrome | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Puncture site haemorrhage | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hepatic haematoma | Hepatobiliary disorders | MedDRA 19.1 | Systematic Assessment |
|
| Alloimmunisation | Immune system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Drug Hypersensititity | Immune system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Transplant rejection | Immune system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Localised infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Streptococcal sepsis | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Cervical vertebral fracture | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Complications of transplant surgery | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Upper limb fracture | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| HLA marker study positive | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Panel-reactive antibody increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Ketosis | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Adenocarcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.1 | Systematic Assessment |
|
| Diabetic neuropathy | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Generalised tonic-clonic seizure | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Acute psychosis | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Urinary retantion | Renal and urinary disorders | MedDRA 19.1 | Systematic Assessment |
|
| Oropharyngeal ache | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pulmonary embolism | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Haemorrhage | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
| Peritoneal haemorrhage | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Angina pectoris | Cardiac disorders | MedDRA 19.1 | Systematic Assessment |
|
| Bradycardia | Cardiac disorders | MedDRA 19.1 | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vitreous floaters | Eye disorders | MedDRA 19.1 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Lip oedema | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Catheter site haemorrhage | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Catheter site pain | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Chills | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Generalised oedema | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Implant site haemorrhage | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Malaise | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Vessel puncture site erythema | General disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hepatic haemorrhage | Hepatobiliary disorders | MedDRA 19.1 | Systematic Assessment |
|
| Coccidioidomycosis | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 19.1 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Head injury | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Incision site pain | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Post procedural heamatoma | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Wound Dehiscence | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Blood magnesium decreased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Blood potassium decreased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Blood pressure decreased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| C-reactive protein increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Heart rate increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Liver function test increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Portal vein presssure increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Weight increased | Investigations | MedDRA 19.1 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Fluid retention | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hyperkalaemia | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypervolaemia | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 19.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| joint swelling | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Migrane | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Emotional distress | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 19.1 | Systematic Assessment |
|
| Urinary retention | Renal and urinary disorders | MedDRA 19.1 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Upper-airway cough syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 19.1 | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Skin esfoliation | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hot flush | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypertension | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 19.1 | Systematic Assessment |
|
Not provided
Not provided
| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| transplant 2 |
|
|
| transplant 2 |
|
|
| last transplant |
|
|
| ANCOVA |
| 0.5560 |
This is a treatment p value |
| least square mean difference |
| 0.028 |
| 2-Sided |
| 95 |
| -0.068 |
| 0.124 |
| Superiority |
| This is the analytic statics for Day 365 (last Transplant) | ANCOVA | Treatment p value | 0.2537 | Treatment p value | least square mean difference | 0.056 | 2-Sided | 95 | -0.042 | 0.154 | Superiority |
| Transplant 2 |
|
|
| Last transplant |
|
|
| ANCOVA |
Treatment p value |
| 0.5966 |
Treatment p value |
| least square mean difference |
| 4.2 |
| 2-Sided |
| 95 |
| -11.8 |
| 20.2 |
| Superiority |
| This is the analytic statics for Day 365 (last Transplant) | ANCOVA | 0.5005 | Treatment p value | least square mean difference | 6.1 | 2-Sided | 95 | -12.1 | 24.4 | Superiority |
| Transplant 2 |
|
|
| Last Transplant |
|
|
| least square mean difference |
| 0.6069 |
Treatment p value |
| least square mean difference |
| 0.16 |
| 2-Sided |
| 95 |
| -0.46 |
| 0.78 |
| Superiority |
| This is the analytic statics for Day 365 (last Transplant) | ANCOVA | Treatment p value | 0.6437 | Treatment p value | Least square mean difference | 0.17 | 2-Sided | 95 | -0.56 | 0.93 | Superiority |
| Transplant 2 |
|
|
| Last Transplant |
|
|
| ANCOVA |
| 0.7853 |
Treatment p value |
| least square mean difference |
| 1.0 |
| 2-Sided |
| 95 |
| -6.3 |
| 8.3 |
| Superiority |
| This is the analytic statistics for Day 365 (last Transplant) | ANCOVA | 0.6583 | Treatment p value | least square mean difference | 1.9 | 2-Sided | 95 | -6.6 | 10.4 | Superiority |
| 15 min - day 75 - Transplant 1 |
|
|
| 30 min - day 75 - Transplant 1 |
|
|
| 60 min - day 75 - Transplant 1 |
|
|
| 90 min - day 75 - Transplant 1 |
|
|
| 120 min - day 75 - Transplant 1 |
|
|
| Basal - day 75 - Transplant 2 |
|
|
| 15 min - day 75 - Transplant 2 |
|
|
| 30 min - day 75 - Transplant 2 |
|
|
| 60 min - day 75 - Transplant 2 |
|
|
| 90 min - day 75 - Transplant 2 |
|
|
| 120 min - day 75 - Transplant 2 |
|
|
| Basal - day 365 - Last transplant |
|
|
| 15 min - day 365 - Last transplant |
|
|
| 30 min - day 365 - Last transplant |
|
|
| 60 min - day 365 - Last transplant |
|
|
| 90 min - day 365 - Last transplant |
|
|
| 120 min - day 365 - Transplant 2 |
|
|
| 15 min - day 75 - Transplant 1 |
|
|
| 30 min - day 75 - Transplant 1 |
|
|
| 60 min - day 75 - Transplant 1 |
|
|
| 90 min - day 75 - Transplant 1 |
|
|
| 120 min - day 75 - Transplant 1 |
|
|
| Basal - day 75 - Transplant 2 |
|
|
| 15 min - day 75 - Transplant 2 |
|
|
| 30 min - day 75 - Transplant 2 |
|
|
| 60 min - day 75 - Transplant 2 |
|
|
| 90 min - day 75 - Transplant 2 |
|
|
| 120 min - day 75 - Transplant 2 |
|
|
| Basal - day 365 - Last transplant |
|
|
| 15 min - day 365 - Last transplant |
|
|
| 30 min - day 365 - Last transplant |
|
|
| 60 min - day 365 - Last transplant |
|
|
| 90 min - day 365 - Last transplant |
|
|
| 120 min - day 365 - Transplant 2 |
|
|
| 15 min - day 75 - Transplant 1 |
|
|
| 30 min - day 75 - Transplant 1 |
|
|
| 60 min - day 75 - Transplant 1 |
|
|
| 90 min - day 75 - Transplant 1 |
|
|
| 120 min - day 75 - Transplant 1 |
|
|
| Basal - day 75 - Transplant 2 |
|
|
| 15 min - day 75 - Transplant 2 |
|
|
| 30 min - day 75 - Transplant 2 |
|
|
| 60 min - day 75 - Transplant 2 |
|
|
| 90 min - day 75 - Transplant 2 |
|
|
| 120 min - day 75 - Transplant 2 |
|
|
| Basal - day 365 - Last transplant |
|
|
| 15 min - day 365 - Last transplant |
|
|
| 30 min - day 365 - Last transplant |
|
|
| 60 min - day 365 - Last transplant |
|
|
| 90 min - day 365 - Last transplant |
|
|
| 120 min - day 365 - Transplant 2 |
|
|
| day 75 - Transplant 2 |
|
|
| day 365 - Last transplant |
|
|
| ANOVA |
| 0.8753 |
Treatment p value |
| Least square mean difference |
| 0.10 |
| 2-Sided |
| 95 |
| -1.18 |
| 1.38 |
| Superiority |
| This is the analytic statistics for Day 365 (last Transplant) | ANOVA | 0.3955 | Treatment p value | Least square mean difference | -0.59 | 2-Sided | 95 | -1.97 | 0.80 | Superiority |
| day 75 - Transplant 2 |
|
|
| day 365 - Last transplant |
|
|
| ANOVA |
| 0.0328 |
Treatment p value |
| Least square mean difference |
| -0.218 |
| 2-Sided |
| 95 |
| -0.417 |
| -0.019 |
| Superiority |
| This is the analytic statistics for Day 365 (last Transplant) | ANOVA | 0.1059 | This is the analytic statistics for Day 75 (Transplant 2) | Least square mean difference | -0.177 | 2-Sided | 95 | -0.393 | 0.039 | Superiority |
| pre-transplant 1 - negative |
|
|
| day 75 - Transplant 1 - positive |
|
|
| day 75 - Transplant 1 - negative |
|
|
| pre-transplant 2 - positive |
|
|
| pre-transplant 2 - negative |
|
|
| day 75 - Transplant 2 - positive |
|
|
| day 75 - Transplant 2 - negative |
|
|
| day 365 - Last transplant - positive |
|
|
| day 365 - Last transplant - negative |
|
|
| pre-transplant 1 - negative |
|
|
| day 75 - Transplant 1 - positive |
|
|
| day 75 - Transplant 1 - negative |
|
|
| pre-transplant 2 - positive |
|
|
| pre-transplant 2 - negative |
|
|
| day 75 - Transplant 2 - positive |
|
|
| day 75 - Transplant 2 - negative |
|
|
| day 365 - Last transplant - positive |
|
|
| day 365 - Last transplant - negative |
|
|
| day 75 - Transplant 1 - positive |
|
| day 75 - Transplant 1 - negative |
|
| pre-transplant 2 - positive |
|
| pre-transplant 2 - negative |
|
| day 75 - Transplant 2 - positive |
|
| day 75 - Transplant 2 - negative |
|
| day 365 - Last transplant - positive |
|
| day 365 - Last transplant - negative |
|
| day 75 - Transplant 1 - positive |
|
| day 75 - Transplant 1 - negative |
|
| pre-transplant 2 - positive |
|
| pre-transplant 2 - negative |
|
| day 75 - Transplant 2 - positive |
|
| day 75 - Transplant 2 - negative |
|
| day 365 - Last transplant - positive |
|
| day 365 - Last transplant - negative |
|