Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 2010-019424-31 | 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
Not provided
Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).
Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Reparixin | Experimental | Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. |
|
| No experimental intervention | No Intervention | Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Reparixin | Drug | Reparixin + immunosuppression |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 | Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
| day 75 +/- 5 post-transplant |
Not provided
| Measure | Description | Time Frame |
|---|---|---|
| The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
|
Inclusion criteria:
Exclusion criteria:
Recipients of any previous transplant, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.
Recipients of islet from a non-heart beating donor.
A body mass index >30 kg/m2 or patient weight <45 kg.
Pre-transplant average daily insulin requirement >1 IU/kg/day.
Pre-transplant HbA1c >11%.
Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 micromol/L]).
Patients who receive treatment for a medical condition requiring chronic use of systemic steroids.
Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant.
Use of any investigational agent within 4 weeks of enrolment.
Hypersensitivity to:
Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).
Sites will comply with any additional exclusion criteria locally accepted, as per centre practice.
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Lorenzo Piemonti, MD | Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy | Principal Investigator |
| Barbara Ludwig, MD | University Hospital Carl Gustav Carus - Dresden; Germany | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Carl Gustav Carus Dresden | Dresden | 01307 | Germany | |||
| Ospedale San Raffaele |
| 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. | |
| 23912763 | Derived | Citro A, Cantarelli E, Piemonti L. Anti-inflammatory strategies to enhance islet engraftment and survival. Curr Diab Rep. 2013 Oct;13(5):733-44. doi: 10.1007/s11892-013-0401-0. |
Not provided
Not provided
Not provided
A total of 9 patients were enrolled into the study; 6 were randomized to reparixin and 3 to the control group. All in the control group and 2 in the reparixin group were withdrawn after Transplant 1 due to graft loss. 4 in the reparixin group received Transplant 2. Thereafter, 1 was withdrawn due to graft loss. 1 was lost to follow-up.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Reparixin | Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression |
| FG001 | No Experimental Intervention | Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety Population: All patients who were randomized into the study were included in the safety population.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Reparixin | Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression |
| 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 | The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 | Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
| Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Number | percentage of patients | day 75 +/- 5 post-transplant |
|
Through study completion, till follow-up (up to 1 year after the second islet infusion).
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 | Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 13.0 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Luisa Daffonchio, PhD | Dompé SpA | +39 583831 | daffonchio@dompe.it |
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
Not provided
| up to one year after the transplant |
| Time to Achieve Insulin-independence After the Transplant 2 | Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date. | up to 1 year after transplant 2 |
| Total Time of Insulin Independence After the Transplant | Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence. Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days. | up to 1 year after transplant 2 |
| Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). | Months 1, 3, 6, 12 post-transplant |
| Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). | Months 1, 3, 6, 12 post-transplant |
| Absolute Change in Fasted HbA1c From Pre-transplant Levels | The absolute change between the time-point value and baseline value. | Months 1, 3, 6, 12 post-transplant |
| Percentage Change in Fasted HbA1c From Pre-transplant Levels | The absolute percentage between the time-point value and baseline value. | Months 1, 3, 6, 12 post-transplant |
| The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness". | Months 1, 3, 6, 12 post-transplant |
| Number of Participants With Adverse Events by Severity and With Serious Adverse Events | Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant. A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. | up to 1 year after transplant |
| AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
| AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
| AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
| AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 | For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated. AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg). | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
| The Percentage of Patients Free of Severe Hypoglycaemic Events | A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. | Months 1, 3, 6, 12 post-transplant |
| Beta-cell Function as Assessed by Beta-score | The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function. | Months 1, 3, 6, 12 post-transplant |
| Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets. | At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2 |
| Serum Level of Alanine Amino Transferase (ALT) | ALT is commonly measured clinically as part of liver function tests. | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant |
| Serum Level of Aspartate Amino Transferase (AST) | AST is commonly measured clinically as part of liver function tests. | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant |
| Change From Pre-transplant in Cytokine Levels - CXCL8 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
| Change From Pre-transplant in Cytokine Levels - CXCL1 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
| Change From Pre-transplant in Cytokine Levels - IL-6 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
| Milan |
| 20132 |
| Italy |
| BG001 | No Experimental Intervention | Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. |
| 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 + Immunosuppression
Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration.
Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour.
For immunosuppression regimen see the other arm description.
Reparixin: Reparixin + immunosuppression
| OG001 | No Experimental Intervention | Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. |
|
|
| Other Pre-specified | The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant | Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
| Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Number | percentage of patients | up to one year after the transplant |
|
|
|
| Other Pre-specified | Time to Achieve Insulin-independence After the Transplant 2 | Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Mean | Standard Deviation | days | up to 1 year after transplant 2 |
|
|
|
| Other Pre-specified | Total Time of Insulin Independence After the Transplant | Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence. Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Mean | Standard Deviation | total number of days | up to 1 year after transplant 2 |
|
|
|
| Other Pre-specified | Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Mean | Standard Deviation | IU/kg/day | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels | Daily insulin requirement was calculated as the average requirement over the previous week (seven days). | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Mean | Standard Deviation | Percentage change | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Absolute Change in Fasted HbA1c From Pre-transplant Levels | The absolute change between the time-point value and baseline value. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Mean | Standard Deviation | Percentage of Hb | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Percentage Change in Fasted HbA1c From Pre-transplant Levels | The absolute percentage between the time-point value and baseline value. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Mean | Standard Deviation | Percentage change | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness | Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness". | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population | Posted | Number | Percentage of patients | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Number of Participants With Adverse Events by Severity and With Serious Adverse Events | Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant. A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect. | Safety Population: all patients who were randomized into the study. | Posted | Number | participants | up to 1 year after transplant |
|
|
|
| Other Pre-specified | AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Mean | Standard Deviation | mg*hr/dL | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Mean | Standard Deviation | mg*hr/dL | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant | Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received. | Posted | Mean | Standard Deviation | μU*hr/mL | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 | For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated. AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg). | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received. | Posted | Mean | Standard Deviation | (mg*hr/dL)/IEQ/kg | -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | The Percentage of Patients Free of Severe Hypoglycaemic Events | A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Number | Percentage of patients | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Beta-cell Function as Assessed by Beta-score | The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. | Posted | Mean | Standard Deviation | score on a scale | Months 1, 3, 6, 12 post-transplant |
|
|
|
| Other Pre-specified | Beta-cell Function as Assessed by TEF/IEQ/kg Ratio | The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets. | Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received. | Posted | Mean | Standard Deviation | ratio | At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2 |
|
|
|
| Other Pre-specified | Serum Level of Alanine Amino Transferase (ALT) | ALT is commonly measured clinically as part of liver function tests. | Safety population: all patients who were randomized into the study. | Posted | Mean | Standard Deviation | U/L | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant |
|
|
|
| Other Pre-specified | Serum Level of Aspartate Amino Transferase (AST) | AST is commonly measured clinically as part of liver function tests. | Safety population: all patients who were randomized into the study. | Posted | Mean | Standard Deviation | U/L | Pre-transplant and at days 1-7 and months 1 and 3 post-transplant |
|
|
|
| Other Pre-specified | Change From Pre-transplant in Cytokine Levels - CXCL8 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | Safety population: all patients who were randomized into the study. | Posted | Mean | Standard Deviation | pg/mL | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
|
|
|
| Other Pre-specified | Change From Pre-transplant in Cytokine Levels - CXCL1 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | Safety population: all patients who were randomized into the study. | Posted | Mean | Standard Deviation | pg/mL | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
|
|
|
| Other Pre-specified | Change From Pre-transplant in Cytokine Levels - IL-6 | Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion). | Safety population: all patients who were randomized into the study. | Posted | Mean | Standard Deviation | pg/mL | 6, 12, 24, 72, 120, and 168 hours post-transplant 1 |
|
|
|
| 0 |
| 6 |
| 3 |
| 6 |
| 6 |
| 6 |
| EG001 | No Experimental Intervention | Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL. | 0 | 3 | 1 | 3 | 3 | 3 |
| Diarrhea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Gastrointestinal hemorrhage | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Peritoneal hemorrhage | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Drug administration error | Injury, poisoning and procedural complications | MedDRA 13.0 | Systematic Assessment |
|
| Diabetic ketoacidosis | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
|
| Renal impairment | Renal and urinary disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hemorrhage | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | MedDRA 13.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 13.0 | Systematic Assessment |
|
| Infusion site pain | General disorders | MedDRA 13.0 | Systematic Assessment |
|
| Oedema | General disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hepatic haemorrhage | Hepatobiliary disorders | MedDRA 13.0 | Systematic Assessment |
|
| Blood bicarbonate decreased | Investigations | MedDRA 13.0 | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA 13.0 | Systematic Assessment |
|
| Body temperature increased | Investigations | MedDRA 13.0 | Systematic Assessment |
|
| C-reactive protein increased | Investigations | MedDRA 13.0 | Systematic Assessment |
|
| Fibrin degradation product increased | Investigations | MedDRA 13.0 | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 13.0 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 13.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
|
| Neuralgia | Nervous system disorders | MedDRA 13.0 | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 13.0 | Systematic Assessment |
|
Not provided
Not provided
| D004700 | Endocrine System Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| transplant 2 |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| month 3 (transplant 1) |
|
|
| month 6 (transplant 1) |
|
|
| month 1 (transplant 2) |
|
|
| month 3 (transplant 2) |
|
|
| month 6 (transplant 2) |
|
|
| month 12 (transplant 2) |
|
|
| TEAE severe |
|
| SAE |
|
| Month 3, transplant 1 |
|
|
| Month 6, transplant 1 |
|
|
| Month 1, transplant 2 |
|
|
| Month 3, transplant 2 |
|
|
| Month 6, transplant 2 |
|
|
| Month 12, last transplant |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (last transplant) |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| month 3 (transplant 1) |
|
|
| month 6 (transplant 1) |
|
|
| month 1 (transplant 2) |
|
|
| month 3 (transplant 2) |
|
|
| month 6 (transplant 2) |
|
|
| month 12 (transplant 2) |
|
|
| Month 3, transplant 1 |
|
|
| Month 6, transplant 1 |
|
|
| Month 1, transplant 2 |
|
|
| Month 3, transplant 2 |
|
|
| Month 6, transplant 2 |
|
|
| Month 12, transplant 2 |
|
|
| Month 3 (transplant 1) |
|
|
| Month 6 (transplant 1) |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Month 6 (transplant 2) |
|
|
| Month 12 (transplant 2) |
|
|
| Day 1 post-transplant 1 |
|
|
| Day 2 post-transplant 1 |
|
|
| Day 3 post-transplant 1 |
|
|
| Day 4 post-transplant 1 |
|
|
| Day 5 post-transplant 1 |
|
|
| Day 6 post-transplant 1 |
|
|
| Day 7 post-transplant 1 |
|
|
| Month 1 (transplant 1) |
|
|
| Month 3 (transplant 1) |
|
|
| Pre-transplant 2 |
|
|
| Day 1 post-transplant 2 |
|
|
| Day 2 post-transplant 2 |
|
|
| Day 3 post-transplant 2 |
|
|
| Day 4 post-transplant 2 |
|
|
| Day 5 post-transplant 2 |
|
|
| Day 6 post-transplant 2 |
|
|
| Day 7 post-transplant 2 |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| Day 1 post-transplant 1 |
|
|
| Day 2 post-transplant 1 |
|
|
| Day 3 post-transplant 1 |
|
|
| Day 4 post-transplant 1 |
|
|
| Day 5 post-transplant 1 |
|
|
| Day 6 post-transplant 1 |
|
|
| Day 7 post-transplant 1 |
|
|
| Month 1 (transplant 1) |
|
|
| Month 3 (transplant 1) |
|
|
| Pre-transplant 2 |
|
|
| Day 1 post-transplant 2 |
|
|
| Day 2 post-transplant 2 |
|
|
| Day 3 post-transplant 2 |
|
|
| Day 4 post-transplant 2 |
|
|
| Day 5 post-transplant 2 |
|
|
| Day 6 post-transplant 2 |
|
|
| Day 7 post-transplant 2 |
|
|
| Month 1 (transplant 2) |
|
|
| Month 3 (transplant 2) |
|
|
| 12 hours post-transplant |
|
|
| 24 hours post-transplant |
|
|
| 72 hours post-transplant |
|
|
| 120 hours post-transplant |
|
|
| 168 hours post-transplant |
|
|
| 12 hours post-transplant |
|
|
| 24 hours post-transplant |
|
|
| 72 hours post-transplant |
|
|
| 120 hours post-transplant |
|
|
| 168 hours post-transplant |
|
|
| 12 hours post-transplant |
|
|
| 24 hours post-transplant |
|
|
| 72 hours post-transplant |
|
|
| 120 hours post-transplant |
|
|
| 168 hours post-transplant |
|
|