A Phase 3, Multicenter, Randomized, Double-blind, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Transplantation
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 51
- 试验地点
- 9
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Reparixin group
Continuous iv infusion
干预措施: Reparixin (Drug)
Placebo group
Continuous iv infusion
干预措施: Placebo (Drug)
结局指标
主要结局
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
时间窗: 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.
次要结局
- 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 Insulin-independent Patients at Day 75(Day 75±5 after the 1st and 2nd 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)
- Absolute Change From Baseline in Average Daily Insulin Requirements in Efficacy Population 1(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(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(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(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(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(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(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(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(Day 75±5 after the 1st and 2nd islet infusion and day 365±14 after last islet infusion)