Clinical trial NCT01220856: Reparixin in Pancreatic Islet Transplantation
Official title: A Phase 2 Multicenter, Randomized, Open Label, Parallel Assignment, Pilot Study to Assess the Efficacy and Safety of Reparixin Following Islet Transplantation in Patients With Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus
Keywords: Islet transplantation
Type 1 diabetes mellitus
Lead sponsor: Dompé Farmaceutici S.p.A
Sponsor class: INDUSTRY
First posted: 2010-10-14
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).

Detailed description: Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.

Eligibility criteria: Inclusion criteria:

* Ages 18-65 years, inclusive.
* Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for \>5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (\<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice.
* Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) \> 60 mL/min according to the Cockcroft-Gault formula (1976).
* Planned intrahepatic islet transplantation alone from a non-living donor with brain death.
* Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight.
* Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.
* Patients 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, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.
* Recipients of islet from a non-heart beating donor.
* A body mass index \>30 kg/m2 or patient weight \<45 kg.
* Pre-transplant average daily insulin requirement \>1 IU/kg/day.
* Pre-transplant HbA1c \>11%.
* Patients with hepatic dysfunction as defined by increased ALT/AST \> 3 x ULN and increased total bilirubin \> 3mg/dL \[\>51.3 micromol/L\]).
* 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 4 weeks of enrolment.
* Hypersensitivity to:

  * ibuprofen or to more than one non steroidal anti-inflammatory drug
  * 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).

Sites will comply with any additional exclusion criteria locally accepted, as per centre practice.

Primary outcomes:
measure: The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5
timeFrame: day 75 +/- 5 post-transplant
Secondary outcomes:
Other outcomes:
measure: The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant
timeFrame: up to one year after the transplant
measure: Time to Achieve Insulin-independence After the Transplant 2
timeFrame: up to 1 year after transplant 2
measure: Total Time of Insulin Independence After the Transplant
timeFrame: up to 1 year after transplant 2
measure: Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Absolute Change in Fasted HbA1c From Pre-transplant Levels
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Percentage Change in Fasted HbA1c From Pre-transplant Levels
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Number of Participants With Adverse Events by Severity and With Serious Adverse Events
timeFrame: up to 1 year after transplant
measure: AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
timeFrame: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
measure: AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
timeFrame: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
measure: AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
timeFrame: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
measure: AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1
timeFrame: -10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant
measure: The Percentage of Patients Free of Severe Hypoglycaemic Events
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Beta-cell Function as Assessed by Beta-score
timeFrame: Months 1, 3, 6, 12 post-transplant
measure: Beta-cell Function as Assessed by TEF/IEQ/kg Ratio
timeFrame: At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2
measure: Serum Level of Alanine Amino Transferase (ALT)
timeFrame: Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
measure: Serum Level of Aspartate Amino Transferase (AST)
timeFrame: Pre-transplant and at days 1-7 and months 1 and 3 post-transplant
measure: Change From Pre-transplant in Cytokine Levels - CXCL8
timeFrame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
measure: Change From Pre-transplant in Cytokine Levels - CXCL1
timeFrame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
measure: Change From Pre-transplant in Cytokine Levels - IL-6
timeFrame: 6, 12, 24, 72, 120, and 168 hours post-transplant 1
Locations:
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus Dresden
city: Milan
country: Italy
facility: Ospedale San Raffaele
Study officials:
affiliation: Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy
name: Lorenzo Piemonti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Carl Gustav Carus - Dresden; Germany
name: Barbara Ludwig, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Citro A, Cantarelli E, Piemonti L. Anti-inflammatory strategies to enhance islet engraftment and survival. Curr Diab Rep. 2013 Oct;13(5):733-44. doi: 10.1007/s11892-013-0401-0.