Clinical trial NCT01967888: Efficacy and Safety of Reparixin in Pancreatic Islet Auto-transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pancreatectomy for Chronic Pancreatitis
Keywords: Pancreatic islet auto-transplantation
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2013-10-23
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Each patient will be involved in the study for 7 day hospital stay during pancreatectomy followed by islet transplantation, for all required measurements up to hospital discharge and for 2 post-transplant visits scheduled @ day 75+14 and 365+14 after the transplant.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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:

  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.
* 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.

Primary outcomes:
measure: Percentage of Patients Who Were Insulin Independent After Islet Autotransplantation (IAT) at Day 365±14 Days After Transplant.
timeFrame: day 365±14 after the transplant
Secondary outcomes:
measure: Area Under the Curve (AUC) for the Serum C-peptide Level at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: Area Under the Curve (AUC) for the Serum C-peptide Level at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: Average Daily Insulin Requirements at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: Average Daily Insulin Requirements at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: Time Course From Basal to 240 Min of Glucose Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: 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
timeFrame: day 75±14 after the transplant
measure: 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
timeFrame: day 365±14 after the transplant
measure: Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: Time Course From Basal to 240 Min of Insulin Derived From the Mixed Meal Tolerance Test (MMTT) at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: β-cell Function at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: β-cell Function at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: Proportion of Patients With an HbA1c <6.5% at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: Cumulative Number of Severe Hypoglycemic Events From Day 75±14 to Day 365±14 After the Transplant
timeFrame: from day 75±14 to day 365±14 after the transplant
measure: 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
timeFrame: from day 75±14 to day 365±14 after the transplant
measure: Incidence and Severity of Adverse Events and Serious Adverse Events Throughout the Study
timeFrame: up to day 365±14 after the transplant
measure: 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
timeFrame: day 75±14 after the transplant
measure: 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
timeFrame: day 365±14 after the transplant
measure: Proportion of Patients by Steatorrhea Severity at Day 75±14 After the Transplant
timeFrame: day 75±14 after the transplant
measure: Proportion of Patients by Steatorrhea Severity at Day 365±14 After the Transplant
timeFrame: day 365±14 after the transplant
measure: Cumulative Number of Episodes of Documented Asymptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
timeFrame: from day 75±14 to day 365±14 after the transplant
measure: Cumulative Number of Episodes of Documented Symptomatic Hypoglycemia From Day 75±14 to Day 365±14 After the Transplant
timeFrame: from day 75±14 to day 365±14 after the transplant
measure: Cumulative Number of Diabetic Ketoacidosis-related Events
timeFrame: from day 75±14 to day 365±14 after the transplant
measure: Peak C-peptide at Day 75 After the Transplant
timeFrame: Day 75±14 after the transplant
measure: Peak C-peptide at Day 365 After the Transplant
timeFrame: Day 365±14 after the transplant
measure: Time-to-peak C-peptide at Day 75 After the Transplant
timeFrame: day 75±14 and day 365±14 after the transplant
measure: Time-to-peak C-peptide at Day 365 After the Transplant
timeFrame: Day 365±14 after the transplant
measure: Change From Baseline in Post-transplant Alanine Aminotransferase (ALT)
timeFrame: Baseline, Days 2, 3, 7, 75 ±14 after the transplant
measure: Change From Baseline in Post-transplant Aspartate Aminotransferase (AST)
timeFrame: Baseline, Days 2, 3, 7, 75±14 after the transplant
measure: Number of Treatment Emergent Adverse Events Related to Investigational Product
timeFrame: Throughout the study From Day -1 to hospital discharge
measure: Number of Serious Treatment Emergent Adverse Events Related to Investigational Product
timeFrame: 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
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California. Department of Surgery, Division of Transplantation
state: California
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Minneapolis
country: United States
facility: Schulze Diabetes Institute University of Minnesota Medical School
state: Minnesota
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Cincinnati
country: United States
facility: The University of Cincinnati Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: Thomas E. Starzl Transplantation Institute University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Edmonton
country: Canada
facility: University of Alberta, Clinical Islet Transplant Program
state: Alberta
Study officials:
affiliation: Schulze Diabetes Institute; University of Minnesota Amplatz Children's Hospital
name: Melena Bellin, MD
role: PRINCIPAL_INVESTIGATOR
References: