Safety and Tolerability of Intravenous Fish Oil Lipid Emulsion in Children Undergoing Hematopoietic Cell Transplantation
Condition: Hematopoietic Stem Cell Transplantation
Study type: Interventional
Phase: Phase 1

Summary: 
      Children undergoing hematopoietic cell transplantation (HCT) for cancer or blood disorders
      frequently develop gastrointestinal, metabolic and infectious complications related to
      preparative high-dose chemotherapy and/or radiation-related toxicity. Parenteral nutrition
      (PN) with lipid emulsion is commonly required while gastrointestinal complications preclude
      adequate oral or enteral intake. PN and lipids may increase the risk of metabolic and
      infectious complications in HCT patients who are inherently immune compromised.

      Supplementation with omega-3 fatty acids has been linked to improvements in outcomes in
      several populations. Provision of fish oil lipid emulsion (FOLE), rich in omega-3 fatty
      acids, to children undergoing HCT is an innovative nutritional strategy that could mitigate
      the metabolic and inflammatory side effects of HCT and its treatment. With its potential to
      safely maintain essential fatty acid status, normalize blood lipids and alleviate the
      inflammatory response to illness, the use of FOLE may reduce the risk of infections,
      regimen-related toxicity, and other morbidities after HCT.

      A randomized, controlled pilot study is proposed to test the safety and tolerability of FOLE,
      compared to standard lipid emulsion, in 20 children during hospitalization for HCT. Results
      of this study will provide the preliminary data needed for a larger clinical trial examining
      the effect of FOLE on important clinical outcomes in this population. This novel approach to
      nutritional care of this high-risk group will advance clinical knowledge of the impact of
      FOLE, and will support further investigation into nutritional adjuncts to pediatric cancer
      treatment.
    

Detailed description: 
      Parenteral nutrition (PN) is often necessary for children undergoing allogeneic allogeneic
      bone marrow, cord, or peripheral blood stem cell (from any donor, including haploidentical
      donor) hematopoietic cell transplantation (HCT) to avoid malnutrition and growth failure due
      to the gastrointestinal toxicity associated with preparative myeloablative conditioning
      regimens. Intravenous lipid emulsion is a required component of PN to provide energy and
      essential fatty acids when oral or enteral intake is nil or minimal. Soybean oil lipid
      emulsion (SOLE) is the standard lipid emulsion used in PN. Complications such as metabolic
      instability, cholestasis, hypertriglyceridemia, and anorexia, which are common during HCT,
      may also be attributable to the SOLE component of PN. Fish oil based lipid emulsion (FOLE) is
      used in certain populations and is associated with improved outcomes, specifically in infants
      with intestinal failure and PN associated cholestasis. It has been reported that
      supplementation with omega-3 fatty acids from fish oil emulsion may preserve lean body mass,
      improve quality of life, and decrease length of hospital stay. Provision of FOLE to children
      undergoing HCT is a novel and innovative strategy to potentially mitigate the metabolic and
      inflammatory side effects of HCT and its treatment.

      HYPOTHESIS: The provision of FOLE is safe and well tolerated in children following HCT. Our
      aims are to determine the safety profile (as measured by the number of grade 2 or higher
      adverse events) and tolerability of intravenous FOLE (as measured by serum fatty acid
      profiles) among children undergoing HCT compared to children receiving SOLE.

      HYPOTHESIS: The provision of FOLE is associated with reduced incidence of
      hypertriglyceridemia in children following HCT, compared to children receiving SOLE and our
      aim is to determine the number (and percentage) of subjects with fasting hypertriglyceridemia
      during the trial. To explore trends in associations with other relevant outcomes, other
      exploratory outcomes (inflammatory biomarkers, body composition measurements, and quality of
      life indicators) will be assessed in both groups of children following HCT.

      METHODS: This is a randomized, controlled, unblinded pilot study to test the safety and
      tolerability of FOLE, compared to standard SOLE, in children hospitalized for HCT with an
      underlying hematologic malignancy or myelodysplasic syndrome.

      Children cared for in the Dana-Farber Cancer Institute/Boston Children's Cancer and Blood
      Disorders Center and who will be admitted to BCH for allogeneic HCT will be enrolled (10
      subjects in each arm). Patients will be included if they meet all of the entry criteria and
      none of the exclusion criteria.

      All enrolled subjects will receive standard transplant and medical care per HCT guidelines
      and protocols. A baseline study visit will occur between 14 and 7 days prior to transplant
      day (day 0). Regardless of enteral intake, at day 0, subjects will be randomized to either
      control or experimental lipid infusion. The experimental group will receive FOLE and the
      control group will receive SOLE beginning at day 0 of HCT. All patients, in both the control
      and experimental groups, will receive standard nutritional care as follows:

        -  The energy goal for each patient will be the measured resting energy expenditure REE, or
           the estimated energy expenditure determined and calculated by the clinical dietitian, to
           be provided by oral, enteral, and/or parenteral energy intake. Intravenous lipids will
           provide approximately 10 kcal/kg/day. Energy intake from other sources (oral intake,
           enteral feeding, PN) will be titrated to meet the individualized energy goal, accounting
           for the contribution from intravenous lipids.

        -  PN (i.e., dextrose/amino acids) will be initiated if oral or enteral energy intake
           declines to less than estimated or measured (REE) for >3-5 days, but no earlier than
           "day 0" of the transplant course.

        -  Amino acids in PN will be provided according to standard, age-adjusted estimations,
           minus any contributions from oral or enteral protein intake.

        -  Lipids will be provided to all enrolled subjects at 1 g/kg/day. On the first day of the
           lipid infusion, lipids will be infused over 18 hours through a central or peripheral
           venous line per standard procedures.

        -  A lipid panel will be obtained 4 hours after the 1st lipid infusion is completed and
           while the subject is nil per os (NPO) for at least 2 hours.

        -  Should the subject have hypertriglyceridemia >500 mg/dL with associated abdominal pain,
           an amylase/lipase level will be drawn to screen for pancreatitis.

        -  If required (or requested) and after tolerating day 1 of the initial 18-hour lipid
           infusion, the lipid infusion rate may be changed and lipids may be infused over a range
           of 8 to 20 hours if the rate does not exceed the maximal lipid infusion rate

        -  The control group will receive standard SOLE, a 20% lipid solution (Intralipid®, Baxter
           Healthcare, Deerfield, IL, USA).

        -  The experimental group will receive FOLE (Omegaven®, Fresenius Kabi AG, Bad Homburg
           v.d.h., Germany), a 10% lipid solution. The experimental product, Omegaven®, will be
           purchased from the manufacturer, stored in BCH Research Pharmacy, and labeled
           appropriately. The experimental product will not be altered in any way from its original
           manufactured state and may be infused in the same manner as standard SOLE.

        -  After engraftment occurs (3 consecutive days with absolute neutrophil count >500),
           lipids will be discontinued at day 30, if clinically indicated, or when the patient is
           ready for hospital discharge, whichever comes first.

        -  Lipid rates of 0.15 g fat/kg/hour have been associated with fat overload syndrome; all
           rates are below this threshold.

      Standardized demographic and clinical assessments of all study participants will be performed
      via medical record review concomitant with the hospitalization and selected clinic visits.
      Data will include medical record number, underlying diagnosis, type of donor, date of
      transplant, date of birth, gender, conditioning and prophylactic medication regimens. Results
      of routine laboratory tests (serum chemistries, blood cell counts) will be recorded twice
      weekly. Essential fatty acid profiles, pediatric lipid panels, and inflammatory markers will
      be assessed at specified intervals.

      Body weight will be measured by an electronic digital scale accurate to 0.1 kg (same scale
      used at all visits). Standing height will be measured by stadiometer to the nearest 0.1 cm
      (same stadiometer used at all visits). Oral and enteral nutrient intake during the inpatient
      admission period of the study will be evaluated through standard nursing documentation and
      calorie counts. Daily calorie counts are routine practice in the HCT unit. Nutrient intake
      will be tabulated from 24-hour recall at outpatient visits. The total enteral and oral intake
      of calories, protein, carbohydrate, and fat will be calculated by nutrient analysis software
      (ESHA Food Processor, ESHA Research, Inc., Salem, OR). Parenteral intake will be calculated
      by the BCH pharmacy's specifications for PN, lipid emulsions, and intravenous fluid. The
      Pediatric Quality of Life Inventory (Peds QL 4.0) Generic Core and SCT Modules are reliable,
      validated tools for measuring health related quality of life in children and adolescents ages
      2 to 18 with items specific to children who have had HCT. Separate parent and age-appropriate
      child questionnaires that address similar questions regarding quality of life will be
      administered at baseline, day +30, and day +100. Air-displacement plethysmography (ADP) is a
      non-invasive, quick and accurate measure of body density. ADP (BOD POD, Cosmed USA, Concord
      CA) will be used at specified intervals to estimate body composition (percent body fat and
      percent lean mass) in subjects.

      Individual subjects will be withdrawn from the study if they develop:

        1. uncontrolled bleeding attributed to the use of Omegaven

        2. persistent fasting hypertriglyceridemia (triglyceride level > 500 mg/dl on 3 separate
           occasions, obtained 4 hours after the lipid infusion has been completed and while the
           subject is NPO for at least 2 hours)

        3. persistent essential fatty acid deficiency (triene:tetraene >0.2 for 2 consecutive
           measurements)

        4. intolerance or allergy to the assigned lipid emulsion

        5. parent or guardian request

        6. principal investigator believes withdrawal is in the best medical interest of the
           patient

        7. baseline fasting (NPO for 2 hours) triglyceride level > 500 mg/dL on 2 consecutive
           measurements

      Study discontinuation will occur:

        1. upon recommendation of the data and safety monitoring board

        2. two or more serious adverse events, occurring across different subjects, possibly or
           probably related to study participation.

      Adverse events for each study arm will be tabulated and categorized by grade. Incidence of
      adverse events will be presented graphically in a dot plot with each adverse event listed on
      the vertical axis, incidence displayed as a percentage on the horizontal axis, with different
      markers for each study. The primary endpoint, the number of adverse events that are grade 2
      or higher, will be summarized as mean ± SD. Comparison of the primary endpoint across study
      arms will be assessed by the two one-sided tests procedure.

      This consists of testing:

      H1o: μFOLE - μSOLE ≤ θ1 vs H1a: μFOLE - μSOLE > θ1 H2o: μFOLE - μSOLE ≥ θ2 vs H2a: μFOLE -
      μSOLE < θ2. Equivalence will be declared only if both H1o and H2o are rejected, each at α =
      0.05. This is equivalent to testing that the 1 - 2α confidence interval for μFOLE - μSOLE is
      contained within the equivalence interval [θ1, θ2]. If the distribution of adverse events is
      more skewed than expected, then a lognormal distribution will be assumed.
    

Intervention name(s): Omegaven; Soybean oil lipid emulsion
Intervention type(s): Drug; Drug
Intervention description(s): Comparison of FOLE vs. SOLE; Comparison of FOLE vs. SOLE
Other intervention name(s): Fish oil lipid emulsion; Intralipid
Intervention MeSH terms: Soybean oil, phospholipid emulsion
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: intravenous fat emulsions; fish oil lipid emulsion