Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
Primary Purpose
Pancreatectomy for Chronic Pancreatitis
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Reparixin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Pancreatectomy for Chronic Pancreatitis focused on measuring Pancreatic islet auto-transplantation
Eligibility Criteria
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prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.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:
- ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
- 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 exclusion criteria locally accepted, as per centre practice.
Sites / Locations
- University of California. Department of Surgery, Division of Transplantation
- The University of Chicago Medical Center
- Schulze Diabetes Institute University of Minnesota Medical School
- Dartmouth-Hitchcock Medical Center
- The University of Cincinnati Medical Center
- Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center
- Medical University of South Carolina
- Baylor University Medical Center
- University of Alberta, Clinical Islet Transplant Program
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Reparixin
Placebo
Arm Description
Solution for intravenous (IV) infusion with active compound
Physiologic solution
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
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
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
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.
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 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 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 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 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 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 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
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)
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)
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.
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.
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.
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
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
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
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.
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.
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.
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.
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.
Peak C-peptide at Day 75 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
Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.
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-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.
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
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
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.
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
Full Information
NCT ID
NCT01967888
First Posted
October 18, 2013
Last Updated
July 17, 2023
Sponsor
Dompé Farmaceutici S.p.A
1. Study Identification
Unique Protocol Identification Number
NCT01967888
Brief Title
Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
Official Title
A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
February 2014 (Actual)
Primary Completion Date
January 2018 (Actual)
Study Completion Date
January 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dompé Farmaceutici S.p.A
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatectomy for Chronic Pancreatitis
Keywords
Pancreatic islet auto-transplantation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
104 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Reparixin
Arm Type
Experimental
Arm Description
Solution for intravenous (IV) infusion with active compound
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Physiologic solution
Intervention Type
Drug
Intervention Name(s)
Reparixin
Other Intervention Name(s)
DF1681Y
Intervention Description
Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Physiologic solution administered at 0.25 mL/kg/hour
Primary Outcome Measure Information:
Title
Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.
Description
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
Secondary Outcome Measure Information:
Title
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant
Description
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
Title
Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant
Description
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
Title
Average Daily Insulin Requirements at Day 75±14 After the Transplant
Description
Daily insulin is reported as IU/kg and intake averaged over the previous week.
Time Frame
day 75±14 after the transplant
Title
Average Daily Insulin Requirements at Day 365±14 After the Transplant
Description
Daily insulin is reported as IU/kg and intake averaged over the previous week.
Time Frame
day 365±14 after the transplant
Title
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
Description
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
Title
Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
Description
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
Title
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
Description
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
Title
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
Description
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
Title
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
Description
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
Title
Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
Description
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
Title
β-cell Function at Day 75±14 After the Transplant
Description
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
Title
β-cell Function at Day 365±14 After the Transplant
Description
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
Title
Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant
Description
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
Title
Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant
Description
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
Title
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
Description
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
Title
Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study
Description
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
Title
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
Description
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
Title
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
Description
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
Title
Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant
Description
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
Title
Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant
Description
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
Title
Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
Description
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
Title
Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
Description
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
Title
Cumulative Number of Diabetic Ketoacidosis-related Events
Description
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
Title
Peak C-peptide at Day 75 After the Transplant
Description
Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.
Time Frame
Day 75±14 after the transplant
Title
Peak C-peptide at Day 365 After the Transplant
Description
Peak C-peptide (C-P) is a known predictor of Type 1 Diabetes.
Time Frame
Day 365±14 after the transplant
Title
Time-to-peak C-peptide at Day 75 After the Transplant
Description
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
Title
Time-to-peak C-peptide at Day 365 After the Transplant
Description
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
Title
Change From Baseline in Post-transplant Alanine Aminotransferase (ALT)
Description
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
Title
Change From Baseline in Post-transplant Aspartate Aminotransferase (AST)
Description
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
Title
Number of Treatment Emergent Adverse Events Related to Investigational Product
Description
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
Title
Number of Serious Treatment Emergent Adverse Events Related to Investigational Product
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
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 exclusion criteria locally accepted, as per centre practice.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Melena Bellin, MD
Organizational Affiliation
Schulze Diabetes Institute; University of Minnesota Amplatz Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California. Department of Surgery, Division of Transplantation
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Schulze Diabetes Institute University of Minnesota Medical School
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
Facility Name
The University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Baylor University Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
University of Alberta, Clinical Islet Transplant Program
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2C8
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
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