Clinical trial NCT02727608: Complement Inhibitor Eculizumab in Clinical Islet Transplantation
Official title: Induction With Complement Inhibitor Eculizumab in Clinical Islet Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus
Lead sponsor: Uppsala University
Sponsor class: OTHER
First posted: 2016-04-04
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Increased survival of ICC´s transplanted as measured by peak c-peptide
timeFrame: During and within two hours post infusion (day 0).
Secondary outcomes:
measure: Effect of eculizumab on instant blood mediated inflammatory reaction (IBMIR) as determined by complement activation.
timeFrame: At the end of infusion and 1 and 2 h post start of infusion (day 0).
measure: Monitoring of islet-function and survival.
timeFrame: 14, 30 and 75 days post-transplant.
measure: Adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From start of infusion until 75 days post-transplant.
measure: Patient and graft survival at 75 days post treatment.
timeFrame: From start of infusion until 75 days post-transplant.
measure: Estimated glomerular filtration rate (GFR) (Cystatin C)
timeFrame: At day 75
measure: Portal vein thrombosis
timeFrame: The day after infusion
measure: Bleeding
timeFrame: From infusion until 2 hours post start of infusion
Other outcomes:
measure: The percentage of loss of radioactivity in the liver field.
timeFrame: Within the first two hours after start of islet infusion.
measure: Effect of eculizumab on IBMIR
timeFrame: Post infusion
Locations:
city: Uppsala
country: Sweden
facility: Dept of Surgical Sciences, Section of Transplantation Surgery, University Hospital
Study officials:
affiliation: Uppsala University Hospital
name: Gunnar Tufveson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes. 2005 Jul;54(7):2060-9. doi: 10.2337/diabetes.54.7.2060.
citation: Eich T, Eriksson O, Lundgren T; Nordic Network for Clinical Islet Transplantation. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N Engl J Med. 2007 Jun 28;356(26):2754-5. doi: 10.1056/NEJMc070201. No abstract available.
citation: Eich T, Eriksson O, Sundin A, Estrada S, Brandhorst D, Brandhorst H, Langstrom B, Nilsson B, Korsgren O, Lundgren T. Positron emission tomography: a real-time tool to quantify early islet engraftment in a preclinical large animal model. Transplantation. 2007 Oct 15;84(7):893-8. doi: 10.1097/01.tp.0000284730.86567.9f.
citation: Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Kallen R, Ostraat O, Salmela K, Tibell A, Tufveson G, Elgue G, Nilsson Ekdahl K, Korsgren O, Nilsson B. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet. 2002 Dec 21-28;360(9350):2039-45. doi: 10.1016/s0140-6736(02)12020-4.
citation: Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, Bretzel RG, Elgue G, Larsson R, Nilsson B, Korsgren O. Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes. 1999 Oct;48(10):1907-14. doi: 10.2337/diabetes.48.10.1907.
citation: Koh A, Senior P, Salam A, Kin T, Imes S, Dinyari P, Malcolm A, Toso C, Nilsson B, Korsgren O, Shapiro AM. Insulin-heparin infusions peritransplant substantially improve single-donor clinical islet transplant success. Transplantation. 2010 Feb 27;89(4):465-71. doi: 10.1097/TP.0b013e3181c478fd.
citation: Eriksson O, Eich T, Sundin A, Tibell A, Tufveson G, Andersson H, Felldin M, Foss A, Kyllonen L, Langstrom B, Nilsson B, Korsgren O, Lundgren T. Positron emission tomography in clinical islet transplantation. Am J Transplant. 2009 Dec;9(12):2816-24. doi: 10.1111/j.1600-6143.2009.02844.x. Epub 2009 Oct 21.
citation: Friberg AS, Brandhorst H, Buchwald P, Goto M, Ricordi C, Brandhorst D, Korsgren O. Quantification of the islet product: presentation of a standardized current good manufacturing practices compliant system with minimal variability. Transplantation. 2011 Mar 27;91(6):677-83. doi: 10.1097/TP.0b013e31820ae48e.