Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation

NCT ID: NCT01967888

Last Updated: 2023-11-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 104 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-02-28
• Study Completion Date: 2018-01-31

Brief Summary

The study is a phase 2/3, multicenter, double-blind, parallel assignment study. It involves 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).

The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.

Detailed Description

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 included 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). A maximum of 48 patients is allowed for the site of the Primary Investigator.

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.

Conditions

Pancreatectomy for Chronic Pancreatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Reparixin

Solution for intravenous (IV) infusion with active compound

Group Type: EXPERIMENTAL

Reparixin

Intervention Type: DRUG

Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour

Placebo

Physiologic solution

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Physiologic solution administered at 0.25 mL/kg/hour

Interventions

Reparixin

Solution for intravenous (IV) infusion; 2.772 mg/kg body weight/hour administered at 0.25 mL/kg/hour

Intervention Type: DRUG

Placebo

Physiologic solution administered at 0.25 mL/kg/hour

Intervention Type: DRUG

Other Intervention Names

DF1681Y

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dompé Farmaceutici S.p.A

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Melena Bellin, MD

Role: PRINCIPAL_INVESTIGATOR

Schulze Diabetes Institute; University of Minnesota Amplatz Children's Hospital

Locations

University of California. Department of Surgery, Division of Transplantation

San Francisco, California, United States

The University of Chicago Medical Center

Chicago, Illinois, United States

Schulze Diabetes Institute University of Minnesota Medical School

Minneapolis, Minnesota, United States

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

The University of Cincinnati Medical Center

Cincinnati, Ohio, United States

Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Baylor University Medical Center

Dallas, Texas, United States

University of Alberta, Clinical Islet Transplant Program

Edmonton, Alberta, Canada

Countries

United States; Canada

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

REP0112

Identifier Type: -

Identifier Source: org_study_id