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

Primary Purpose

Short Bowel Syndrome, Intestinal Failure, Gastrointestinal Motility Disorder

Status
Unknown status
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Intralipid 20%
SMOFlipid 20%
Sponsored by
The Hospital for Sick Children
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Short Bowel Syndrome focused on measuring Neonates, Short Bowel Syndrome, Intestinal Failure, Liver Failure, Parenteral Nutrition, Intralipid, SMOF

Eligibility Criteria

undefined - 24 Months (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Alberta Children's Hospital
  • Foothills Medical Center
  • Stollery Children's Hospital
  • Hamilton Health Sciences
  • The Hospital for Sick Children

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

1) Intralipid

2) SMOFlipid

Arm Description

Fat Emulsions for Intravenous Nutrition

Fat Emulsions for Intravenous Nutrition

Outcomes

Primary Outcome Measures

Mean serum conjugated bilirubin (umol/L)

Secondary Outcome Measures

Proportion with the development of cholestasis (sustained serum conjugated bilirubin >50 umol/L for greater than 2 weeks in absence of sepsis)
Proportion with progression of liver disease (sustained serum conjugated bilirubin >100 umol/L in absence of sepsis)
Degree of enteral tolerance (%)
Growth parameters
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).
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
Feasibility of trial (recruitment, protocol adherence, estimated effect size

Full Information

First Posted
November 18, 2008
Last Updated
November 2, 2011
Sponsor
The Hospital for Sick Children
Collaborators
Fresenius Kabi
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1. Study Identification

Unique Protocol Identification Number
NCT00793195
Brief Title
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

2. Study Status

Record Verification Date
November 2011
Overall Recruitment Status
Unknown status
Study Start Date
January 2009 (undefined)
Primary Completion Date
September 2011 (Actual)
Study Completion Date
January 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
The Hospital for Sick Children
Collaborators
Fresenius Kabi

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Short Bowel Syndrome, Intestinal Failure, Gastrointestinal Motility Disorder, Mucosal Enteropathy
Keywords
Neonates, Short Bowel Syndrome, Intestinal Failure, Liver Failure, Parenteral Nutrition, Intralipid, SMOF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1) Intralipid
Arm Type
Active Comparator
Arm Description
Fat Emulsions for Intravenous Nutrition
Arm Title
2) SMOFlipid
Arm Type
Experimental
Arm Description
Fat Emulsions for Intravenous Nutrition
Intervention Type
Drug
Intervention Name(s)
Intralipid 20%
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
SMOFlipid 20%
Intervention Description
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.
Primary Outcome Measure Information:
Title
Mean serum conjugated bilirubin (umol/L)
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Proportion with the development of cholestasis (sustained serum conjugated bilirubin >50 umol/L for greater than 2 weeks in absence of sepsis)
Time Frame
12 and 16 weeks
Title
Proportion with progression of liver disease (sustained serum conjugated bilirubin >100 umol/L in absence of sepsis)
Time Frame
12 and 16 weeks
Title
Degree of enteral tolerance (%)
Time Frame
12 and 16 weeks
Title
Growth parameters
Time Frame
12 and 16 weeks
Title
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).
Time Frame
12 and 16 weeks
Title
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
Time Frame
12 and 16 weeks
Title
Feasibility of trial (recruitment, protocol adherence, estimated effect size
Time Frame
4, 12 and 16 weeks

10. Eligibility

Sex
All
Maximum Age & Unit of Time
24 Months
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: ≤ 24 months of age at enrollment 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 ≥ 40% of total calories administered by PN 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 Expectation of the treating physician that the patient will require PN for at least 3 weeks following enrollment. Parents willing to participate including randomization Exclusion Criteria: Sepsis or Hemodynamic Instability of any cause. Coagulopathy (Platelets ≤ 150 000, or INR ≥ 1.4) Hypersensitivity to fish-, egg- or soy protein or to any of the active substances or excipients Current enrollment in another clinical trial involving a surgical or pharmacologic intervention Serum conjugated bilirubin > 50 umol/L Hyperlipidaemia (any of) LDL ≥ 4 mmol/L HDL ≥ 2 mmol/L Total cholesterol ≥ 5 mmol/L Triglycerides ≥ 1.5 mmol/L Treatment with intravenous N-Acetylcysteine or Ursodeoxycholic acid Renal insufficiency Creatinine ≥ 80 umol/L Disorders of Fluid Balance (any of) Serum Sodium < 130 mmol/L Serum Sodium > 145 mmol/L 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Wales
Organizational Affiliation
The Hospital for Sick Children
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
Country
Canada
Facility Name
Foothills Medical Center
City
Calgary
State/Province
Alberta
Country
Canada
Facility Name
Stollery Children's Hospital
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Name
Hamilton Health Sciences
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
26838529
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.
Results Reference
derived

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

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