Reparixin in Pancreatic Islet Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Reparixin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reparixin<br>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<br>* Reparixin + immunosuppression<br>* Other names: REP;|
| No Intervention: No experimental intervention<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Islet transplantation, Type 1 diabetes mellitus