Clinical trial NCT00793195: Can SMOFlipid®, A Composite Parenteral Nutrition Lipid Emulsion, Prevent Progression Of Parenteral Nutrition Associated Liver Disease In Infants?
Official title: Can SMOFlipid®, A Composite Parenteral Nutrition Lipid Emulsion, Prevent Progression Of Parenteral Nutrition Associated Liver Disease In Infants? A Pilot Double Blind Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Short Bowel Syndrome
Intestinal Failure
Gastrointestinal Motility Disorder
Mucosal Enteropathy
Keywords: Neonates
Short Bowel Syndrome
Intestinal Failure
Liver Failure
Parenteral Nutrition
Intralipid
SMOF
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Fresenius Kabi
First posted: 2008-11-19
Enrollment: 24
Sex: ALL
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean serum conjugated bilirubin (umol/L)
timeFrame: 12 weeks
Secondary outcomes:
measure: Proportion with the development of cholestasis (sustained serum conjugated bilirubin >50 umol/L for greater than 2 weeks in absence of sepsis)
timeFrame: 12 and 16 weeks
measure: Proportion with progression of liver disease (sustained serum conjugated bilirubin >100 umol/L in absence of sepsis)
timeFrame: 12 and 16 weeks
measure: Degree of enteral tolerance (%)
timeFrame: 12 and 16 weeks
measure: Growth parameters
timeFrame: 12 and 16 weeks
measure: 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).
timeFrame: 12 and 16 weeks
measure: 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
timeFrame: 12 and 16 weeks
measure: Feasibility of trial (recruitment, protocol adherence, estimated effect size
timeFrame: 4, 12 and 16 weeks
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Calgary
country: Canada
facility: Foothills Medical Center
state: Alberta
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Paul Wales
role: PRINCIPAL_INVESTIGATOR
References:
citation: Diamond IR, Grant RC, Pencharz PB, de Silva N, Feldman BM, Fitzgerald P, Sigalet D, Dicken B, Turner J, Marchand V, Ling SC, Moore AM, Avitzur Y, Wales PW. Preventing the Progression of Intestinal Failure-Associated Liver Disease in Infants Using a Composite Lipid Emulsion: A Pilot Randomized Controlled Trial of SMOFlipid. JPEN J Parenter Enteral Nutr. 2017 Jul;41(5):866-877. doi: 10.1177/0148607115626921. Epub 2016 Feb 2.