Pancreatectomy for Chronic Pancreatitis
Conditions
Keywords
Pancreatic islet auto-transplantation
Brief summary
The study is a phase 2/3, multicenter, double-blind, parallel assignment study. It involves 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT). The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.
Detailed description
In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in IAT (Islet Auto-Transplantation) is independent from immunological processes and does not require immunosuppression management. On the other hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the liver in a syngeneic model of islet transplantation in mice. Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of reparixin in improving graft survival and function. Protection from the loss and/or deterioration of transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft outcome. Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific inflammatory events surrounding the early phases of IAT. The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1) assigned to receive either reparixin \[continuous i.v. infusion for 7 days (168hrs)\], or matched placebo (control group),starting approximately 12hrs before islet infusion. The two groups will be balanced within each centre. All patients who are randomized and receive the Investigational Product (either reparixin or placebo) will be included in the ITT analysis. Patients will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made for events occurring after randomization that could be influenced by the randomized assignment. Recruitment will be competitive among the study sites, until the planned number of patients is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to account for any difference in transplant rate among study sites. Each centre will enroll patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization list). A maximum of 48 patients is allowed for the site of the Primary Investigator. Each patient will be involved in the study for 7 day hospital stay during pancreatectomy followed by islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.
Interventions
DRUGReparixin
Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour
DRUGPlacebo
Physiologic solution administered at 0.25 mL/kg/hour
Sponsors
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients eligible for an IAT following total (or completion) pancreatectomy. * Ages \> 18 years. * Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations. * Patients who have given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
Exclusion criteria
* Recipients of a previous IAT (if completion pancreatectomy). * Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic benign diseases other than chronic pancreatitis, including insulinomas, etc. * 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/AST \> 3 x upper limit of normal (ULN) or increased total bilirubin above the upper limit at local laboratory). Patients with Gilbert's syndrome (elevated unconjugated bilirubin levels in the absence of any evidence of hepatic or biliary tract disease) are not excluded. * Patients with a preoperative International Normalized Ratio (INR) \> 1.5 or any known coagulopathy. * Hypersensitivity to: 1. ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID). 2. medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib. * Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome). * Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use of \<5mg prednisone daily or equivalent dose of hydrocortisone, for physiological replacement only) or with any immune modulators in the 4 weeks prior to enrolment. * Patients with pre-existing diabetes or evidence of impaired β-cells function, based on pre-operative fasting blood glucose \>115 mg/dL and/or a HbA1c \> 6.5%, or requiring treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks prior to enrolment. * Use of any investigational agent in the 4 weeks prior to enrolment, including any anti-cytokine/chemokine agents. * Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males). (NB: pregnancy should be avoided in patients or partners during the first month after completing the treatment with the Investigational Product; no other specific warnings are described, considering the treatment course of the Investigational Product, its PK profile, and the lack of significant adverse effects on mating performance and fertility in animal studies). * Patients with past or current history of alcohol abuse based on clinical history and/or past treatment for alcohol addiction. * Patients with evidence of pre-operative portal hypertension as per clinical history and abdominal/liver imaging by ultrasound techniques. Sites will comply with any additional or more restrictive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant. | day 365±14 after the transplant | Insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: * a glycated hemoglobin (HbA1c) level \<6.5%; * fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement; * a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement); * a laboratory fasting glucose in the non-diabetic range (\<126 mg/dL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant | day 365±14 after the transplant | AUC for the serum C-peptide level is calculated during the first 4 hours of a mixed meal tolerance test (MMTT), normalized by the number of Islet Equivalent (IEQ)/kg |
| Average Daily Insulin Requirements at Day 75±14 After the Transplant | day 75±14 after the transplant | Daily insulin is reported as IU/kg and intake averaged over the previous week. |
| Average Daily Insulin Requirements at Day 365±14 After the Transplant | day 365±14 after the transplant | Daily insulin is reported as IU/kg and intake averaged over the previous week. |
| Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | day 75±14 after the transplant | Data of this outcome are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=42; 46 * 30 min; N=40; 46 * 60 min; N=40; 46 * 90 min; N=40; 46 * 120 min; N=41; 46 * 180 min; N=40; 46 * 240 min; N=39; 44 |
| Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | day 365±14 after the transplant | Data are reported as model estimates over all timepoints This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=34; 42 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=34; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 41 * 240 min; N=33; 41 |
| Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | day 75±14 after the transplant | Data are reported as model estimates over all timepoints. This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=44; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=43; 47 * 30 min; N=41; 47 * 60 min; N=42; 47 * 90 min; N=42; 47 * 120 min; N=42; 47 * 180 min; N=41; 47 * 240 min; N=40; 44 |
| Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | day 365±14 after the transplant | Data are reported as model estimates over all timepoints. This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=33; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=33; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 40 * 240 min; N=33; 41 |
| Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | day 75±14 after the transplant | Data are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=43; 47 * 30 min; N=41; 47 * 60 min; N=41; 47 * 90 min; N=41; 47 * 120 min; N=42; 47 * 180 min; N=41; 47 * 240 min; N=40; 44 |
| Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | day 365±14 after the transplant | Data are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=34; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal) * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=34; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 41 * 240 min; N=33; 40 |
| β-cell Function at Day 75±14 After the Transplant | day 75±14 after the transplant | This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for: * fasting plasma glucose, * HbA1c, * stimulated C-peptide * insulin requirement subscales. The higher the total score, the better the outcome. * Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome) * HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome) * Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome) * Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome) |
| β-cell Function at Day 365±14 After the Transplant | day 365±14 after the transplant | This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for glucose, HbA1c, stimulated C-peptide and insulin requirement subscales. The higher the total score the better the outcome. * Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome) * HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome) * Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome) * Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome) |
| Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant | day 365±14 after the transplant | Percentage of patients with a glycated haemoglobin (HbA1c) \<6.5% at day 365±14 after the transplant. |
| Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant | from day 75±14 to day 365±14 after the transplant | A severe hypoglycemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level \<54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration. |
| Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive | from day 75±14 to day 365±14 after the transplant | Percentage of patients with an HbA1c \<6.5% at day 365±14 after the transplant AND free of severe hypoglycemic events from day 75±14 to day 365±14 after the transplant inclusive.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. |
| Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | up to day 365±14 after the transplant | The percentages of patients with any treatment emergent adverse events (TEAE, serious and non serious) and with serious TEAE by severity are presented. Patients with multiple events within a particular system organ class or preferred term were counted only under the category of their most severe event within that system organ class or preferred term. A serious AE was defined as any untoward medical occurrence that at any dose: * Resulted in death * Was life-threatening (ie, the patient was at risk of death at the time of the event) * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above |
| Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant | day 75±14 after the transplant | AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg |
| Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | day 365±14 after the transplant | Malnutrition risk levels are defined as: * Poor prognosis = pre-albumin level \<5.0 mg/dL * Significant risk = pre-albumin level 5.0 to 10.9 mg/dL * Increased risk = pre-albumin level 11.0 to 15.0 mg/dL * Normal = pre-albumin level \> 15.0 (up to 35.0) mg/dL |
| Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | day 75±14 after the transplant | Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: * No steatorrhea; * Steatorrhea few times per week; * Steatorrhea daily; * Stool incontinence. |
| Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | day 365±14 after the transplant | Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: * No steatorrhea; * Steatorrhea few times per week; * Steatorrhea daily; * Stool incontinence. |
| Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | from day 75±14 to day 365±14 after the transplant | The following definition applies: \- Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration \<70mg/dL. |
| Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | from day 75±14 to day 365±14 after the transplant | The following definition applies: \- Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration \<70mg/dL. |
| Cumulative Number of Diabetic Ketoacidosis-related Events | from day 75±14 to day 365±14 after the transplant | A diabetic ketoacidosis event is defined as the presence of: * hyperglycemia (blood glucose \>200 mg/dL); * pH \<7.3 or HCO3 \<15; * ketones positive in the serum or urine. |
| Peak C-peptide at Day 75 After the Transplant | Day 75±14 after the transplant | Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes. |
| Peak C-peptide at Day 365 After the Transplant | Day 365±14 after the transplant | Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes. |
| Time-to-peak C-peptide at Day 75 After the Transplant | day 75±14 and day 365±14 after the transplant | The time-to-peak value in minutes was computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test Case Report Form. |
| Time-to-peak C-peptide at Day 365 After the Transplant | Day 365±14 after the transplant | The time to peak value in minutes will be computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test CRF. |
| Change From Baseline in Post-transplant Alanine Aminotransferase (ALT) | Baseline, Days 2, 3, 7, 75 ±14 after the transplant | Data are reported as model estimates over all timepoints. This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * baseline; N=50; 52 * Day 2 post-transplant; N=49; 51 * Day 3 post-transplant; N=47; 50 * Day 7 post-transplant; N=47; 50 * Day 75 post-transplant; N=44; 47 |
| Change From Baseline in Post-transplant Aspartate Aminotransferase (AST) | Baseline, Days 2, 3, 7, 75±14 after the transplant | Data are reported as model estimates over all timepoints. This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * baseline; N=50; 52 * Day 2 post-transplant; N=49; 51 * Day 3 post-transplant; N=47; 50 * Day 7 post-transplant; N=47; 50 * Day 75 post-transplant; N=44; 47 |
| Number of Treatment Emergent Adverse Events Related to Investigational Product | Throughout the study From Day -1 to hospital discharge | Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called Adverse reactions (ADR). An adverse reaction is defined as any untoward medical occurrence in a patient or clinical investigation patient, which has a causal relationship with the administered medicinal product. |
| Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | Throughout the study From Day -1 to hospital discharge for all adverse events, and from then to day 365 post-transplantation only for serious adverse events | Serious Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called serious Adverse reactions. A serious adverse reaction is defined as any untoward medical occurrence with a causal relationship with the administered medicinal product, that at any dose: * Resulted in death * Was life-threatening (ie, the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.) * Required patient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above |
| Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | day 75±14 after the transplant | Malnutrition risk levels are defined as: * Poor prognosis = pre-albumin level \<5.0 mg/dL * Significant risk = pre-albumin level 5.0 to 10.9 mg/dL * Increased risk = pre-albumin level 11.0 to 15.0 mg/dL * Normal = pre-albumin level \> 15.0 (up to 35.0) mg/dL |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Reparixin Solution for intravenous (IV) infusion with active compound
Reparixin: Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour | 50 |
| Placebo Physiologic solution
Placebo: Physiologic solution administered at 0.25 mL/kg/hour | 52 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did Not Have Transplant | 1 | 0 |
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Patient didn't proceed to pancreatectomy | 0 | 1 |
| Overall Study | Research visit not done, data recorded | 1 | 0 |
| Overall Study | Subject excluded after randomization | 1 | 0 |
| Overall Study | Subject Unable To Comply With Final Day | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Reparixin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 46 Participants | 52 Participants | 98 Participants |
| Age, Continuous | 40.0 years STANDARD_DEVIATION 14.4 | 39.0 years STANDARD_DEVIATION 10 | 39.5 years STANDARD_DEVIATION 12.2 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 49 Participants | 49 Participants | 98 Participants |
| Region of Enrollment Canada | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 46 participants | 49 participants | 95 participants |
| Sex: Female, Male Female | 33 Participants | 38 Participants | 71 Participants |
| Sex: Female, Male Male | 17 Participants | 14 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 52 |
| other Total, other adverse events | 46 / 50 | 48 / 52 |
| serious Total, serious adverse events | 29 / 50 | 30 / 52 |
Outcome results
Primary
Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.
Insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: * a glycated hemoglobin (HbA1c) level \<6.5%; * fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement; * a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement); * a laboratory fasting glucose in the non-diabetic range (\<126 mg/dL).
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin | Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant. | 20.0 Percentage of participants |
| Placebo | Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant. | 21.2 Percentage of participants |
p-value: 0.54295% CI: [-14.3, 0]Cochran-Mantel-Haenszel
Secondary
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant
AUC for the serum C-peptide level is calculated during the first 4 hours of a mixed meal tolerance test (MMTT), normalized by the number of Islet Equivalent (IEQ)/kg
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant | 0.5563432 (ng/mL)/(IEQ/kg)*1000 | Standard Deviation 0.3133415 |
| Placebo | Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant | 0.6865954 (ng/mL)/(IEQ/kg)*1000 | Standard Deviation 0.446446 |
p-value: 0.16195% CI: [-0.287431, 0.0517825]t-test, 2 sided
Secondary
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant
AUC for the serum C-peptide level is calculated during the first 4 hours of an MMTT, normalized by the number of Islet Equivalent (IEQ)/kg
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant | 0.5314796 (ng/mL)/(IEQ/kg)*1000 | Standard Deviation 0.3520819 |
| Placebo | Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant | 0.6827533 (ng/mL)/(IEQ/kg)*1000 | Standard Deviation 0.4769178 |
p-value: 0.09295% CI: [-0.317803, -0.0025525]t-test, 2 sided
Secondary
Average Daily Insulin Requirements at Day 365±14 After the Transplant
Daily insulin is reported as IU/kg and intake averaged over the previous week.
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Average Daily Insulin Requirements at Day 365±14 After the Transplant | 0.1723 IU/kg/day | Standard Deviation 0.1893 |
| Placebo | Average Daily Insulin Requirements at Day 365±14 After the Transplant | 0.1823 IU/kg/day | Standard Deviation 0.1994 |
p-value: 0.81795% CI: [-0.0939, 0.0689]t-test, 2 sided
Secondary
Average Daily Insulin Requirements at Day 75±14 After the Transplant
Daily insulin is reported as IU/kg and intake averaged over the previous week.
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Average Daily Insulin Requirements at Day 75±14 After the Transplant | 0.2125 IU/kg/day | Standard Deviation 0.1643 |
| Placebo | Average Daily Insulin Requirements at Day 75±14 After the Transplant | 0.2190 IU/kg/day | Standard Deviation 0.1589 |
p-value: 0.84695% CI: [-0.0508, 0.0781]t-test, 2 sided
Secondary
Change From Baseline in Post-transplant Alanine Aminotransferase (ALT)
Data are reported as model estimates over all timepoints. This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * baseline; N=50; 52 * Day 2 post-transplant; N=49; 51 * Day 3 post-transplant; N=47; 50 * Day 7 post-transplant; N=47; 50 * Day 75 post-transplant; N=44; 47
Time frame: Baseline, Days 2, 3, 7, 75 ±14 after the transplant
Population: Safety Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Change From Baseline in Post-transplant Alanine Aminotransferase (ALT) | 60.4105 U/L | Standard Error 40.9699 |
| Placebo | Change From Baseline in Post-transplant Alanine Aminotransferase (ALT) | 29.0615 U/L | Standard Error 40.2724 |
p-value: =0.501895% CI: [-60.998, 123.7]Mixed Models Analysis
Secondary
Change From Baseline in Post-transplant Aspartate Aminotransferase (AST)
Data are reported as model estimates over all timepoints. This safety parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * baseline; N=50; 52 * Day 2 post-transplant; N=49; 51 * Day 3 post-transplant; N=47; 50 * Day 7 post-transplant; N=47; 50 * Day 75 post-transplant; N=44; 47
Time frame: Baseline, Days 2, 3, 7, 75±14 after the transplant
Population: Safety population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Change From Baseline in Post-transplant Aspartate Aminotransferase (AST) | 46.8755 U/L | Standard Error 27.8248 |
| Placebo | Change From Baseline in Post-transplant Aspartate Aminotransferase (AST) | 23.3301 U/L | Standard Error 26.6545 |
p-value: =0.453795% CI: [-38.6619, 85.7528]Mixed Models Analysis
Secondary
Cumulative Number of Diabetic Ketoacidosis-related Events
A diabetic ketoacidosis event is defined as the presence of: * hyperglycemia (blood glucose \>200 mg/dL); * pH \<7.3 or HCO3 \<15; * ketones positive in the serum or urine.
Time frame: from day 75±14 to day 365±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Cumulative Number of Diabetic Ketoacidosis-related Events | 0.0 number of events | Standard Deviation 0 |
| Placebo | Cumulative Number of Diabetic Ketoacidosis-related Events | 0.0 number of events | Standard Deviation 0 |
p-value: 1Wilcoxon rank-sum test
Secondary
Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
The following definition applies: \- Asymptomatic hypoglycemia = An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration \<70mg/dL.
Time frame: from day 75±14 to day 365±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | 1.5 number of episodes | Standard Deviation 4.3 |
| Placebo | Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | 4.4 number of episodes | Standard Deviation 25.6 |
p-value: 0.448Wilcoxon rank-sum test
Secondary
Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
The following definition applies: \- Documented symptomatic hypoglycemia = An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration \<70mg/dL.
Time frame: from day 75±14 to day 365±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | 4.6 number of episodes | Standard Deviation 13.9 |
| Placebo | Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant | 4.8 number of episodes | Standard Deviation 17.8 |
p-value: 0.91Wilcoxon rank-sum test
Secondary
Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant
A severe hypoglycemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level \<54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time frame: from day 75±14 to day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant | 0.1 number of events | Standard Deviation 0.94 |
| Placebo | Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant | 0.0 number of events | Standard Deviation 0.21 |
p-value: 0.33995% CI: [0.29, 34.97]Anderson-Gill model
Secondary
Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study
The percentages of patients with any treatment emergent adverse events (TEAE, serious and non serious) and with serious TEAE by severity are presented. Patients with multiple events within a particular system organ class or preferred term were counted only under the category of their most severe event within that system organ class or preferred term. A serious AE was defined as any untoward medical occurrence that at any dose: * Resulted in death * Was life-threatening (ie, the patient was at risk of death at the time of the event) * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above
Time frame: up to day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE- Mild events | 90.0 percentage of patients |
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE - Moderate events | 90.0 percentage of patients |
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE - Severe events | 64.0 percentage of patients |
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Mild events | 18.0 percentage of patients |
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Moderate events | 22.0 percentage of patients |
| Reparixin | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Severe events | 42.0 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Moderate events | 13.5 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE- Mild events | 92.3 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Mild events | 23.1 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE - Moderate events | 80.8 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | serious TEAE- Severe events | 32.7 percentage of patients |
| Placebo | Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study | TEAE - Severe events | 53.8 percentage of patients |
Secondary
Number of Serious Treatment Emergent Adverse Events Related to Investigational Product
Serious Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called serious Adverse reactions. A serious adverse reaction is defined as any untoward medical occurrence with a causal relationship with the administered medicinal product, that at any dose: * Resulted in death * Was life-threatening (ie, the patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.) * Required patient hospitalization or prolongation of existing hospitalization * Resulted in persistent or significant disability/incapacity * Was an important medical event that, based upon appropriate medical judgment, may have jeopardized the patient and may have required medical or surgical intervention to prevent one of the outcomes listed above
Time frame: Throughout the study From Day -1 to hospital discharge for all adverse events, and from then to day 365 post-transplantation only for serious adverse events
Population: Safety population: Safety Population consists of all randomized patients. Summarization and analysis of this population were based on treatment received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | possibly related | 4 Number of events |
| Reparixin | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | probably related | 0 Number of events |
| Reparixin | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | highly probably related | 0 Number of events |
| Placebo | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | possibly related | 1 Number of events |
| Placebo | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | probably related | 0 Number of events |
| Placebo | Number of Serious Treatment Emergent Adverse Events Related to Investigational Product | highly probably related | 0 Number of events |
Secondary
Number of Treatment Emergent Adverse Events Related to Investigational Product
Treatment emergent adverse events - possibly, probably and highly probably - related to investigational product are called Adverse reactions (ADR). An adverse reaction is defined as any untoward medical occurrence in a patient or clinical investigation patient, which has a causal relationship with the administered medicinal product.
Time frame: Throughout the study From Day -1 to hospital discharge
Population: Safety Population:Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Number of Treatment Emergent Adverse Events Related to Investigational Product | highly probably related | 0 Number of events |
| Reparixin | Number of Treatment Emergent Adverse Events Related to Investigational Product | possibly related | 20 Number of events |
| Reparixin | Number of Treatment Emergent Adverse Events Related to Investigational Product | probably related | 0 Number of events |
| Placebo | Number of Treatment Emergent Adverse Events Related to Investigational Product | highly probably related | 0 Number of events |
| Placebo | Number of Treatment Emergent Adverse Events Related to Investigational Product | possibly related | 28 Number of events |
| Placebo | Number of Treatment Emergent Adverse Events Related to Investigational Product | probably related | 0 Number of events |
Secondary
Peak C-peptide at Day 365 After the Transplant
Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.
Time frame: Day 365±14 after the transplant
Population: ITT Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Peak C-peptide at Day 365 After the Transplant | 2.630 ng/mL | Standard Deviation 1.467 |
| Placebo | Peak C-peptide at Day 365 After the Transplant | 3.170 ng/mL | Standard Deviation 1.843 |
Secondary
Peak C-peptide at Day 75 After the Transplant
Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.
Time frame: Day 75±14 after the transplant
Population: ITT population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Peak C-peptide at Day 75 After the Transplant | 2.640 ng/mL | Standard Deviation 1.529 |
| Placebo | Peak C-peptide at Day 75 After the Transplant | 2.900 ng/mL | Standard Deviation 1.753 |
Secondary
Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant
Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: * No steatorrhea; * Steatorrhea few times per week; * Steatorrhea daily; * Stool incontinence.
Time frame: day 365±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | no steatorrhea | 52.4 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | steatorrhea few times per week | 26.2 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | steatorrhea daily | 21.4 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | stool incontinence | 0 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | stool incontinence | 0 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | no steatorrhea | 58.7 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | steatorrhea daily | 21.7 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant | steatorrhea few times per week | 19.6 percentage of participants |
Secondary
Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant
Levels of steatorrhea severity (evaluated in the 4 weeks prior to day 75±14 and 365±14), are defined as: * No steatorrhea; * Steatorrhea few times per week; * Steatorrhea daily; * Stool incontinence.
Time frame: day 75±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | no steatorrhea | 54.5 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | steatorrhea few times per week | 29.5 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | steatorrhea daily | 11.4 percentage of participants |
| Reparixin | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | stool incontinence | 4.5 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | stool incontinence | 4.2 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | no steatorrhea | 64.6 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | steatorrhea daily | 6.3 percentage of participants |
| Placebo | Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant | steatorrhea few times per week | 25.0 percentage of participants |
Secondary
Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant
Malnutrition risk levels are defined as: * Poor prognosis = pre-albumin level \<5.0 mg/dL * Significant risk = pre-albumin level 5.0 to 10.9 mg/dL * Increased risk = pre-albumin level 11.0 to 15.0 mg/dL * Normal = pre-albumin level \> 15.0 (up to 35.0) mg/dL
Time frame: day 365±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Poor prognosis | 5.0 percentage of participants |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Significant risk | 2.5 percentage of participants |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Increased risk | 27.5 percentage of participants |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Normal | 65.0 percentage of participants |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Normal | 84.1 percentage of participants |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Poor prognosis | 0 percentage of participants |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Increased risk | 9.1 percentage of participants |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant | Significant risk | 6.8 percentage of participants |
Secondary
Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant
Malnutrition risk levels are defined as: * Poor prognosis = pre-albumin level \<5.0 mg/dL * Significant risk = pre-albumin level 5.0 to 10.9 mg/dL * Increased risk = pre-albumin level 11.0 to 15.0 mg/dL * Normal = pre-albumin level \> 15.0 (up to 35.0) mg/dL
Time frame: day 75±14 after the transplant
Population: Safety Population consists of all randomized patients. Summarization and analysis of this population was based on treatment actually received. Patients randomized but not treated were analyzed in the total summary statistics only.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | poor prognosis | 0 percentage of patients |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | significant risk | 9.5 percentage of patients |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | increased risk | 45.2 percentage of patients |
| Reparixin | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | normal | 45.2 percentage of patients |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | normal | 67.4 percentage of patients |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | poor prognosis | 0 percentage of patients |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | increased risk | 28.3 percentage of patients |
| Placebo | Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant | significant risk | 4.3 percentage of patients |
Secondary
Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant
Percentage of patients with a glycated haemoglobin (HbA1c) \<6.5% at day 365±14 after the transplant.
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin | Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant | 64.3 percentage of participants |
| Placebo | Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant | 62.2 percentage of participants |
p-value: 0.84295% CI: [-18.2, 22.33]Chi-squared
Secondary
Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive
Percentage of patients with an HbA1c \<6.5% at day 365±14 after the transplant AND free of severe hypoglycemic events from day 75±14 to day 365±14 after the transplant inclusive.A severe hypoglycemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level \<54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time frame: from day 75±14 to day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Reparixin | Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive | 64.1 percentage of participants |
| Placebo | Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive | 59.1 percentage of participants |
p-value: 0.6495% CI: [-15.91, 25.93]Chi-squared
Secondary
Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
Data are reported as model estimates over all timepoints. This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=33; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=33; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 40 * 240 min; N=33; 41
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 1.6052 ng/mL | Standard Error 0.24507 |
| Placebo | Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 1.8822 ng/mL | Standard Error 0.24763 |
p-value: =0.28895% CI: [-0.7936, 0.2396]Mixed Models Analysis
Secondary
Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
Data are reported as model estimates over all timepoints. This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=44; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=43; 47 * 30 min; N=41; 47 * 60 min; N=42; 47 * 90 min; N=42; 47 * 120 min; N=42; 47 * 180 min; N=41; 47 * 240 min; N=40; 44
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 1.8976 ng/mL | Standard Error 0.20787 |
| Placebo | Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 2.1051 ng/mL | Standard Error 0.20104 |
p-value: =0.35895% CI: [-0.6538, 0.2389]Mixed Models Analysis
Secondary
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
Data are reported as model estimates over all timepoints This parameters was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=34; 42 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=34; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 41 * 240 min; N=33; 41
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 157.9988 mg/dL | Standard Error 12.00455 |
| Placebo | Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 180.9442 mg/dL | Standard Error 12.08647 |
p-value: =0.07495% CI: [-48.1826, 2.2918]Mixed Models Analysis
Secondary
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
Data of this outcome are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=42; 46 * 30 min; N=40; 46 * 60 min; N=40; 46 * 90 min; N=40; 46 * 120 min; N=41; 46 * 180 min; N=40; 46 * 240 min; N=39; 44
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 157.0894 mg/dL | Standard Error 11.9816 |
| Placebo | Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 166.5535 mg/dL | Standard Error 11.45706 |
p-value: 0.5795% CI: [-42.49, 23.5618]Mixed Models Analysis
Secondary
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
Data are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=34; 41 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal) * 15 min; N=34; 41 * 30 min; N=34; 41 * 60 min; N=34; 41 * 90 min; N=34; 41 * 120 min; N=34; 41 * 180 min; N=33; 41 * 240 min; N=33; 40
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 22.85522 UIU/mL | Standard Error 3.718512 |
| Placebo | Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant | 21.77905 UIU/mL | Standard Error 3.757573 |
p-value: =0.78595% CI: [-6.76562, 8.91796]Mixed Models Analysis
Secondary
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
Data are reported as model estimates over all timepoints. This parameter was assessed at the following timepoints on the following numbers of patients for Reparixin and placebo, respectively: * basal; N=43; 48 (Basal is: 2 basal samples taken separately between -20 to 0 minutes before the meal followed by samples through 240 minutes after the meal). * 15 min; N=43; 47 * 30 min; N=41; 47 * 60 min; N=41; 47 * 90 min; N=41; 47 * 120 min; N=42; 47 * 180 min; N=41; 47 * 240 min; N=40; 44
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 23.67209 UIU/mL | Standard Error 3.497499 |
| Placebo | Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant | 23.57493 UIU/mL | Standard Error 3.378854 |
p-value: =0.9895% CI: [-7.41834, 7.61266]Mixed Models Analysis
Secondary
Time-to-peak C-peptide at Day 365 After the Transplant
The time to peak value in minutes will be computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test CRF.
Time frame: Day 365±14 after the transplant
Population: ITT Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time-to-peak C-peptide at Day 365 After the Transplant | 97.8 minutes | Standard Deviation 90.9 |
| Placebo | Time-to-peak C-peptide at Day 365 After the Transplant | 102.0 minutes | Standard Deviation 56.2 |
Secondary
Time-to-peak C-peptide at Day 75 After the Transplant
The time-to-peak value in minutes was computed as the time of the peak value (HH:MM on a 24-hour clock) minus the end time of the mixed meal (HH:MM on a 24-hour clock) as recorded on the mixed meal tolerance test Case Report Form.
Time frame: day 75±14 and day 365±14 after the transplant
Population: ITT Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | Time-to-peak C-peptide at Day 75 After the Transplant | 104.2 minutes | Standard Deviation 93.6 |
| Placebo | Time-to-peak C-peptide at Day 75 After the Transplant | 108.7 minutes | Standard Deviation 59.4 |
Secondary
β-cell Function at Day 365±14 After the Transplant
This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for glucose, HbA1c, stimulated C-peptide and insulin requirement subscales. The higher the total score the better the outcome. * Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome) * HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome) * Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome) * Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)
Time frame: day 365±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Reparixin | β-cell Function at Day 365±14 After the Transplant | 5.9 score on a scale | Standard Deviation 2 |
| Placebo | β-cell Function at Day 365±14 After the Transplant | 5.4 score on a scale | Standard Deviation 2.4 |
p-value: 0.403Wilcoxon (Mann-Whitney)
Secondary
β-cell Function at Day 75±14 After the Transplant
This variable is assessed by β-score (assessment of β-cell function after islet transplantation). The total score is calculated on a 0-8 scoring system (higher is a better outcome) that gives 0-2 points each for: * fasting plasma glucose, * HbA1c, * stimulated C-peptide * insulin requirement subscales. The higher the total score, the better the outcome. * Fasting (or before breakfast) plasma glucose (mg/dL) : ≤99, Score 2; 100-124, Score 1; ≥ 125, Score 0 (the higher the subscore the better the outcome) * HbA1c (%): ≤6.1, Score 2; 6.2-6.9, Score 1; ≥ 7.0, Score 0 (the higher the subscore the better the outcome) * Daily average (previous week) insulin (IU/kg/day): ---, Score 2; 0.01-0.24, Score 1; ≥ 0.25, Score 0 (the higher the subscore the better the outcome) * Stimulated C-peptide (ng/mL): ≥ 0.9, Score 2; 0.3-0.89, Score 1; ≤0.3, Score 0 (the higher the subscore the better the outcome)
Time frame: day 75±14 after the transplant
Population: ITT Population consists of all patients who were randomized and received the Investigational Product (either reparixin or placebo). Summarization and analysis of this population is based on randomized treatment, regardless of treatment actually received.~Eligible patients are included in this population whether or not they receive IAT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reparixin | β-cell Function at Day 75±14 After the Transplant | 5.7 score on a scale | Standard Deviation 1.6 |
| Placebo | β-cell Function at Day 75±14 After the Transplant | 5.2 score on a scale | Standard Deviation 1.9 |
p-value: 0.176Wilcoxon (Mann-Whitney)