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

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.

Study Overview

• Status: Completed
• Conditions: Crohn Disease
• Intervention / Treatment: Drug: Omegaven 10%; Drug: Intralipid 20%

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.

• Study Type: Interventional
• Enrollment (Anticipated): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Radboud University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: treatment order A; Participants in this arm first receive 'Omegaven 10%' and after crossing over the 'Intralipid 20%'	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.; Other Names: fish oil; N-3 polyunsaturated fatty acids atty acids; Drug: 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.; Other Names: soybean oil; N-6 polyunsaturated fatty acids atty acids
Active Comparator: treament order B; Participants in this arm first receive 'Intralipid 20%' and after crossing over the 'Omegaven 10%'	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.; Other Names: fish oil; N-3 polyunsaturated fatty acids atty acids; Drug: 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.; Other Names: soybean oil; N-6 polyunsaturated fatty acids atty acids

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Study Director: G. Wanten, MD, PhD, Radboud University Nijmegen Medical Center; Principal Investigator: F. Hoentjen, MD, PhD, Radboud University Nijmegen Medical Center; Principal Investigator: D de Jong, MD, PhD, Radboud University Nijmegen Medical Center; Principal Investigator: P. Calder, MD, PhD, University Hospital Southampton NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: January 16, 2015
• First Submitted That Met QC Criteria: January 23, 2015
• First Posted (Estimate): January 29, 2015

Study Record Updates

• Last Update Posted (Estimate): November 10, 2015
• Last Update Submitted That Met QC Criteria: November 9, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: GW/MB/42964; 2013-001212-30 (EudraCT Number)