Clinical trial NCT01817959: Study to Assess Efficacy & Safety of Reparixin in Pancreatic Islet Transplantation
Official title: A Phase 3, Multicenter, Randomized, Double-blind, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Islet Transplantation in Diabetes Mellitus Type 1
Keywords: Pancreatic islet transplantation
Diabetes Mellitus Type 1
Islet transplantation graft survival & function
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2013-03-26
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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, multicentre, randomised, double-blind, parallel assignment study aimed at assessing the efficacy and safety of reparixin in preventing graft dysfunction after islet transplantation in T1D subjects.

At least 42 patients receiving pancreatic islet transplant were involved. Patients might receive up to 2 islet transplants, with the second transplant on average 6 months after the first one. Patients were randomly (2:1) assigned to receive either reparixin or placebo (control group). The Investigational Product was administered as an added on treatment to the immunosuppressant regimen.

Eligibility 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 (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:

  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.

Primary outcomes:
measure: 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
timeFrame: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion
measure: 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
timeFrame: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 365±14 after the last islet infusion
Secondary outcomes:
measure: Percentage of Insulin-independent Patients at Day 75
timeFrame: Day 75±5 after the 1st and 2nd islet infusion
measure: Percentage of Insulin-independent Patients at Day 365
timeFrame: Day 365±14 after last islet infusion
measure: 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
timeFrame: HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion
measure: Percentage of Patients Who Did Not Receive a 2nd Islet Infusion
timeFrame: Day 365±14 after the 1st islet infusion
measure: Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1
timeFrame: Day 365±14 after the last islet infusion
measure: Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion
measure: Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: β-cell Function as Assessed by β-score in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
measure: β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1
timeFrame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion
Other outcomes:
measure: Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1
timeFrame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion
measure: Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1
timeFrame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,
measure: Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1
timeFrame: Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion
measure: Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1
timeFrame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion,
Locations:
city: Chicago
country: United States
facility: The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation
state: Illinois
city: Praha
country: Czechia
facility: Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes.
city: Milan
country: Italy
facility: Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele
city: Milan
country: Italy
facility: S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3
city: Göteborg
country: Sweden
facility: Transplant Institute - Sahlgrenska University Hospital
city: Malmö
country: Sweden
facility: Department of Nephrology and Transplantation; Skane University Hospital
city: Stockholm
country: Sweden
facility: Department of Transplantation Surgery; The Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital
Study officials:
affiliation: Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele
name: Lorenzo PIEMONTI, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Transplantation Surgery; The Karolinska University Hospital
name: Torbjörn LUNDGREN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery; Uppsala University Hospital
name: Gunnar TUFVESON, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Nephrology and Transplantation; Skane University Hospital
name: Ehab RAFAEL, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute of Transplantation, Newcastle upon Tyne Hospitals - Freeman Hospital
name: James SHAW, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Institute for Clinical and Experimental Medicine (IKEM), Department of Diabetes.
name: Frantisek SAUDEK, MD, DrSc
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Chicago Medical Center, Department of Surgery
name: Piotr WITKOWSKI, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Milano
name: Federico BERTUZZI, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Transplant Institute - Sahlgrenska University Hospital
name: Bengt GUSTAFSSON, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.