Complement Inhibitor Eculizumab in Clinical Islet Transplantation

Study Overview
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Brief Summary
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This is a dual centre, single arm, exploratory study of the possibility to use eculizumab (Soliris) to prevent/reduce destruction of islets of Langerhans after portal infusion of the islets in patients with diabetics accepted for islet transplant.

Detailed Description
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This is a dual centre, single arm, exploratory study of the possibility to use eculizumab (Soliris) to prevent/reduce destruction of islets of Langerhans after portal infusion of the islets in patients with diabetics accepted for islet transplant. Ten patients from 2 centres (Uppsala University Hospital and Karolinska University Hospital in Stockholm) will be transplanted. The purpose of the study is to investigate if selective complement inhibition by eculizumab combined with standard anticoagulation during and after transplantation can further reduce the extent of early tissue loss after portal infusion of islets.

Official Title
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Induction With Complement Inhibitor Eculizumab in Clinical Islet Transplantation

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Eculizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients between 18 to 65 years of age Patients able to provide written informed consent Absent stimulated c-peptide (< 0.1 nmol/L). This includes also previously islet-transplanted patients with no detectable c-peptide. Patients at fear of severe hypoglycemia Female patients of child bearing potential must have a negative pregnancy test (s-β-HCG) and must be practicing an effective, reliable medical accepted contraceptive regimen while on eculizumab treatment and to study end at 75 days. Patients vaccinated against Neisseria meningitides or patients accepting adequate antibiotic prophylaxis Exclusion Criteria: Body mass index > 30 kg/m2 Untreated proliferative diabetes retinopathy Recipient of any other concomitant organ transplantation - Glomerular filtration rate < 50 mL/min before first islet transplantation Positive T-cell cross-matching by Complement Depending Cytotoxicity (CDC) Pregnancy or lactating Active ongoing infection, bacterial or viral Unresolved meningococcal disease Known bleeding disorder Known complement disorder Have received any other investigational drug within 30 days before inclusion History of drug or alcohol abuse within the last year

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eculizumab<br>Intravenous infusion | Drug: Eculizumab<br>* Intravenous infusion (1200 mg) over 35 minutes. Consecutive infusions (900 mg) on Days 1, 7 and 14.<br>* Other names: Soliris;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increased survival of ICC´s transplanted as measured by peak c-peptide | Determined by PET-scan of 2-deoxy-27fluoro-D-glucose (18F) (FDG)-labelled islets infused in the portal vein. | During and within two hours post infusion (day 0). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of eculizumab on instant blood mediated inflammatory reaction (IBMIR) as determined by complement activation. | Extent of early tissue loss | At the end of infusion and 1 and 2 h post start of infusion (day 0). | 
| Monitoring of islet-function and survival. | Evaluation of insulin-independency, the extent of reduction of baseline insulin requirement, continuous glucose monitoring system (CGMS) performance, HbA1c, number of hypoglycemic events per week. | 14, 30 and 75 days post-transplant. | 
| Adverse events (AEs) and serious adverse events (SAEs) | Will be assigned Medical Drug Regulatory Activities (MedDRA) preferred terms and tabulated as incidence rate | From start of infusion until 75 days post-transplant. | 
| Patient and graft survival at 75 days post treatment. | Graft survival is measured by measurable stimulated c-peptide (>0,1 nmol/L) | From start of infusion until 75 days post-transplant. | 
| Estimated glomerular filtration rate (GFR) (Cystatin C) | Cystatin C value | At day 75 | 
| Portal vein thrombosis | Assessment by per protocol ultrasound | The day after infusion | 
| Bleeding | will be assessed by hemoglobin and thrombocyte monitoring (important while portal vein catheter is in place and withdrawn (within first week). | From infusion until 2 hours post start of infusion |