Reparixin in Pancreatic Islet Transplantation

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Dompé s.p.a.
ClinicalTrials.gov Identifier:
NCT01220856
First received: October 7, 2010
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).


Condition Intervention Phase
Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
Drug: Reparixin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Multicenter, Randomized, Open Label, Parallel Assignment, Pilot Study to Assess the Efficacy and Safety of Reparixin Following Islet Transplantation in Patients With Type 1 Diabetes Mellitus

Resource links provided by NLM:


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

Primary Outcome Measures:
  • The proportion of insulin-independent patients following a single donor-single islet cell transplantation [ Time Frame: day 75 +/- 5 post-transplant ] [ Designated as safety issue: No ]
  • The proportion of insulin-independent patients after a single donor-single islet cell transplantation [ Time Frame: up to one year after the transplant ] [ Designated as safety issue: No ]
  • Time to achieve insulin-independence after the transplant [ Time Frame: up to 1 year after the transplant ] [ Designated as safety issue: No ]
  • Total time of insulin independence after the transplant [ Time Frame: up to 1 year after the transplant ] [ Designated as safety issue: No ]
  • Change in average daily insulin requirements (absolute and % decrease from pre-transplant levels) [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]
  • HbA1c (absolute and % decrease from pre-transplant levels) [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]
  • The proportion of patients free of severe hypoglycaemic events [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]
  • The proportion of patients free of hypoglycaemic events with reduced awareness [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]
  • Basal (fasting) and -10 to 120 min time course of glucose, C-peptide and insulin derived from the mixed meal tolerance test [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]
  • Beta-cell function as assessed by beta-score and Transplant Estimated Function [ Time Frame: month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Incidence and severity of Adverse Events and Serious Adverse Events [ Time Frame: up to 1 year after transplant ] [ Designated as safety issue: Yes ]
  • Standard laboratory tests (hematology, clinical chemistry, coagulation) [ Time Frame: day -1 pre-transplant ] [ Designated as safety issue: Yes ]
  • Blood pressure and heart rate [ Time Frame: day -1 pre-transplant ] [ Designated as safety issue: Yes ]
  • ALT/AST, PT/PTT, fibrin degradation products, C-reactive protein [ Time Frame: daily up to day 6 post-transplant ] [ Designated as safety issue: Yes ]
  • Time course of inflammatory chemokines/cytokines [ Time Frame: day -1 pre-transplant ] [ Designated as safety issue: No ]
  • Plasma levels of reparixin and its major metabolite [ Time Frame: day 3 and day 7 of drug infusion ] [ Designated as safety issue: No ]
  • Standard laboratory tests (hematology, clinical chemistry, coagulation) [ Time Frame: day 6/7 post-transplant ] [ Designated as safety issue: Yes ]
  • Blood pressure and heart rate [ Time Frame: day 6/7 post-transplant ] [ Designated as safety issue: Yes ]
  • ALT/AST [ Time Frame: month 1-3 post-transplant ] [ Designated as safety issue: Yes ]
  • Time course of inflammatory chemokines/cytokines [ Time Frame: 6-12-24--72-120-168 hrs after islet infusion ] [ Designated as safety issue: No ]
  • Auto-antibodies and anti-HLA antibodies [ Time Frame: day -1 pre-transplant ] [ Designated as safety issue: No ]
  • Auto-antibodies and anti-HLA antibodies [ Time Frame: day 6/7 post- transplant; month 1-3-6-12 post- transplant ] [ Designated as safety issue: No ]

Enrollment: 9
Study Start Date: July 2010
Study Completion Date: June 2014
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Reparixin
Reparixin + Immunosuppression
Drug: Reparixin
Reparixin + immunosuppression
No Intervention: No experimental intervention
Immunosuppression only

Detailed Description:

Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Ages 18-65 years, inclusive.
  • Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for >5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice.
  • Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) > 60 mL/min according to the Cockcroft-Gault formula (1976).
  • Planned intrahepatic islet transplantation alone from a non-living donor with brain death.
  • Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight.
  • Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
  • Patients 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, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.
  • Recipients of islet from a non-heart beating donor.
  • A body mass index >30 kg/m2 or patient weight <45 kg.
  • Pre-transplant average daily insulin requirement >1 IU/kg/day.
  • Pre-transplant HbA1c >11%.
  • Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 micromol/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 4 weeks of enrolment.
  • Hypersensitivity to:

    • ibuprofen or to more than one non steroidal anti-inflammatory drug
    • 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).

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

  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: NCT01220856

Locations
Germany
University Hospital Carl Gustav Carus Dresden
Dresden, Germany, 01307
Italy
Ospedale San Raffaele
Milan, Italy, 20132
Sponsors and Collaborators
Dompé s.p.a.
Investigators
Principal Investigator: Lorenzo Piemonti, MD Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy
Principal Investigator: Barbara Ludwig, MD University Hospital Carl Gustav Carus - Dresden; Germany
  More Information

No publications provided by Dompé s.p.a.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Dompé s.p.a.
ClinicalTrials.gov Identifier: NCT01220856     History of Changes
Other Study ID Numbers: REP0110, 2010-019424-31
Study First Received: October 7, 2010
Last Updated: June 27, 2014
Health Authority: Europe: European Medicines Agency
Italy: The Italian Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Dompé s.p.a.:
Islet transplantation
Type 1 diabetes mellitus

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 August 18, 2014