Can SMOFlipid®, A Composite Parenteral Nutrition Lipid Emulsion, Prevent Progression Of Parenteral Nutrition Associated Liver Disease In Infants?

Phase 2

• Conditions: Short Bowel Syndrome; Intestinal Failure; Gastrointestinal Motility Disorder; Mucosal Enteropathy
• Interventions: Drug: Intralipid 20%; Drug: SMOFlipid 20%

• Registration Number: NCT00793195
• Lead Sponsor: The Hospital for Sick Children

Brief Summary

The aim of this study is to determine the feasibility of conducting a trial to examine the efficacy of an ω3FA (Omega-3 fatty acid) containing balanced lipid emulsion in the prevention of progression of PNALD in infants with Intestinal Failure/Short Bowel Syndrome (SBS) and early liver dysfunction.

Detailed Description

Parenteral nutrition (PN) associated liver disease (PNALD), remains the primary cause of morbidity and mortality in infants with Short Bowel Syndrome (SBS) and intestinal failure. Although, the etiology is likely multi-factorial, lipids within parenteral nutrition solution have been implicated in its development. The standard lipid used in PN is typically, a soy based lipid (eg: Intralipid® - Fresenius Kabi) that primarily contains omega-6 fatty acids (ω6FAs). Animal and human studies have suggested that addition of omega-3 fatty acids (ω3FAs) to parenteral nutrition may decrease the incidence of hepatic injury, as well as have beneficial immunologic effects. SMOFlipid® (Fresenius Kabi) is a composite lipid emulsion, which contains polyunsaturated ω3 and ω6FAs, monounsaturated FAs, as well as medium chain FAs as integral constituents. All components (Soy-bean oil, medium chain triglycerides, olive oil, fish oil) have been used in humans, and the drug is approved for use in children in Europe. Based on its composition, we believe that this lipid preparation has the potential to prevent progression of liver disease in infants with SBS who are demonstrating evidence of liver dysfunction.

Study Timeline

• Study First Submitted: 2008-11-18
• Study First Submitted QC: 2008-11-18
• Study First Posted: 2008-11-19
• Study Start: 2009-01
• Primary Completion: 2011-09
• Status Verified: 2011-11
• Last Update Submitted: 2011-11-02
• Last Update Posted: 2011-11-03
• Study Completion: 2012-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. ≤ 24 months of age at enrollment

2. Evidence of early hepatic dysfunction

   • Serum conjugated bilirubin ≥ 17 umol/L on 2 consecutive readings 7 days apart

     • No evidence of sepsis

       • Normal Temperature (T between 35.5C and 38.0C)
       • Normal leukocyte count
       • Normal platelet count
       • No systemic septic symptoms

     • No prior administration of Omegaven

3. ≥ 40% of total calories administered by PN

4. Meet one of the following diagnostic categories

   • Short Bowel Syndrome

     • Abdominal surgical procedure including gastroschisis closure by any means and percutaneous drainage procedures within the past 6 months and has been receiving PN since surgery

   • Intestinal Failure

     • One of the following diagnoses for which the child is dependent on PN

       • Gastrointestinal Motility Disorder
       • Mucosal Enteropathy

5. Expectation of the treating physician that the patient will require PN for at least 3 weeks following enrollment.

6. Parents willing to participate including randomization

Exclusion Criteria

1. Sepsis or Hemodynamic Instability of any cause.

2. Coagulopathy (Platelets ≤ 150 000, or INR ≥ 1.4)

3. Hypersensitivity to fish-, egg- or soy protein or to any of the active substances or excipients

4. Current enrollment in another clinical trial involving a surgical or pharmacologic intervention

5. Serum conjugated bilirubin > 50 umol/L

6. Hyperlipidaemia (any of)

   • LDL ≥ 4 mmol/L
   • HDL ≥ 2 mmol/L
   • Total cholesterol ≥ 5 mmol/L
   • Triglycerides ≥ 1.5 mmol/L

7. Treatment with intravenous N-Acetylcysteine or Ursodeoxycholic acid

8. Renal insufficiency

   • Creatinine ≥ 80 umol/L

9. Disorders of Fluid Balance (any of)

   • Serum Sodium < 130 mmol/L
   • Serum Sodium > 145 mmol/L

10. Unstable conditions

    • Acute pulmonary edema

    • Decompensated cardiac insufficiency

    • Severe post-traumatic conditions

    • Uncompensated diabetes mellitus

    • Acute myocardial infarction

    • Stroke within 3 months

    • Thromboembolic event within 3 months

    • Metabolic acidosis

      • Serum Bicarbonate < 17 mmol/L

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1) Intralipid	Intralipid 20%	Fat Emulsions for Intravenous Nutrition
2) SMOFlipid	SMOFlipid 20%	Fat Emulsions for Intravenous Nutrition

Primary Outcome Measures

Name	Time	Method
Mean serum conjugated bilirubin (umol/L)	12 weeks

Secondary Outcome Measures

Name	Time	Method
Proportion with the development of cholestasis (sustained serum conjugated bilirubin >50 umol/L for greater than 2 weeks in absence of sepsis)	12 and 16 weeks
Proportion with progression of liver disease (sustained serum conjugated bilirubin >100 umol/L in absence of sepsis)	12 and 16 weeks
Degree of enteral tolerance (%)	12 and 16 weeks
Growth parameters	12 and 16 weeks
Biochemical outcomes shall assess mean levels of "hepatic markers" (AST, ALT, ALP, GGT), coagulation parameters (PT, PTT, INR, platelets), serum lipid levels (triglycerides and cholesterol), serum albumin, and Nephelometry (lipid clearance).	12 and 16 weeks
Immunologic outcomes shall include assessment of RBC phospholipids composition, C-reactive Protein (CRP) and serum immunologic marker (IL-1b, IL-2R, IL-6, IL-8, IL-10, TNF-α) assessment	12 and 16 weeks
Feasibility of trial (recruitment, protocol adherence, estimated effect size	4, 12 and 16 weeks

Trial Locations

Locations (5)

Stollery Children's Hospital; 🇨🇦 Edmonton, Alberta, Canada

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

Hamilton Health Sciences; 🇨🇦 Hamilton, Ontario, Canada

Alberta Children's Hospital; 🇨🇦 Calgary, Alberta, Canada

Foothills Medical Center; 🇨🇦 Calgary, Alberta, Canada