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

Short Bowel Syndrome Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00793195
• Other study ID #: 1000012566
• Status: Active, not recruiting
• Phase: Phase 2
• First received: November 18, 2008
• Last updated: November 2, 2011
• Start date: January 2009
• Est. completion date: January 2012

Study information

• Verified date: November 2011
• Source: The Hospital for Sick Children
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 24
• Est. completion date: January 2012
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 24 Months

Eligibility

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

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gastrointestinal Motility Disorder
• Intestinal Failure
• Liver Diseases
• Mucosal Enteropathy
• Short Bowel Syndrome

Intervention

Drug:
• Intralipid 20%
Dosing will be formulated according to a Nomogram for Parenteral Nutrition (PN) composition, which takes into account the percentage of the subject's caloric intake consumed parenterally. PN solution will be infused continuously over 12-24 hours by infusion pump, and the duration each day will depend on the enteral tolerance of the child. PN shall not be discontinued, unless the patient is taking 95% of calories enterally with good growth as evidence by appropriate weight gain. Subjects will receive the trial lipid for a total duration of 12 weeks or if they develop a serum conjugated bilirubin (sustained for 7 days) of 100 umol/l (6mg/dl) or full enteral tolerance prior to this end-point. Once the trial lipid is discontinued, in the event that PN is continued, subjects will return to the standard lipid preparation. A final follow-up data-point will be collected 4 weeks after the trial lipid is stopped.
• SMOFlipid 20%
Dosing will be formulated according to a Nomogram for Parenteral Nutrition (PN) composition, which takes into account the percentage of the subject's caloric intake consumed parenterally. PN solution will be infused continuously over 12-24 hours by infusion pump, and the duration each day will depend on the enteral tolerance of the child. PN shall not be discontinued, unless the patient is taking 95% of calories enterally with good growth as evidence by appropriate weight gain. Subjects will receive the trial lipid for a total duration of 12 weeks or if they develop a serum conjugated bilirubin (sustained for 7 days) of 100 umol/l (6mg/dl) or full enteral tolerance prior to this end-point. Once the trial lipid is discontinued, in the event that PN is continued, subjects will return to the standard lipid preparation. A final follow-up data-point will be collected 4 weeks after the trial lipid is stopped.

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Foothills Medical Center	Calgary	Alberta
Canada	Stollery Children's Hospital	Edmonton	Alberta
Canada	Hamilton Health Sciences	Hamilton	Ontario
Canada	The Hospital for Sick Children	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
The Hospital for Sick Children	Fresenius Kabi

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean serum conjugated bilirubin (umol/L)		12 weeks	Yes
Secondary	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	Yes
Secondary	Proportion with progression of liver disease (sustained serum conjugated bilirubin >100 umol/L in absence of sepsis)		12 and 16 weeks	Yes
Secondary	Degree of enteral tolerance (%)		12 and 16 weeks	No
Secondary	Growth parameters		12 and 16 weeks	No
Secondary	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	Yes
Secondary	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-a) assessment		12 and 16 weeks	No
Secondary	Feasibility of trial (recruitment, protocol adherence, estimated effect size		4, 12 and 16 weeks	No