A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Assignment Study to Assess the Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 104
- 试验地点
- 9
- 主要终点
- Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.
研究概览
简要总结
The study is a phase 2/3, multicenter, double-blind, parallel assignment study. It involves 100 adult recipients of an intra-hepatic pancreatic Islet Auto-Transplantation (IAT).
The objective of this clinical trial is to assess whether reparixin leads to improved transplant outcome as measured by the proportion of insulin-independent patients following IAT. The safety of reparixin in the specific clinical setting will be also evaluated.
详细描述
In contrast to allo-transplantation in type 1 diabetes patients, where immunological mechanisms involving allo- and auto-antibodies affect long-term graft function, outcome in IAT (Islet Auto-Transplantation) is independent from immunological processes and does not require immunosuppression management. On the other hand, early inflammatory events intrinsic to the intra-portal islet infusion have been demonstrated to impact islet engraftment. Among possible mechanisms, PMNs have been found to be the predominant cell types infiltrating the liver in a syngeneic model of islet transplantation in mice.
Data obtained in experimental models of islet transplantation in mice demonstrate a clear effect of reparixin in improving graft survival and function. Protection from the loss and/or deterioration of transplanted islets was evident regardless of the immunological mechanisms involved in islet damage, suggesting that the ability of reparixin to modulate early inflammatory responses readily impact graft outcome.
Thus, the use of reparixin may emerge as a potential useful medication in the control of non specific inflammatory events surrounding the early phases of IAT.
The goal of this study is to reach a total of 100 adult patients who are randomized and receive IAT after total or completion pancreatectomy. Patients will be randomly (1:1) assigned to receive either reparixin [continuous i.v. infusion for 7 days (168hrs)], or matched placebo (control group),starting approximately 12hrs before islet infusion. The two groups will be balanced within each centre. All patients who are randomized and receive the Investigational Product (either reparixin or placebo) will be included in the ITT analysis. Patients will be in the ITT analysis whether or not they receive IAT, because exclusions cannot be made for events occurring after randomization that could be influenced by the randomized assignment.
Recruitment will be competitive among the study sites, until the planned number of patients is enrolled. Competitive recruitment has been chosen to increase the speed of recruitment and to account for any difference in transplant rate among study sites. Each centre will enroll patients as rapidly as possible, up to a maximum of 40 patients (as per the randomization list). A maximum of 48 patients is allowed for the site of the Primary Investigator.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients eligible for an IAT following total (or completion) pancreatectomy.
- •Ages > 18 years.
- •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 a previous IAT (if completion pancreatectomy).
- •Patients undergoing total pancreatectomy due to either pancreatic cancer or pancreatic benign diseases other than chronic pancreatitis, including insulinomas, etc.
- •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/AST > 3 x upper limit of normal (ULN) or increased total bilirubin above the upper limit at local laboratory). Patients with Gilbert's syndrome (elevated unconjugated bilirubin levels in the absence of any evidence of hepatic or biliary tract disease) are not excluded.
- •Patients with a preoperative International Normalized Ratio (INR) > 1.5 or any known coagulopathy.
- •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.
- •Concurrent sepsis (as per positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome).
- •Treatment with systemic steroids in the 2 weeks prior to enrolment (except for the use of <5mg prednisone daily or equivalent dose of hydrocortisone, for physiological replacement only) or with any immune modulators in the 4 weeks prior to enrolment.
- •Patients with pre-existing diabetes or evidence of impaired β-cells function, based on pre-operative fasting blood glucose >115 mg/dL and/or a HbA1c > 6.5%, or requiring treatment with any anti-diabetic medication (e.g. insulin, metformin, etc) within the 2 weeks prior to enrolment.
- •Use of any investigational agent in the 4 weeks prior to enrolment, including any anti-cytokine/chemokine agents.
- •Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males). (NB: pregnancy should be avoided in patients or partners during the first month after completing the treatment with the Investigational Product; no other specific warnings are described, considering the treatment course of the Investigational Product, its PK profile, and the lack of significant adverse effects on mating performance and fertility in animal studies).
- •Patients with past or current history of alcohol abuse based on clinical history and/or past treatment for alcohol addiction.
- •Patients with evidence of pre-operative portal hypertension as per clinical history and abdominal/liver imaging by ultrasound techniques.
- •Sites will comply with any additional or more restrictive exclusion criteria locally accepted, as per centre practice.
研究组 & 干预措施
Reparixin
Solution for intravenous (IV) infusion with active compound
干预措施: Reparixin (Drug)
Placebo
Physiologic solution
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.
时间窗: day 365±14 after the transplant
Insulin-independence is defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: * a glycated hemoglobin (HbA1c) level \<6.5%; * fingerstick fasting blood glucose not exceeding 126 mg/dL more than three times in the past week (based on a minimum of one daily measurement; * a 2 hour post-prandial blood glucose not exceeding 180 mg/dL more than four times in the past week (based on a minimum of one daily measurement); * a laboratory fasting glucose in the non-diabetic range (\<126 mg/dL).
次要结局
- Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Average Daily Insulin Requirements at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Average Daily Insulin Requirements at Day 365±14 After the Transplant(day 365±14 after the transplant)
- β-cell Function at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant(from day 75±14 to day 365±14 after the transplant)
- Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Peak C-peptide at Day 75 After the Transplant(Day 75±14 after the transplant)
- Peak C-peptide at Day 365 After the Transplant(Day 365±14 after the transplant)
- Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant(from day 75±14 to day 365±14 after the transplant)
- Cumulative Number of Diabetic Ketoacidosis-related Events(from day 75±14 to day 365±14 after the transplant)
- Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Time Course From Basal to 240 Min of C-peptide Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant(day 365±14 after the transplant)
- β-cell Function at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant(day 365±14 after the transplant)
- Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant AND Free of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant Inclusive(from day 75±14 to day 365±14 after the transplant)
- Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study(up to day 365±14 after the transplant)
- Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant(from day 75±14 to day 365±14 after the transplant)
- Proportion of Patients Falling Into One of the Following Malnutrition Risk Levels (Poor Prognosis, Significant Risk, Increased Risk, Normal) According to Pre-albumin Level at Day 75±14 After the Transplant(day 75±14 after the transplant)
- Time-to-peak C-peptide at Day 75 After the Transplant(day 75±14 and day 365±14 after the transplant)
- Time-to-peak C-peptide at Day 365 After the Transplant(Day 365±14 after the transplant)
- Change From Baseline in Post-transplant Alanine Aminotransferase (ALT)(Baseline, Days 2, 3, 7, 75 ±14 after the transplant)
- Change From Baseline in Post-transplant Aspartate Aminotransferase (AST)(Baseline, Days 2, 3, 7, 75±14 after the transplant)
- Number of Treatment Emergent Adverse Events Related to Investigational Product(Throughout the study From Day -1 to hospital discharge)
- Number of Serious Treatment Emergent Adverse Events Related to Investigational Product(Throughout the study From Day -1 to hospital discharge for all adverse events, and from then to day 365 post-transplantation only for serious adverse events)