Crossover Study on the Effect of Omegaven in Combination With Different Lipid Emulsions in Home Parenteral Nutrition

Study Overview
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Brief Summary
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The aim of this study was to evaluate the safety and tolerance of ClinOleic or Lipoplus or SMOFlipid lipid emulsions. After 6 weeks of each lipid emulsion, Omegaven (fish oil) was added for a further 4 weeks. The safety and tolerance was evaluated after each lipid emulsion cycle by biochemistry, hematology and coagulation variables, vital signs and adverse events. We also analysed fatty acid profiles in plasma or erythrocyte phospholipids, antioxidant enzyme activities, lipid peroxidation products, plasma lipids and pro-inflammatory cytokine production after in vitro stimulation of whole blood by lipopolysacharide in HPN patients. The non-interventional group of healthy controls was included for comparison.

Detailed Description
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Intravenous lipid emulsions (LEs) are an indispensable part of home parenteral nutrition (HPN). All commercially obtainable LEs are applicable for HPN in providing a source of energy and essential fatty acids. The originally used soyabean oil-based LE (Intralipid) have been suspected of being associated with a higher risk of pro-inflammatory lipid-mediator production due to their high content of n-6 polyunsaturated fatty acids. The more modern mixes of soyabean oil, and/or olive oil, and/or fish oil LEs with beneficial responses compared with Intralipid are available. Given that there are no clear clinical recommendations for LE application in HPN, we performed this cross-over design, phase 4 study comparing ClinOleic, Lipoplus or SMOFlipid in chronic intestinal failure patients with additional escalation of fish oil using Omegaven.

Official Title
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A Prospective, Randomized, Controlled, Double-blind, Crossover-Design, Mono-center, Phase IV Study Comparing the Effect of Omegaven in Combination With Clinoleic or Lipoplus or SMOFlipid in Home Parenteral Nutrition Patients

Conditions
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Parenteral Nutrition

Intervention / Treatment
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* Drug: ClinOleic (baseline)
* Drug: ClinOleic + Omegaven
* Drug: Lipoplus (baseline)
* Drug: Lipoplus + Omegaven
* Drug: SMOFlipid (baseline)
* Drug: SMOFlipid + Omegaven


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Home parenteral nutrition patients in need of parenteral nutrition administration > 4 days/week Parenteral duration expectancy > 8 months Stable clinical condition without any complications in the past 2 months Written consent from the subject Exclusion Criteria: Known hypersensitivity to any of the active substances or excipients Unstable conditions Active cancer or its treatment Established immunodeficiency Advanced organ dysfunction from chronic disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Home Parenteral Nutrition, Cross-over<br>Random Cycle Sequence - Cycle 1: Clinoleic (baseline), 50g/per day, 42 days Clinoleic + Omegaven, 40g + 10g/per day, 28 days. Cycle 2: Lipoplus (baseline), 50g/per day, 42 days Lipoplus + Omegaven, 40g + 10g/per day, 28 days. Cycle 3: SMOFlipid (baseline), 50g/per day, 42 days SMOFlipid + Omegaven, 40g + 10g/per day, 28 days. | Drug: ClinOleic (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: ClinOleic 20% Baxter;Drug: ClinOleic + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: ClinOleic 20% Baxter + Omegaven 10% Fresenius Kabi;Drug: Lipoplus (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: Lipoplus 20% BBraun Melsungen;Drug: Lipoplus + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: Lipoplus 20% BBraun Melsungen + Omegaven 10% Fresenius Kabi;Drug: SMOFlipid (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: SMOFlipid 20% Fresenius Kabi;Drug: SMOFlipid + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: SMOFlipid 20% Fresenius Kabi + Omegaven 10% Fresenius Kabi;|
| Active Comparator: 2 Home Parenteral Nutrition, Cross-over<br>Random Cycle Sequence - Cycle 1: Clinoleic (baseline), 50g/per day, 42 days Clinoleic + Omegaven, 40g + 10g/per day, 28 days. Cycle 2: Lipoplus (baseline), 50g/per day, 42 days Lipoplus + Omegaven, 40g + 10g/per day, 28 days. Cycle 3: SMOFlipid (baseline), 50g/per day, 42 days SMOFlipid + Omegaven, 40g + 10g/per day, 28 days. | Drug: ClinOleic (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: ClinOleic 20% Baxter;Drug: ClinOleic + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: ClinOleic 20% Baxter + Omegaven 10% Fresenius Kabi;Drug: Lipoplus (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: Lipoplus 20% BBraun Melsungen;Drug: Lipoplus + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: Lipoplus 20% BBraun Melsungen + Omegaven 10% Fresenius Kabi;Drug: SMOFlipid (baseline)<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: SMOFlipid 20% Fresenius Kabi;Drug: SMOFlipid + Omegaven<br>* Lipid emulsion in pharmacy compounded all-in-one admixture<br>* Other names: SMOFlipid 20% Fresenius Kabi + Omegaven 10% Fresenius Kabi;|
| No Intervention: Comparator3<br>Healthy Control | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline lipid emulsion production of TNF-alpha after in vitro stimulation of whole blood by lipopolysacharide at 4 weeks of Omegaven lipid emulsion addition | The whole blood culture supernatant concentration of TNF-alpha (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion production of IL-1-beta after in vitro stimulation of whole blood by lipopolysacharide at 4 weeks of Omegaven lipid emulsion addition | The whole blood culture supernatant concentration of IL-1-beta (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion production of IL-6 after in vitro stimulation of whole blood by lipopolysacharide at 4 weeks of Omegaven lipid emulsion addition | The whole blood culture supernatant concentration of IL-6 (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion production of IL-8 after in vitro stimulation of whole blood by lipopolysacharide at 4 weeks of Omegaven lipid emulsion addition | The whole blood culture supernatant concentration of IL-8 (ng/L) | day 42, day 70 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline lipid emulsion plasma concentration of TNF-alpha at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of TNF-alpha (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of IL-1-beta at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of IL-1-beta (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of IL-6 at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of IL-6 (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of IL-8 at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of IL-8 (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration ratio of oxidized LDL/LDL cholesterol at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration ratio of oxidized LDL/LDL cholesterol (ox-LDL/LDL-C) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of triglycerides at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of triglycerides (mmol/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of total cholesterol at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of total cholesterol (mmol/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of HDL cholesterol at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of HDL cholesterol (mmol/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of LDL cholesterol at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of LDL cholesterol (mmol/L) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma phospholipid fatty acid profile at 4 weeks of Omegaven lipid emulsion addition | The plasma phospholipid fatty acid profile (mol%) | day 42, day 70 | 
| Change from baseline lipid emulsion erythrocyte phospholipid fatty acid profile at 4 weeks of Omegaven lipid emulsion addition | The erythrocyte phospholipid fatty acid profile (mol%) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma concentration of fibrothelial growth factor 19 at 4 weeks of Omegaven lipid emulsion addition | The plasma concentration of fibrothelial growth factor 19 (ng/L) | day 42, day 70 | 
| Change from baseline lipid emulsion erythrocyte superoxide dismutase activity at 4 weeks of Omegaven lipid emulsion addition | The erythrocyte activity of SOD (U/g Hb) | day 42, day 70 | 
| Change from baseline lipid emulsion erythrocyte catalase activity at 4 weeks of Omegaven lipid emulsion addition | The erythrocyte activity of CAT (U/g Hb) | day 42, day 70 | 
| Change from baseline lipid emulsion erythrocyte glutathione peroxidase activity at 4 weeks of Omegaven lipid emulsion addition | The erythrocyte activity of GPX (U/g Hb) | day 42, day 70 | 
| Change from baseline lipid emulsion erythrocyte glutathione reductase activity at 4 weeks of Omegaven lipid emulsion addition | The erythrocyte activity of GR (U/g Hb) | day 42, day 70 | 
| Change from baseline lipid emulsion plasma paraoxonase 1 activity at 4 weeks of Omegaven lipid emulsion addition | The plasma activity of PON1 (U/L) | day 42, day 70 | 
| Alteration of liver function | Liver function tests | week 6, week 10, week 16, week 20, week 26, week 30 | 
| Septic complications | Catheter-related bloodstream infections | week 6, week 10, week 16, week 20, week 26, week 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lipid emulsion, olive oil, fish oil, intestinal failure, home parenteral nutrition