Complement Inhibitor Eculizumab in Clinical Islet Transplantation

Diabetes Mellitus Clinical Trial

— ICC  

Official title:

Induction With Complement Inhibitor Eculizumab in Clinical Islet Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02727608
• Other study ID #: ICC version 2
• Secondary ID: 2014-005421-12
• Status: Completed
• Phase: Phase 2
• Start date: May 15, 2016
• Est. completion date: June 2018

Study information

• Verified date: October 2018
• Source: Uppsala University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: June 2018
• Est. primary completion date: May 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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-ß-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

Related Conditions & MeSH terms

• Diabetes Mellitus

Intervention

Drug:
• Eculizumab
Intravenous infusion (1200 mg) over 35 minutes. Consecutive infusions (900 mg) on Days 1, 7 and 14.

Locations

Country	Name	City	State
Sweden	Dept of Surgical Sciences, Section of Transplantation Surgery, University Hospital	Uppsala

Sponsors (1)

Lead Sponsor	Collaborator
Uppsala University

Country where clinical trial is conducted

Sweden, 

References & Publications (8)

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. — View 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. — View 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. — View Citation

Eriksson O, Eich T, Sundin A, Tibell A, Tufveson G, Andersson H, Felldin M, Foss A, Kyllönen 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. — View 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. — View 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. — View Citation

Moberg L, Johansson H, Lukinius A, Berne C, Foss A, Källen R, Østraat Ø, 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The percentage of loss of radioactivity in the liver field.	When logistically feasible. Determined by positron emission tomography (PET)-scan of 2-deoxy-27fluoro-D-glucose ((18F) (FDG)-labelled islets infused in the portal vein as assessed during treatment (only possible at the Uppsala site).	Within the first two hours after start of islet infusion.
Other	Effect of eculizumab on IBMIR	Determined by coagulation activation (TAT)	Post infusion
Primary	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	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).
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Estimated glomerular filtration rate (GFR) (Cystatin C)	Cystatin C value	At day 75
Secondary	Portal vein thrombosis	Assessment by per protocol ultrasound	The day after infusion
Secondary	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