Immune Modulation by Parenteral Fish Oil in Patients With Crohn's Disease

Study Overview
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Brief Summary
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To evaluate the effects of infusion of a Fish oil-based lipid emulsion on TNF-α production and other relevant immune functions. A soybean oil emulsion, rich in the omega-6 polyunsaturated fatty acid linoleic acid, will serve as control.

Detailed Description
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Rationale: Fish oil (FO), rich in omega-3 polyunsaturated fatty acids, exerts a range of anti-inflammatory actions that render it a potential therapeutic agent to treat Crohn's disease, a chronic inflammatory disease that primarily affects the bowel. Recent evidence suggests that a lack of effect in previous studies might be due to the fact that genetic background was not taken into account. For instance, a study in healthy subjects showed that production of the pro-inflammatory cytokine Tumor Necrosis Factor-alpha (TNF-α) following FO supplementation decreased in individuals within the highest tertile of pre-supplementational TNF-α production, remained unaltered in the middle tertile, and increased in the lowest tertile of pre-supplementational TNF-α production. TNF-α plays a pivotal role in the pathogenesis of Crohn's disease, hence the treatment with anti-TNF-α agents. Based on these notions, and because FO supplementation via the enteral route is strongly dose limited due to fat-induced side effects such as diarrhea, we hypothesize that parenteral FO supplementation might be beneficial in those patients with Crohn's disease with a high inherent TNF-α production. Study design: Single center, randomized, single blinded, lipid-controlled, cross-over pilot trial. Study population: Adult patients with Crohn's disease with previous bowel surgery, currently in remission (without the need for immunosuppressive drugs) and with a high inherent TNF-α production. Intervention: First, patients with a high inherent TNF-α will be identified by assessment of TNF-α production in a group 100 patients who meet in- and exclusion criteria. Patients within the highest tertile will be classified as high producers. Next, 5 patients within the highest tertile will be randomized to receive 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 bodyweight /hr. 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 at least 2-3 weeks. Main study parameters/endpoints: Early (T=day 4) and late (T=day 11) effects of infusions on TNF-α production by whole blood cultures. Secondary outcomes: effect on leukocyte counts, leukocyte functions and on (anti-)oxidant status, the occurrence of oxidative damage and analysis of specific Single Nucleotide Polymorphisms (SNPs) related to TNF-α production.

Official Title
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Modulation of Immune Function by Parenteral Fish Oil in Patients With Crohn's Disease and High Inherent Tumor Necrosis Factor-alpha Production: a Randomized, Single Blinded, Cross-over Study

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Omegaven 10%
* Drug: Intralipid 20%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with Crohn's disease with previous bowel surgery, currently in remission (without the need for immunosuppressive drugs) and with a high inherent TNF-α production. Exclusion Criteria: Patients with other active inflammatory / immune mediated underlying diseases Smoking > 5 cigarettes a day Diet with >2 portions of fatty fish (tuna, salmon, mackerel, herring, and trout) a week History of metabolic disorder (especially diabetes or lipid disorders) Crohn's disease activity, including the presence of active fistulas On need for medical (other than 5-aminosalicylic acid preparations) or surgical treatment for Crohn's disease activity Use of non-steroidal anti-inflammatory drugs or aspirin C-reactive protein levels of >10 mg/l History of venous or arterial thrombosis Active malignancy Presence of severe pulmonary, cardiovascular, renal, liver, coagulation or hematological disease Pregnancy or lactation Age <18 yrs Allergy for one of the following components: fish, chicken, eggs or soy beans

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: treatment order A<br>Participants in this arm first receive 'Omegaven 10%' and after crossing over the 'Intralipid 20%' | Drug: Omegaven 10%<br>* intravenous administration 10% (w/v) fish oil emulsion (Omegaven) for 1 hour on three consecutive days at a dose of 0.2 g/kg bodyweight/hr.<br>* Other names: N-3 polyunsaturated fatty acids atty acids;Drug: Intralipid 20%<br>* intravenous administration of 20% (w/v) lipid-control (Intralipid®), for 1 hour on three consecutive days at a dose of 0.2 g/kg bodyweight/hr.<br>* Other names: N-6 polyunsaturated fatty acids atty acids;|
| Active Comparator: treament order B<br>Participants in this arm first receive 'Intralipid 20%' and after crossing over the 'Omegaven 10%' | Drug: Omegaven 10%<br>* intravenous administration 10% (w/v) fish oil emulsion (Omegaven) for 1 hour on three consecutive days at a dose of 0.2 g/kg bodyweight/hr.<br>* Other names: N-3 polyunsaturated fatty acids atty acids;Drug: Intralipid 20%<br>* intravenous administration of 20% (w/v) lipid-control (Intralipid®), for 1 hour on three consecutive days at a dose of 0.2 g/kg bodyweight/hr.<br>* Other names: N-6 polyunsaturated fatty acids atty acids;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of TNF-α production in pg/ml | whole blood cultures are stimulated with 1 ng/ml lipopolysaccharide for 4 hours. TNF-alpha levels are measured in the supernatant with an enzyme-linked immunosorbent assay. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| short term change in leukocyte functions | Change in expression of cell surface markers on neutrophils and monocytes (CD11, CD66, CD62 and CD63) by immune fluorescent staining and subsequent flowcytometric analysis. Between day 0 and day 4 patients receive on intralipid or omegaven 3 consecutive days. Differences are compared by paired t-test or wilcoxon signed rank test | day 0 and day 4 | 
| long term change in leukocyte functions | Change in expression of cell surface markers on neutrophils and monocytes (CD11, CD66, CD62 and CD63) by immune fluorescent staining and subsequent flowcytometric analysis. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 11 | 
| change in Oxygen radical production by neutrophils | Differences are compared by paired t-test or wilcoxon signed rank test | day 0 and day 4 | 
| change in Oxygen radical production by neutrophils | Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 11 | 
| short term effects on in cytokine production | whole blood cultures are stimulated with 1 ng/ml lipopolysaccharide for 24 hours. Interleukin (IL)-1B, Il-6 and IL-10 levels are measured in the supernatant with an enzyme-linked immunosorbent assay. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 4 | 
| Long term effects on in cytokine production | whole blood cultures are stimulated with 1 ng/ml lipopolysaccharide for 24 hours. Il-1B, Il-6 and IL-10 levels (pg/ml ) are measured in the supernatant with an enzyme-linked immunosorbent assay . Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 11 | 
| Composition of phospholipids in the cell membrane | to evaluate fatty acid incorporationDifferences are compared by paired t-test or wilcoxon signed rank test. | day 0, day4 and day 11 | 
| Change of TNF-α production in pg/ml | whole blood cultures are stimulated with 1 ng/ml lipopolysaccharide for 4 hours. TNF-alpha levels are measured in the supernatant with an enzyme-linked immunosorbent assay. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 11 | 
| (anti-) Oxidant status and oxidative damage | Oxidative stress will be measured by both lipid and protein peroxidation and antioxidant capacity. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 4 | 
| (anti-) Oxidant status and oxidative damage | Oxidative stress will be measured by both lipid and protein peroxidation and antioxidant capacity. Differences are compared by paired t-test or wilcoxon signed rank test. | day 0 and day 11 |