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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 3, Multicenter, Randomized, Double-blind, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Transplantation

Conditions
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Islet Transplantation in Diabetes Mellitus Type 1

Intervention / Treatment
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* Drug: Reparixin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: 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). Additional exclusion criteria specific for US centre.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reparixin group<br>Continuous iv infusion | Drug: Reparixin<br>* 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.<br>* Other names: REP;|
| Placebo Comparator: Placebo group<br>Continuous iv infusion | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Insulin-independent Patients at Day 75 | 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). | Day 75±5 after the 1st and 2nd islet infusion | 
| Percentage of Insulin-independent Patients at Day 365 | 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). | 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 | 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. | 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 | This endpoint describes subjects who were not allocated to a 2nd islet infusion because they were insulin independent after the 1st islet infusion. | Day 365±14 after the 1st islet infusion | 
| Cumulative Number of Severe Hypoglycaemic Events in the Efficacy Population 1 | 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. | Day 365±14 after the last islet infusion | 
| Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| Percent Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| Absolute Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| Percent Change in HbA1c % From Pre-transplant Levels in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365+14 after last islet infusion | 
| Basal (Fasting) and 0 to 120 Min Time Course of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| Basal (Fasting) and 0 to 120 Min Time Course of C-peptide (Non-normalized) Derived From the MMTT in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| Basal (Fasting) and 0 to 120 Min Time Course of Insulin Derived From the MMTT in Efficacy Population 1 | 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. | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| β-cell Function as Assessed by β-score in Efficacy Population 1 | 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 | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 
| β-cell Function as Assessed by Transplant Estimated Function (TEF) in Efficacy Population 1 | 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) | Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pancreatic islet transplantation, Diabetes Mellitus Type 1, Islet transplantation graft survival & function