Study to Assess Efficacy & Safety of Reparixin in Pancreatic Islet Transplantation (REP0211)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Dompé s.p.a.
Sponsor:
Information provided by (Responsible Party):
Dompé s.p.a.
ClinicalTrials.gov Identifier:
NCT01817959
First received: March 7, 2013
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after organ transplantion. 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 type 1 diabetes (T1D) patients.


Condition Intervention Phase
Islet Transplantation in Diabetes Mellitus Type 1,
Drug: Reparixin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Transplantation

Resource links provided by NLM:


Further study details as provided by Dompé s.p.a.:

Primary Outcome Measures:
  • Area Under the Curve (AUC) for the serum C-peptide level during the first 2 hours of an MMTT (Mixed Meal Tolerance Test), normalized by the number of Islet Equivalent (IEQ)/kg [ Time Frame: Day 75+5 after the 1st islet infusion and day 365+14 after the last islet infusion ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Proportion of insulin-independent patients [ Time Frame: Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ] [ Designated as safety issue: No ]
  • Proportion of patients who achieve and maintain an HbA1c <7.0% (or o reduction in HbA1c > 2%) AND are free of severe hypoglycaemic events [ Time Frame: Day 365+14 after the last islet infusion ] [ Designated as safety issue: No ]
  • Proportion of patients receiving a 2nd islet infusion [ Time Frame: Day 365+14 after the 1st islet infusion ] [ Designated as safety issue: Yes ]
  • Cumulative number of severe hypoglycaemic events [ Time Frame: Day 365+14 after the last islet infusion ] [ Designated as safety issue: No ]
  • Change in average daily insulin requirements (absolute decrease from pre-transplant levels and % decrease from pre-transplant levels). [ Time Frame: Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ] [ Designated as safety issue: No ]
  • HbA1c % (absolute decrease from pre-transplant levels and % decrease from pre-transplant levels). [ Time Frame: Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ] [ Designated as safety issue: No ]
  • Basal (fasting) and 0 to 120 min time course of glucose, C-peptide and insulin derived from the MMTT [ Time Frame: Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ] [ Designated as safety issue: No ]
  • β-cell function as assessed by β-score and Transplant Estimated Function (TEF) [ Time Frame: Day 75+5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ] [ Designated as safety issue: No ]
  • Incidence and severity of Adverse Events and Serious Adverse Events [ Time Frame: Throughout the study up to day 365+14 after last islet infusion ] [ Designated as safety issue: Yes ]
  • Changes in standard laboratory parameters, as a measure of safety [ Time Frame: Pre-infusion hospital admission and post-infusion hospital discharge ] [ Designated as safety issue: Yes ]
    Hematocrit, hemoglobin, red blood cells, platelets, white blood cells, differential white blood cells count, sodium, potassium, serum creatinine, blood urea nitrogen, total bilirubin, ALT, AST, PT, PTT

  • Changes in vital signs, as a measure of safety [ Time Frame: Day 0 (hospital admission), day 7 (hospital discharge), ±365 days after the 1st and 2nd islet infusion ] [ Designated as safety issue: Yes ]
    Blood pressure, heart rate, body mass index

  • ALT/AST, PT/PTT, fibrin degradation products (XDPs), C-reactive protein (CRP) [ Time Frame: All daily up to day 6 after the 1st and 2nd islet infusion; ALT/AST also on day 75+5 after the 1st and 2nd islet infusion ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Auto-antibodies (GAD, IA-2, optional: ZnT8) [ Time Frame: Pre-infusion hospital admission, day 6/7 and day 75+5 after the 1st and 2nd islet infusion and day 365+14 after the last islet infusion ] [ Designated as safety issue: No ]
  • Anti-HLA antibodies [ Time Frame: pre-infusion hospital admission, day 6/7 and day 75+5 after the 1st and 2nd islet infusion and day 365+14 after the last islet infusion ] [ Designated as safety issue: No ]
  • Time course of inflammatory chemokines/cytokines as assessed by serum level of CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, IL-10 [ Time Frame: Pre-infusion hospital admission and 6, 12, 24, 72, 120 and 168hrs after the 1st and 2nd islet infusion ] [ Designated as safety issue: No ]
  • Time-course of coagulation/complement activation markers as assessed by blood level of C3a, sC5b-9, Thrombin-antithrombin complexes (TAT), D-dimer (inclusive of markers of PMN/monocyte activation) [ Time Frame: Pre-infusion hospital admission and 1, 6, 12, 24, 72, 120 and 168hrs after the 1st and 2nd islet infusion ] [ Designated as safety issue: No ]

Estimated Enrollment: 42
Study Start Date: July 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Reparixin group
Continuous iv infusion
Drug: Reparixin
Continuous i.v. infusion into a central vein for 7 days, starting approximately 12 hrs (6-18 hrs) before each pancreatic islet infusion.
Placebo Comparator: Placebo group
Continuous iv infusion
Drug: Placebo
Continuous infusion at a volume/rate matching active treatment.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01817959

Contacts
Contact: Pier Adelchi Ruffini, MD +39 02 58383500 pieradelchi.ruffini@dompe.it

Locations
United States, Illinois
The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation Recruiting
Chicago, Illinois, United States, 60637
Contact: Piotr WITKOWSKI, MD, PhD         
Czech Republic
Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes. Recruiting
Praha, Czech Republic, 14021
Contact: Frantisek SAUDEK, Professor         
Italy
Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele Recruiting
Milan, Italy, 20132
Contact: Lorenzo PIEMONTI, MD         
S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3 Recruiting
Milan, Italy, 20162
Contact: Federico BERTUZZI, MD         
Sweden
Transplant Institute - Sahlgrenska University Hospital Recruiting
Göteborg, Sweden, 41345
Contact: Bengt GUSTAFSSON, MD, PhD         
Department of Nephrology and Transplantation; Skane University Hospital Recruiting
Malmö, Sweden, 20502
Contact: Ehab RAFAEL, MD, PhD         
Department of Transplantation Surgery; The Karolinska University Hospital Recruiting
Stockholm, Sweden, 14186
Contact: Torbjörn LUNDGREN, MD, PhD         
Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital Recruiting
Uppsala, Sweden, 75185
Contact: Gunnar TUFVESON, Professor         
United Kingdom
Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital Recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Contact: James SHAW, Professor         
Sponsors and Collaborators
Dompé s.p.a.
Investigators
Principal Investigator: Lorenzo PIEMONTI, MD Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele
Principal Investigator: Torbjörn LUNDGREN, MD, PhD Department of Transplantation Surgery; The Karolinska University Hospital
Principal Investigator: Gunnar TUFVESON, Professor Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital
Principal Investigator: Ehab RAFAEL, MD, PhD Department of Nephrology and Transplantation; Skane University Hospital
Principal Investigator: James SHAW, Professor Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital
Principal Investigator: Frantisek SAUDEK, MD, DrSc Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes.
Principal Investigator: Piotr WITKOWSKI, MD, PhD The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation
Principal Investigator: Federico BERTUZZI, MD S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano
Principal Investigator: Bengt GUSTAFSSON, MD, PhD Transplant Institute - Sahlgrenska University Hospital
  More Information

No publications provided

Responsible Party: Dompé s.p.a.
ClinicalTrials.gov Identifier: NCT01817959     History of Changes
Other Study ID Numbers: REP0211, 2011-006201-10
Study First Received: March 7, 2013
Last Updated: June 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dompé s.p.a.:
Pancreatic islet transplantation
Diabetes Mellitus Type 1
Islet transplantation graft survival & function

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on September 18, 2014