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

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

Sponsors

Lead Sponsor: Radboud University

Source Radboud University
Brief Summary

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

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.

Overall Status Completed
Start Date 2014-01-01
Completion Date 2015-09-01
Primary Completion Date 2015-05-01
Phase Phase 4
Study Type Interventional
Primary Outcome
Measure Time Frame
Change of TNF-α production in pg/ml day 0 and day 4
Secondary Outcome
Measure Time Frame
short term change in leukocyte functions day 0 and day 4
long term change in leukocyte functions day 0 and day 11
change in Oxygen radical production by neutrophils day 0 and day 4
change in Oxygen radical production by neutrophils day 0 and day 11
short term effects on in cytokine production day 0 and day 4
Long term effects on in cytokine production day 0 and day 11
Composition of phospholipids in the cell membrane day 0, day4 and day 11
Change of TNF-α production in pg/ml day 0 and day 11
(anti-) Oxidant status and oxidative damage day 0 and day 4
(anti-) Oxidant status and oxidative damage day 0 and day 11
Enrollment 6
Condition
Intervention

Intervention Type: Drug

Intervention Name: Omegaven 10%

Description: 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.

Intervention Type: Drug

Intervention Name: Intralipid 20%

Description: 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.

Eligibility

Criteria:

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

Gender:

All

Minimum Age:

18 Years

Maximum Age:

70 Years

Healthy Volunteers:

No

Overall Official
Location
Facility: Radboud University Medical Center
Location Countries

Netherlands

Verification Date

2015-11-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: treatment order A

Type: Active Comparator

Description: Participants in this arm first receive 'Omegaven 10%' and after crossing over the 'Intralipid 20%'

Label: treament order B

Type: Active Comparator

Description: Participants in this arm first receive 'Intralipid 20%' and after crossing over the 'Omegaven 10%'

Study Design Info

Allocation: Randomized

Intervention Model: Crossover Assignment

Primary Purpose: Treatment

Masking: Single (Outcomes Assessor)

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