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

NCT01817959 | Completed Phase 3 Results

• 2 other identifiers: REP02112011-006201-10
• Study Type: interventional
• Target: 51
• Locations: 5 countries
• Sites: 9

Brief Summary

The objective of this clinical trial was: \- to assess whether Reparixin leads to improved transplant outcome as measured by glycaemic control following intra-hepatic infusion of pancreatic islets in patients with Type 1 diabetes (T1D). The safety of Reparixin in the specific clinical setting was also evaluated. Background: The chemokine CXCL8 plays a key role in the recruitment and activation of polymorphonuclear neutrophils in post-ischemia reperfusion injury after organ transplantation. 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 T1D patients.

Conditions

Islet Transplantation in Diabetes Mellitus Type 1

Keywords

Pancreatic islet transplantation; Diabetes Mellitus Type 1; Islet transplantation graft survival & function

Outcome Measures

Primary Outcomes (2)

• 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

  The MMTT was to be performed ideally after an overnight fast. The test was to be initiated before 10 a.m. The Boost Original complete nutritional drink (Nestlé Nutrition) was used for the MMTT. Subjects were given 6 mL/kg of Boost preparation up to a maximum of 360 mL, to be drunk within 5 min. Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal.

  Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion

• 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

  The MMTT was to be performed ideally after an overnight fast. The test was to be initiated before 10 a.m. The Boost Original complete nutritional drink (Nestlé Nutrition) was used for the MMTT. Subjects were given 6 mL/kg of Boost preparation up to a maximum of 360 mL, to be drunk within 5 min. Blood samples for the C-peptide assay (the primary assessment) were withdrawn in fasting condition (basal), just prior to the meal (time 0, within 15 min prior to the meal) and then at 15, 30, 60, 90, 120 min after the meal.

  Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 365±14 after the last islet infusion

Secondary Outcomes (14)

• Percentage of Insulin-independent Patients at Day 75

  Day 75±5 after the 1st and 2nd islet infusion

• Percentage of Insulin-independent Patients at Day 365

  Day 365±14 after last islet infusion

• Percentage of Patients Who Achieve and Maintain an HbA1c <7.0% (or a Reduction in HbA1c > 2%) AND Are Free of Severe Hypoglycaemic Events After Transplant in the Efficacy Population 1

  HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion

• Percentage of Patients Who Did Not Receive a 2nd Islet Infusion

  Day 365±14 after the 1st islet infusion

• Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1

  Day 365±14 after the last islet infusion

Other Outcomes (4)

• Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1

  At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion

• Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1

  At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,

• Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1

  Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion

Study Arms (2)

Reparixin group

EXPERIMENTAL

Continuous iv infusion

Drug: Reparixin

Placebo group

PLACEBO COMPARATOR

Continuous iv infusion

Drug: Placebo

Interventions

Reparixin DRUG

Continuous i.v. infusion into a central vein for 7 days, starting approximately 12 hrs (6-18 hrs) before each pancreatic islet infusion.The Investigational Product (IP) were to be administered as an add-on treatment for the immunosuppressant regimen.

Also known as: REP

Reparixin group

Placebo DRUG

Continuous infusion at a volume/rate matching active treatment.The placebo was to be administered as well as an add-on treatment for the immunosuppressant regimen.

Placebo group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 (alanine aminotranferase) / AST (aspartate aminotransferase) \> 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:
• ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID).
• 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).

Sponsors & Collaborators

• Dompé Farmaceutici S.p.A: lead

Study Sites (9)

The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation

Chicago, Illinois, 60637, United States

Location

Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes.

Prague, 14021, Czechia

Location

Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele

Milan, 20132, Italy

Location

S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3

Milan, 20162, Italy

Location

Transplant Institute - Sahlgrenska University Hospital

Gothenburg, 41345, Sweden

Location

Department of Nephrology and Transplantation; Skane University Hospital

Malmo, 20502, Sweden

Location

Department of Transplantation Surgery; The Karolinska University Hospital

Stockholm, 14186, Sweden

Location

Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital

Uppsala, 75185, Sweden

Location

Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (3)

• Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res. 2024 Dec 20;2024:5151171. doi: 10.1155/jdr/5151171. eCollection 2024.

  PMID: 39735417 DERIVED

• Bachul PJ, Golab K, Basto L, Zangan S, Pyda JS, Perez-Gutierrez A, Borek P, Wang LJ, Tibudan M, Tran DK, Anteby R, Generette GS, Chrzanowski J, Fendler W, Perea L, Jayant K, Lucander A, Thomas C, Philipson L, Millis JM, Fung J, Witkowski P. Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation. Cell Transplant. 2021 Jan-Dec;30:9636897211001774. doi: 10.1177/09636897211001774.

  PMID: 33908301 DERIVED

• Maffi P, Lundgren T, Tufveson G, Rafael E, Shaw JAM, Liew A, Saudek F, Witkowski P, Golab K, Bertuzzi F, Gustafsson B, Daffonchio L, Ruffini PA, Piemonti L; REP0211 Study Group. Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes. Diabetes Care. 2020 Apr;43(4):710-718. doi: 10.2337/dc19-1480. Epub 2020 Feb 4.

  PMID: 32019854 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

reparixin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Clinical Development & Operations
• Organization: Dompé farmaceutici s.p.a.

clinical.trials@dompe.com

+39 02 583831

Study Officials

• 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

  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 - Freeman Hospital

  PRINCIPAL INVESTIGATOR

• Frantisek SAUDEK, MD, DrSc

  Institute for Clinical and Experimental Medicine (IKEM), Department of Diabetes.

  PRINCIPAL INVESTIGATOR

• Piotr WITKOWSKI, MD, PhD

  The University of Chicago Medical Center, Department of Surgery

  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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2013
• First Posted: March 26, 2013
• Study Start: October 1, 2012
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2017
• Last Updated: January 3, 2024
• Results First Posted: December 18, 2019

Record last verified: 2021-09

Locations

SE (4); CZ (1); GB (1); IT (2); US (1)