Immune Modulation by Parenteral Fish Oil in Patients With Crohn's Disease
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| 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:
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:
|
| 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:
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:
|
Outcome Measures
Primary Outcome Measures
- Change of TNF-α production in pg/ml [day 0 and day 4]
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.
Secondary Outcome Measures
- short term change in leukocyte functions [day 0 and day 4]
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
- long term change in leukocyte functions [day 0 and day 11]
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.
- change in Oxygen radical production by neutrophils [day 0 and day 4]
Differences are compared by paired t-test or wilcoxon signed rank test
- change in Oxygen radical production by neutrophils [day 0 and day 11]
Differences are compared by paired t-test or wilcoxon signed rank test.
- short term effects on in cytokine production [day 0 and day 4]
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.
- Long term effects on in cytokine production [day 0 and day 11]
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.
- Composition of phospholipids in the cell membrane [day 0, day4 and day 11]
to evaluate fatty acid incorporationDifferences are compared by paired t-test or wilcoxon signed rank test.
- Change of TNF-α production in pg/ml [day 0 and day 11]
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.
- (anti-) Oxidant status and oxidative damage [day 0 and day 4]
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.
- (anti-) Oxidant status and oxidative damage [day 0 and day 11]
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.
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Radboud University Medical Center | Nijmegen | Netherlands | 6525 GA |
Sponsors and Collaborators
- 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 Documents (Full-Text)
None provided.More Information
Publications
None provided.- GW/MB/42964
- 2013-001212-30