The Anti-Interleukin-1 in Diabetes Action trial

The aim of the Anti-Interleukin-1 in Diabetes Action trial (AIDA) study is to
test the feasibility, safety/tolerability and potential efficacy of anti-IL-1
therapy in maintaining or enhancing beta-cell function in people with new-onset
Type 1 diabetes.

The hypothesis is that anti-IL-1 treatment as add-on therapy to conventional
insulin therapy will preserve or enhance beta-cell function assessed as the 2
h-area under the curve (AUC) for C-peptide in response to standard mixed meal.
For 20 years it has been recognized that the pro-inflammatory cytokine
interleukin-1 is selec-tively cytotoxic to rodent and human beta-cells in vitro
and anti-IL-1 therapies reduce diabetes incidence in animal prevention models.
The following observations can be highlighted: 1) IL-1 alone or in combination
with other inflammatory cytokines causes beta-cell destruction in rodent and
human islets and in perfused pancreas via the MAPK and NFkB signalling
pathways, 2) IL-1 given i.p. to non-diabetes prone animals causes transient
insulinopenic diabetes 3) IL-1 is expressed early in NOD islets 4) anti-IL-1
intervention prevents diabetes development in models of Type 1 diabetes and
islet graft destruction and 5) transgenic mice with knock-out of the IL-1
receptor reduces diabetes incidence by 30%. We recently reported that 13 w of
IL-1 receptor antagonist therapy improved glycaemia and beta-cell function in
Type 2 diabetes, a disorder in which glucose-induced beta-cell apoptosis may be
IL-1 dependent and the intervention is safe.

The aim of the Anti-Interleukin-1 in Diabetes Action trial (AIDA) study is to
test the feasibility, safety/tolerability and potential efficacy of anti-IL-1
therapy in maintaining or enhancing beta-cell function in people with new-onset
Type 1 diabetes.

A randomized, placebo-controlled, double-masked, parallel-group, multi-centre
trial of IL-1 antagonism in subjects with newly-diagnosed Type 1 diabetes.
Patients are instructed to inject 100 mg human recombinant interleukin-1
receptor antagonist (anakinra, Kineret®, Amgen, CA) or placebo s.c. once daily
for 2 years. Endpoints will be evaluated every three months, with an interim
analysis after 6 months.

The patients are instructed to administer anti-IL-1 therapy in the form of
recombinant human non-glycosylated interleukin-1 receptor antagonist (anakinra)
at a dose of 100 mg once daily or placebo by subcutaneous injection at the same
time-point in the morning. There will be a mixed meal test at every hospital
visit.

During the trial period the patient will visit the hospital six times. This
will take approximately 3-4 hours. During the first visit the studie docter
will take a history and a physical exam. We also take blood and do an
urineanalysis. Hereafter a ECG and a fundusphoto will be performed. This all is
to exclude any unknown diseases or diabetic complications. Then there will be a
mixed meal test. The next visits there will be a short history taken and a
physical exam. Also shall there be blood withdrawn and a mixed meal test. After
the first return visit the patient will start using the studie medication. The
patient has to inject the studiemedication s.c. every day at the same timepoint.

We think the burden on the patient will be relatively mild because the patient
only has to come to hospital for six times in nine months. Also will the use of
the studie medication in this group of patients not be a heavy burden because
of they have to do a subcutanous injection a few times a day with their insulin
therapy.

Anakinra has been shown to be a drug with few side effects. The adverse effects
of anti-IL-1 therapy have been reversible upon withdrawal.