Modulation of immune function by parenteral fish oil in patients with Crohn*s disease and high inherent Tumor Necrosis Factor-alfa production, a randomized, single blinded, cross-over study

Fish oil (rich in omega-3 fatty acids) has anti-inflammatory characteristics.
Trials investigating the ability of fish oil capsules for treatment of patients
with Crohn*s disease (a chronic inflammatory bowel disease) show discordant
results. It is reasonable that these divergent results are due to
inter-individual variation in cytokine production (like TNF-α). TNF-α is a
cytokine, which plays a central position in the pathofysiology of Crohn*s
disease, hence anti-TNF-α agents (infliximab (Remicade®) en adalimumab
(Humira®)) have an important role in today*s treatment of Crohn*s disease.

It is known that administration of fish oil can decrease TNF-α production in
healthy people with a high inherent TNF-α production, however this is not
applicable for people with a middle or low TNF-α production, in which TNF-α
production is unaffected or even increases in the case of a low inherent TNF-α
production. Based on these results we formulated the hypothesis that omega-3
fatty acids can be used as a treatment in a selected group of patients.

By administering an emulsion of fish oil to patients with Crohn*s disease with
a high inherent TNF-α production we expect to find a positive result. With
intravenous administration patients experience less side effects like nausea,
diarrhea and fish-smell, furthermore the omega-3 fatty acids are incorporated
faster. Intravenous administration of fish oil is already used as a component
of total parenteral feeding in addition to soybean oil.

To evaluate the effect of parenteral supplementation of fishoil based emulsion
(rich in omega-3 fatty acids) compared with a soy bean oil emulsion (rich in
omega-6 fatty acids) on the leukocyte functions (amongst others production of
TNF-α and other cytokines) in patients with Crohn's disease and a high inherent
TNF-α production.

First phase: patients with a high inherent TNF- α will be identified by
assessment of TNF-α production in a group 100 patients with Crohn's disease who
meet in- and exclusion criteria. Patients in the highest tertile are classified
as 'high producers'. From this group 12 random patients are invited for the
second part of this trial.


second phase:
Single center, randomized, single blinded, lipid-controlled, cross-over pilot
trial in 12 patients with Crohn's disease and a high TNF-α production. (see
intervetion for additional information)

First, patients with a high inherent TNF- α will be identified by assessment of
TNF-α production in a group 100 patients with Crohn's disease who meet in- and
exclusion criteria. Patients within the highest tertile will be classified as
high producers.

Next, 12 patients within the highest tertile will be randomized to intravenous
administration of 20% (w/v) lipid-control (Intralipid®), and, after crossing
over, 10% (w/v) fish oil emulsion (Omegaven®), or vice-versa for 1 hour on
three consecutive days at a dose of 0.2 g/Kg BW/hr. So patients who are blinded
for the intervention receive both emulsions.

Study parameters will be assessed in blood drawn prior to the first infusion
(T=0) and 1 (T=4) and 8 days (T=11) after the third infusion. Between the two
treatment arms, there will be a wash-out interval of 2-3 weeks.

An intravenous infusion of one of both lipid emulsions will be administered for
1 hour on three consecutive days. Blood samples will be drawn by peripheral
venapuncture on day 1 prior to the first infusion (50cc), on day 2 and 3 prior
to the infusion 3 cc (serum lipid concentration control) and on one day (day
4)(50cc) and one week (day 11) (50cc) after the third infusion. Of these, four
(day 1, 2 and 3) do not require an additional puncture since they can be drawn
from the venflon that is inserted the infusions and remains there for a couple
of days. This whole protocol will be performed two times with a wash-out
interval of two weeks, so patients receive both interventions.

Risk associated with participation can be categorized as *low* and include an
allergic reaction to the lipid infusion, infection extravasation of infused
emulsion or placebo or a hematoma at the puncture site.