Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

In contrast to allo-transplantation in type 1 diabetes patients, where immunological
mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in
IAT (Islet Auto-Transplantation) is independent from immunological processes and does not
require immunosuppression management. On the other hand, early inflammatory events intrinsic
to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among
possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the
liver in a syngeneic model of islet transplantation in mice.

Data obtained in experimental models of islet transplantation in mice demonstrate a clear
effect of reparixin in improving graft survival and function. Protection from the loss and/or
deterioration of transplanted islets was evident regardless of the immunological mechanisms
involved in islet damage, suggesting that the ability of reparixin to modulate early
inflammatory responses readily impact graft outcome.

Thus, the use of reparixin may emerge as a potential useful medication in the control of non
specific inflammatory events surrounding the early phases of IAT.

The goal of this study is to reach a total of 100 adult patients who are randomized and
receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1)
assigned to receive either reparixin [continuous i.v. infusion for 7 days (168hrs)], or
matched placebo (control group),starting approximately 12hrs before islet infusion. The two
groups will be balanced within each centre. All patients who are randomized and receive the
Investigational Product (either reparixin or placebo) will be inlcuded in the ITT analysis.
Patients will be in the ITT analysis whether or not they receive IAT, because exclusions
cannot be made for events occurring after randomization that could be influenced by the
randomized assignment.

Recruitment will be competitive among the study sites, until the planned number of patients
is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and
to account for any difference in transplant rate among study sites. Each centre will enroll
patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization
list).

Each patient will be involved in the study for 7 day hospital stay during pancreatectomy
followed by islet transplantation, for all required measurements up to hospital discharge and
for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.

Inclusion Criteria:

- Patients eligible for an IAT following total (or completion) pancreatectomy.

- Ages > 18 years.

- 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 a previous IAT (if completion pancreatectomy).

- Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic
benign diseases other than chronic pancreatitis, including insulinomas, etc.

- 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) or increased total bilirubin above the upper limit at local laboratory).
Patients with Gilbert's syndrome (elevated unconjugated bilirubin levels in the
absence of any evidence of hepatic or biliary tract disease) are not excluded.

- Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known
coagulopathy.

- 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.

- Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other
signs of systemic sepsis syndrome).

- Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use
of <5mg prednisone daily or equivalent dose of hydrocortisone, for physiological
replacement only) or with any immune modulators in the 4 weeks prior to enrolment.

- Patients with pre-existing diabetes or evidence of impaired β-cells function, based on
pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring
treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the
2 weeks prior to enrolment.

- Use of any investigational agent in the 4 weeks prior to enrolment, including any
anti-cytokine/chemokine agents.

- Pregnant or breast-feeding women; unwillingness to use effective contraceptive
measures (females and males). (NB: pregnancy should be avoided in patients or partners
during the first month after completing the treatment with the Investigational
Product; no other specific warnings are described, considering the treatment course of
the Investigational Product, its PK profile, and the lack of significant adverse
effects on mating performance and fertility in animal studies).

- Patients with past or current history of alcohol abuse based on clinical history
and/or past treatment for alcohol addiction.

- Patients with evidence of pre-operative portal hypertension as per clinical history
and abdominal/liver imaging by ultrasound techniques.

Sites will comply with any additional or more restrictive exclusion criteria locally
accepted, as per centre practice.