Reparixin in Pancreatic Islet Transplantation

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

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).

Study Overview

• Status: Completed
• Conditions: Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Reparixin

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Dresden, Germany, 01307
    • University Hospital Carl Gustav Carus Dresden
• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reparixin; Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description.	Drug: Reparixin; Reparixin + immunosuppression; Other Names: REP
No Intervention: No experimental intervention; Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5	Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: 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).	day 75 +/- 5 post-transplant

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant	Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: 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).	up to one year after the transplant
Time to Achieve Insulin-independence After the Transplant 2	Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date.	up to 1 year after transplant 2
Total Time of Insulin Independence After the Transplant	Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence. Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.	up to 1 year after transplant 2
Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels	Daily insulin requirement was calculated as the average requirement over the previous week (seven days).	Months 1, 3, 6, 12 post-transplant
Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels	Daily insulin requirement was calculated as the average requirement over the previous week (seven days).	Months 1, 3, 6, 12 post-transplant
Absolute Change in Fasted HbA1c From Pre-transplant Levels	The absolute change between the time-point value and baseline value.	Months 1, 3, 6, 12 post-transplant
Percentage Change in Fasted HbA1c From Pre-transplant Levels	The absolute percentage between the time-point value and baseline value.	Months 1, 3, 6, 12 post-transplant
The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness	Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness".	Months 1, 3, 6, 12 post-transplant
Number of Participants With Adverse Events by Severity and With Serious Adverse Events	Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant. A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.	up to 1 year after transplant
AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant	Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant	C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant	Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1	For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated. AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
The Percentage of Patients Free of Severe Hypoglycaemic Events	A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.	Months 1, 3, 6, 12 post-transplant
Beta-cell Function as Assessed by Beta-score	The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.	Months 1, 3, 6, 12 post-transplant
Beta-cell Function as Assessed by TEF/IEQ/kg Ratio	The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.	At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2
Serum Level of Alanine Amino Transferase (ALT)	ALT is commonly measured clinically as part of liver function tests.	Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
Serum Level of Aspartate Amino Transferase (AST)	AST is commonly measured clinically as part of liver function tests.	Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
Change From Pre-transplant in Cytokine Levels - CXCL8	Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).	6, 12, 24, 72, 120, and 168 hours post-transplant 1
Change From Pre-transplant in Cytokine Levels - CXCL1	Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).	6, 12, 24, 72, 120, and 168 hours post-transplant 1
Change From Pre-transplant in Cytokine Levels - IL-6	Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).	6, 12, 24, 72, 120, and 168 hours post-transplant 1

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Investigators: Principal Investigator: Lorenzo Piemonti, MD, Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy; Principal Investigator: Barbara Ludwig, MD, University Hospital Carl Gustav Carus - Dresden; Germany

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2010
• Primary Completion (Actual): April 30, 2013
• Study Completion (Actual): April 30, 2013

Study Registration Dates

• First Submitted: October 7, 2010
• First Submitted That Met QC Criteria: October 13, 2010
• First Posted (Estimate): October 14, 2010

Study Record Updates

• Last Update Posted (Actual): March 11, 2021
• Last Update Submitted That Met QC Criteria: February 18, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Type 1 diabetes mellitus; Islet transplantation
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: REP0110; 2010-019424-31 (EudraCT Number)