Back to resultsReparixin in Pancreatic Islet Transplantation
Primary Purpose
Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Reparixin
Sponsored by
About this trial
This is an interventional treatment trial for Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus focused on measuring Islet transplantation, Type 1 diabetes mellitus
Eligibility Criteria
Inclusion criteria:
- Ages 18-65 years, inclusive.
- Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for >5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice.
- Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) > 60 mL/min according to the Cockcroft-Gault formula (1976).
- Planned intrahepatic islet transplantation alone from a non-living donor with brain death.
- Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight.
- Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
- Patients 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prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.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 any previous transplant, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.
- Recipients of islet from a non-heart beating donor.
- A body mass index >30 kg/m2 or patient weight <45 kg.
- Pre-transplant average daily insulin requirement >1 IU/kg/day.
- Pre-transplant HbA1c >11%.
- Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 micromol/L]).
- Patients who receive treatment for a medical condition requiring chronic use of systemic steroids.
- Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant.
- Use of any investigational agent within 4 weeks of enrolment.
Hypersensitivity to:
- ibuprofen or to more than one non steroidal anti-inflammatory drug
- medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
- Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).
Sites will comply with any additional exclusion criteria locally accepted, as per centre practice.
Sites / Locations
- University Hospital Carl Gustav Carus Dresden
- Ospedale San Raffaele
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Reparixin
No experimental intervention
Arm Description
Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description.
Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Outcomes
Primary Outcome Measures
The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5
Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
HbA1c level of less than 7%;
glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
Secondary Outcome Measures
Full Information
NCT ID
NCT01220856
First Posted
October 7, 2010
Last Updated
February 18, 2021
Sponsor
Dompé Farmaceutici S.p.A
1. Study Identification
Unique Protocol Identification Number
NCT01220856
Brief Title
Reparixin in Pancreatic Islet Transplantation
Official Title
A Phase 2 Multicenter, Randomized, Open Label, Parallel Assignment, Pilot Study to Assess the Efficacy and Safety of Reparixin Following Islet Transplantation in Patients With Type 1 Diabetes Mellitus
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Completed
Study Start Date
July 28, 2010 (Actual)
Primary Completion Date
April 30, 2013 (Actual)
Study Completion Date
April 30, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dompé Farmaceutici S.p.A
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).
Detailed Description
Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
Keywords
Islet transplantation, Type 1 diabetes mellitus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
9 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Reparixin
Arm Type
Experimental
Arm Description
Reparixin + Immunosuppression
Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration.
Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour.
For immunosoppression regimen see the other arm description.
Arm Title
No experimental intervention
Arm Type
No Intervention
Arm Description
Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Intervention Type
Drug
Intervention Name(s)
Reparixin
Other Intervention Name(s)
REP
Intervention Description
Reparixin + immunosuppression
Primary Outcome Measure Information:
Title
The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5
Description
Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
HbA1c level of less than 7%;
glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
Time Frame
day 75 +/- 5 post-transplant
Other Pre-specified Outcome Measures:
Title
The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant
Description
Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by:
HbA1c level of less than 7%;
glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period);
glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
Time Frame
up to one year after the transplant
Title
Time to Achieve Insulin-independence After the Transplant 2
Description
Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date.
Time Frame
up to 1 year after transplant 2
Title
Total Time of Insulin Independence After the Transplant
Description
Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence.
Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.
Time Frame
up to 1 year after transplant 2
Title
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels
Description
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels
Description
Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
Absolute Change in Fasted HbA1c From Pre-transplant Levels
Description
The absolute change between the time-point value and baseline value.
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
Percentage Change in Fasted HbA1c From Pre-transplant Levels
Description
The absolute percentage between the time-point value and baseline value.
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness
Description
Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness".
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
Number of Participants With Adverse Events by Severity and With Serious Adverse Events
Description
Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant.
A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.
Time Frame
up to 1 year after transplant
Title
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description
Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.
AUC was calculated using the trapezoidal rule.
Time Frame
-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
Title
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description
C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.
AUC was calculated using the trapezoidal rule.
Time Frame
-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
Title
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description
Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints.
AUC was calculated using the trapezoidal rule.
Time Frame
-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
Title
AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1
Description
For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated.
AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).
Time Frame
-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
Title
The Percentage of Patients Free of Severe Hypoglycaemic Events
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
Months 1, 3, 6, 12 post-transplant
Title
Beta-cell Function as Assessed by Beta-score
Description
The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function.
Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.
Time Frame
Months 1, 3, 6, 12 post-transplant
Title
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio
Description
The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.
Time Frame
At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2
Title
Serum Level of Alanine Amino Transferase (ALT)
Description
ALT is commonly measured clinically as part of liver function tests.
Time Frame
Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
Title
Serum Level of Aspartate Amino Transferase (AST)
Description
AST is commonly measured clinically as part of liver function tests.
Time Frame
Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
Title
Change From Pre-transplant in Cytokine Levels - CXCL8
Description
Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame
6, 12, 24, 72, 120, and 168 hours post-transplant 1
Title
Change From Pre-transplant in Cytokine Levels - CXCL1
Description
Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame
6, 12, 24, 72, 120, and 168 hours post-transplant 1
Title
Change From Pre-transplant in Cytokine Levels - IL-6
Description
Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame
6, 12, 24, 72, 120, and 168 hours post-transplant 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria:
Ages 18-65 years, inclusive.
Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for >5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice.
Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) > 60 mL/min according to the Cockcroft-Gault formula (1976).
Planned intrahepatic islet transplantation alone from a non-living donor with brain death.
Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight.
Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
Patients 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 any previous transplant, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.
Recipients of islet from a non-heart beating donor.
A body mass index >30 kg/m2 or patient weight <45 kg.
Pre-transplant average daily insulin requirement >1 IU/kg/day.
Pre-transplant HbA1c >11%.
Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 micromol/L]).
Patients who receive treatment for a medical condition requiring chronic use of systemic steroids.
Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant.
Use of any investigational agent within 4 weeks of enrolment.
Hypersensitivity to:
ibuprofen or to more than one non steroidal anti-inflammatory drug
medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.
Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).
Sites will comply with any additional exclusion criteria locally accepted, as per centre practice.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lorenzo Piemonti, MD
Organizational Affiliation
Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Barbara Ludwig, MD
Organizational Affiliation
University Hospital Carl Gustav Carus - Dresden; Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Carl Gustav Carus Dresden
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Ospedale San Raffaele
City
Milan
ZIP/Postal Code
20132
Country
Italy
12. IPD Sharing Statement
Citations:
PubMed Identifier
23912763
Citation
Citro A, Cantarelli E, Piemonti L. Anti-inflammatory strategies to enhance islet engraftment and survival. Curr Diab Rep. 2013 Oct;13(5):733-44. doi: 10.1007/s11892-013-0401-0.
Results Reference
derived
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Reparixin in Pancreatic Islet Transplantation
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