Clinical trial NCT02349594: Immune Modulation by Parenteral Fish Oil in Patients With Crohn's Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Crohn Disease
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2015-01-29
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change of TNF-α production in pg/ml
timeFrame: day 0 and day 4
Secondary outcomes:
measure: short term change in leukocyte functions
timeFrame: day 0 and day 4
measure: long term change in leukocyte functions
timeFrame: day 0 and day 11
measure: change in Oxygen radical production by neutrophils
timeFrame: day 0 and day 4
measure: change in Oxygen radical production by neutrophils
timeFrame: day 0 and day 11
measure: short term effects on in cytokine production
timeFrame: day 0 and day 4
measure: Long term effects on in cytokine production
timeFrame: day 0 and day 11
measure: Composition of phospholipids in the cell membrane
timeFrame: day 0, day4 and day 11
measure: Change of TNF-α production in pg/ml
timeFrame: day 0 and day 11
measure: (anti-) Oxidant status and oxidative damage
timeFrame: day 0 and day 4
measure: (anti-) Oxidant status and oxidative damage
timeFrame: day 0 and day 11
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
Study officials:
affiliation: Radboud University Nijmegen Medical Center
name: G. Wanten, MD, PhD
role: STUDY_DIRECTOR
affiliation: Radboud University Nijmegen Medical Center
name: F. Hoentjen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Nijmegen Medical Center
name: D de Jong, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Southampton NHS Foundation Trust
name: P. Calder, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: