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Trial record 1 of 1 for:    REP0211
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Study to Assess Efficacy & Safety of Reparixin in Pancreatic Islet Transplantation (REP0211)

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ClinicalTrials.gov Identifier: NCT01817959
Recruitment Status : Completed
First Posted : March 26, 2013
Results First Posted : December 18, 2019
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Dompé Farmaceutici S.p.A

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.


Condition or disease Intervention/treatment Phase
Islet Transplantation in Diabetes Mellitus Type 1 Drug: Reparixin Drug: Placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, 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
Study Start Date : October 2012
Actual Primary Completion Date : December 2016
Actual Study Completion Date : December 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.The Investigational Product (IP) were to be administered as an add-on treatment for the immunosuppressant regimen.
Other Name: REP

Placebo Comparator: Placebo group
Continuous iv infusion
Drug: Placebo
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.




Primary Outcome Measures :
  1. 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: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 75±5 after the 1st islet infusion ]
    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.

  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 [ Time Frame: Basal, -15' prior to meal, 15', 30', 60', 90', 120' following meal, Day 365±14 after the last islet infusion ]
    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.


Secondary Outcome Measures :
  1. Percentage of Insulin-independent Patients at Day 75 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion ]

    For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by:

    • a glycated hemoglobin (HbA1c) level of less than 7%;
    • a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period);
    • a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period).

  2. Percentage of Insulin-independent Patients at Day 365 [ Time Frame: Day 365±14 after last islet infusion ]

    For the purpose of this study, insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycaemic control, as defined by:

    • a glycated hemoglobin (HbA1c) level of less than 7%;
    • a glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than three times a week (based on measuring capillary glucose level a minimum of 7 times in a 7 day period);
    • a glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than four times a week (based on measuring capillary glucose level 14 times in a 7 day period).

  3. 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 [ Time Frame: HbA1c at Day 365±14 after the last islet infusion; severe hypoglycaemic events from Day 75 to Day 365 after the last islet infusion ]
    For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

  4. Percentage of Patients Who Did Not Receive a 2nd Islet Infusion [ Time Frame: Day 365±14 after the 1st islet infusion ]
    This endpoint describes subjects who were not allocated to a 2nd islet infusion because they were insulin independent after the 1st islet infusion.

  5. Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1 [ Time Frame: Day 365±14 after the last islet infusion ]
    The cumulative number of severe hypoglycaemic events after last transplant was assessed. For the purpose of this study, a severe hypoglycaemic event is defined as an event with one of the following symptoms: memory loss, confusion, uncontrollable behaviour, irrational behaviour, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness or visual symptoms, in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54 mg/dL (3.0 mmol/L) or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

  6. Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    Change from baseline is assessed as absolute decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week.

  7. Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    Change from baseline is assessed as percentage decrease from pre-transplant levels. For the purpose of this study, daily insulin is averaged over the previous week.

  8. Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    Change from baseline in Glycated haemoglobin (HbA1c) was assessed as absolute decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: <5.7% Normal; 5.7-6.4% prediabetes; >6.5 diabetes.

  9. Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion ]
    Change from baseline in Glycated haemoglobin (HbA1c) was assessed as percentage decrease from pre-transplant levels. Diagnostic standards for HbA1c from American Diabetes Association are: <5.7% Normal; 5.7-6.4% prediabetes; >6.5 diabetes.

  10. Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    Glucose levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.

  11. Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    C-peptide levels not normalized by the number of islet equivalent (IEQ)/kg were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.

  12. Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]
    Insulin levels were measured at the baseline in fasting condition, and at the following timepoints: 15, 30, 60, 90, 120 min after mixed meal at the hereunder reported time frame.

  13. β-cell Function as Assessed by β-score in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]

    The β-score ranges from 0 (no graft function) to 8 (interpreted as an index of excellent graft function), and gives 0-2 points each for glucose, HbA1C, stimulated C-peptide and insulin requirement. Both for the total and partial scores the higher the score, the better the outcome.

    Fasting plasma glucose (mg/dL): ≤99 (Score 2); 100 - 124 (Score 1); ≥125 (Score 0); HbA1c (%): ≤6.1(Score 2); 6.2 - 6.9 (Score 1); ≥ 7.0 (Score 0); Daily average (previous week) insulin (IU/kg/day): --- (Score 2); 0.01 - 0.24 (score 1); ≥ 0.25 (Score 0) Stimulated C-peptide (ng/mL): ≥ 0.9; 0.3 - 0.89; ≤0.3


  14. β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 [ Time Frame: Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion ]

    TEF selects the two pivotal components of the β-score (DIR and A1C) and links them together through a simple description of how insulin supply influences the patient's glycemic control.

    TEF was evaluated by the following equation: TEF = a.DIR + b.HbA1c + c where DIR = daily insulin requirement (average in the previous week); a = -1; b = 1/-5.43; c = -a.DIR (pre-transplant) - b.HbA1c (pre-transplant)



Other Outcome Measures:
  1. Frequency of Patients Positive/Negative for Autoantibodies Against Glutamic Acid Decarboxylase (GAD) in Efficacy Population 1 [ Time Frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion ]
    Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex.

  2. Frequency of Patients Positive/Negative for Autoantibodies Against Islet Antigen-2 (IA-2) in Efficacy Population 1 [ Time Frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, ]
    Auto-antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by immunoprecipitation of recombinant antigens. The Luminescent Immuno-Precipitation System based on chimeric autoantigens fused to luciferase enzyme was suggested as the preferred method to be used. Luciferase activity was measured in recovered immune-complex.

  3. Frequency of Patients Positive/Negative for Autoantibodies Against Class I Human Leucocyte Antigen (HLA) in Efficacy Population 1 [ Time Frame: Pre-transplant, day 75±5 after the 1st and 2nd islet infusion and day 365±14 after the last islet infusion ]
    Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded.

  4. Frequency of Patients Positive/Negative for Autoantibodies Against Class II Human Leucocyte Antigen (HLA) in Efficacy Population 1 [ Time Frame: At pre-transplant, Day 75±5 after the 1st and 2nd islet infusion and Day 365±14 days after the last islet infusion, ]
    Anti-HLA antibodies were assayed on cell-free serum samples obtained as per centre practice ideally by the Luminex analyzer. Class I and II positive/negative results were recorded.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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 (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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01817959


Locations
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United States, Illinois
The University of Chicago Medical Center, Department of Surgery, Division of Abdominal Organ Transplantation
Chicago, Illinois, United States, 60637
Czechia
Institute for Clinical and Experimental Medicine (IKEM), Diabetes Centre; Department of Diabetes.
Praha, Czechia, 14021
Italy
Dipartimento di Medicina Interna e Specialistica; IRCCS Ospedale San Raffaele
Milan, Italy, 20132
S.S.D. Diabetologia, Azienda Ospedaliera Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3
Milan, Italy, 20162
Sweden
Transplant Institute - Sahlgrenska University Hospital
Göteborg, Sweden, 41345
Department of Nephrology and Transplantation; Skane University Hospital
Malmö, Sweden, 20502
Department of Transplantation Surgery; The Karolinska University Hospital
Stockholm, Sweden, 14186
Division for Transplantation and Liver Surgery; Department of Surgery; Uppsala University Hospital
Uppsala, Sweden, 75185
United Kingdom
Institute of Transplantation, Newcastle upon Tyne Hospitals - NHS Foundation Trust, Freeman Hospital
Newcastle upon Tyne, United Kingdom, NE7 7DN
Sponsors and Collaborators
Dompé Farmaceutici S.p.A
Investigators
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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 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
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Responsible Party: Dompé Farmaceutici S.p.A
ClinicalTrials.gov Identifier: NCT01817959    
Other Study ID Numbers: REP0211
2011-006201-10 ( EudraCT Number )
First Posted: March 26, 2013    Key Record Dates
Results First Posted: December 18, 2019
Last Update Posted: February 17, 2020
Last Verified: January 2020
Keywords provided by Dompé Farmaceutici S.p.A:
Pancreatic islet transplantation
Diabetes Mellitus Type 1
Islet transplantation graft survival & function
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases