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

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 study aimed at assessing the efficacy and safety of reparixin in preventing
graft dysfunction after islet transplantation in T1D patients.

At least 42 patients receiving pancreatic islet transplant will be involved. Patients may
receive up to 2 islet transplants, with the second transplant on average 6 months after the
first one. Patients will be randomly (2:1) assigned to receive either reparixin or placebo
(control group). The Investigational Products will be 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not part of normal medical care, with the understanding that consent may be withdrawn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/AST > 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.