Study to Assess Efficacy & Safety of Reparixin in Pancreatic Islet Transplantation

A Phase 3, Multicenter, Randomized, Double-blind, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Transplantation

The objective of this clinical trial was:

- to assess whether Reparixin leads to improved transplant outcome as measured by glycaemic control following intra-hepatic infusion of pancreatic islets in patients with Type 1 diabetes (T1D). The safety of Reparixin in the specific clinical setting was also evaluated.

Background: The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after organ transplantation. Reparixin is the first low molecular weight blocker of CXCL8 biological activity in clinical development. Thus, the use of reparixin may emerge as a potential key component in the sequentially integrated approach to immunomodulation and control of non specific inflammatory events surrounding the early phases of pancreatic islet transplantation in T1D patients.

Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation.

Several strategies are being evaluated, including anti-TNFα, aimed to prevent early inflammatory events that limit islet engraftment. Among possible mechanisms CXCL8 could play a crucial role in triggering the inflammatory reaction and might represent a relevant therapeutic target to prevent early graft failure.

Preliminary data obtained in transplanted patients recruited in the ongoing pilot trial coupled with the safety shown in human phase 1 and 2 studies provide a sound rationale for further development of reparixin in islet transplantation and prompted the conduct of this phase 3 clinical, multicentre, randomised, double-blind, parallel assignment study aimed at assessing the efficacy and safety of reparixin in preventing graft dysfunction after islet transplantation in T1D subjects.

At least 42 patients receiving pancreatic islet transplant were involved. Patients might receive up to 2 islet transplants, with the second transplant on average 6 months after the first one. Patients were randomly (2:1) assigned to receive either reparixin or placebo (control group). The Investigational Product was administered as an added on treatment to the immunosuppressant regimen.

Inclusion Criteria:

• Ages 18-70 years, inclusive.
• Patients eligible for a pancreatic islet transplantation program
• Planned intrahepatic islet transplantation alone from a non-living donor with brain death.
• 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 any previous transplant, including recipients of previous pancreatic islet transplantation.

• Recipients of islet from a non-heart beating donor.

• Pre-transplant average daily insulin requirement >1 IU/kg/day.

• Pre-transplant (the more recent value obtained within the 4 months prior to enrolment) HbA1c >11%.

• 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 (alanine aminotranferase) / AST (aspartate aminotransferase) > 3 x upper limit of normal (ULN) and increased total bilirubin > 3mg/dL [>51.3 µmol/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 12 weeks of enrolment, including "anti-inflammatory" strategies (e.g. anti-TNFα, anti-IL-1 RA).

• Hypersensitivity to:

  1. ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
  2. medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.

• Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).

Additional exclusion criteria specific for US centre.