Open, Randomized, Active Comparator-controlled, Multi-Center Study to Evaluate Safety and Efficacy of IBsolvMIR® in Islet Transplantation

Type 1 Diabetes (T1D) is an organ-specific disease in which the immune system
attacks the insulin-producing β-cells. The onset of the disease typically
occurs before adulthood and seriously affects a person*s quality of life
(Atkinson, 1994).
T1D is successfully treated with life-long daily exogenous insulin injections
and monitoring of blood glucose levels. However, even careful glucose control
cannot adequately substitute for the finely tuned normal balance of the glucose
levels found in healthy body, and many patients will therefore develop
secondary long-term complications. Therefore, despite marked improvements in
diabetes care in recent years, insulin-dependent diabetes is one of the leading
causes of end-stage renal disease, blindness and amputation. Additionally,
hypoglycemia unawareness is a serious consequence of recurrent hypoglycemia
often requiring emergency care.
The only currently available method for restoring endogenous insulin production
is to replace the patient*s destroyed insulin-producing β-cells (islets),
either by whole pancreas transplantation or by transplanting the islets, which
constitute only 1% of the whole organ.
Pancreatic islet transplantation has become a feasible option in the treatment
of T1D which offers advantages over whole pancreas transplantation. In 2000,
the Edmonton group first reported successful islet transplantation into the
liver. The intervention is minimal and the procedure can be performed on an
almost outpatient basis. A key aspect of the Edmonton approach is to use an
average of two sequential islet transplants to reach insulin independence.
However, in most patients who reached insulin-independence, insulin treatment
is to be resumed within 2 years after transplantation (Shapiro, 2000; Ryan,
2001; Shapiro, 2006).
Analysis of results from the NIH sponsored Collaborative Islet Transplant
Registry indicate a central role of controlling inflammation in the immediate
post-transplant period and its potential impact on long term outcome
(Naziruddin, 2011).
The study drug IBsolvMIR is a type of low molecular weight dextran sulfate
(LMW-DS) and it has been shown that LMW-DS inhibits activation of the
complement cascade and contact activation of the coagulation system (Wuillemin,
te Velthuis et al. 1997; Fiorante, Banz et al. 2001) which are important
entities in this early inflammation (IBMIR, Instant Blood-mediated Inflammatory
Reaction).
LMW-DS has also been shown to have direct effects on cell interactions, such as
inhibition of E-selectin-mediated adhesion of neutrophils to endothelial cells
(Matsumiya, Yamaguchi et al. 1999). We have demonstrated the efficacy of LMW-DS
in preventing the IBMIR (Goto, Groth et al. 2004) already at a concentration of
0.1 mg/mL LMW-DS totally prevented the IBMIR in human blood.

To determine safety and efficacy of low molecular weight dextran sulphate
during islet transplantation

This is a Phase II open, randomized, active comparator-controlled multi center
study in patients with severe type-1 diabetes. This is a two-armed study where
patients are randomized in a 2:1 ratio between IBsolvMIR and heparin. Eighteen
patients are planned to be included.

The study consists of up to 8 visits; screening, transplantation surgery with
bolus administration of study drug or active comparator, IBsolvMIR doses on day
1, 3 and 6 after surgery, follow up visits on day 7 and 14, and follow-up phone
call on day 44.

The primary endpoint is to study AEs up to 44 days following study drug
administration. The secondary endpoints are to evaluate changes in TAT,
C-peptide, C3a and HGF at baseline and during the first 24 hours after study
drug administration, as well as evaluate a change in levels of
C-peptide-glucose-creatinine ratio on day 14 compared to baseline.

IBsolvmir (low molecular weight dextran sulphate) instead of heparin during
islet transplantation

Phase 1 and 1/2 studies have not shown any relevant risk of an IBsolvMIR
infusion. The burden consists of an IV dose of LMW-DS right before islet
transplant and at day 1, 3 and 6. For the infusion at day 3 and 6 with the
bloodsampling, an intravenous catheter will have to be placed

Possible advantages include better islet graft survival