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

Crohn Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02349594
• Other study ID #: GW/MB/42964
• Secondary ID: 2013-001212-30
• Status: Completed
• Phase: Phase 4
• First received: January 16, 2015
• Last updated: November 9, 2015
• Start date: January 2014
• Est. completion date: September 2015

Study information

• Verified date: November 2015
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)Netherlands: Independent Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 6
• Est. completion date: September 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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-a 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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• Omegaven 10%
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.
• Intralipid 20%
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.

Locations

Country	Name	City	State
Netherlands	Radboud University Medical Center	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change of TNF-a 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	No
Secondary	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	No
Secondary	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	No
Secondary	change in Oxygen radical production by neutrophils	Differences are compared by paired t-test or wilcoxon signed rank test	day 0 and day 4	No
Secondary	change in Oxygen radical production by neutrophils	Differences are compared by paired t-test or wilcoxon signed rank test.	day 0 and day 11	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Change of TNF-a 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	No
Secondary	(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	No
Secondary	(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	No