Phase 3 Study to Compare Safety and Efficacy of Smoflipid 20% to Intralipid 20% in Hospitalized Neonates and Infants

Study Overview
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Brief Summary
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To show the superiority in safety of Smoflipid over Intralipid® as measured by the number of study patients in each treatment group with conjugated bilirubin exceeding 2 mg/dL during the first 28 days of study treatment, confirmed by a second sample collected 7 days after the first sample.

Official Title
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A Prospective, Randomized, Controlled, Double-Blind, Parallel-Group, Phase 3 Study to Compare Safety and Efficacy of Smoflipid 20% to Intralipid 20% in Hospitalized Neonates and Infants Requiring 28 Days of Parenteral Nutrition

Conditions
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Hospitalized Neonates and Infants, Expected to Require Parenteral Nutrition for 28 Days

Intervention / Treatment
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* Drug: Smoflipid 20% (investigational lipid for parenteral nutrition)
* Drug: Intralipid® 20%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Neonates and infants, expected to require parenteral nutrition (PN) for 28 days Postmenstrual age ≥ 24 weeks Birth weight ≥ 750g Gastroschisis, duodenal, jejunal or ileal atresia, volvulus, spontaneous intestinal perforation or necrotizing enterocolitis (Bell's stage 2B or higher) At least 80% of nutritional needs at baseline received by PN Signed and dated informed consent obtained from at least one parent or legal guardian Exclusion Criteria: Conjugated bilirubin > 0.6 mg/dL Any known pre-, intra- or posthepatic complication increasing conjugated bilirubin levels > 0.6, mg/dL during study participation Suspected liver disease or liver damage based on either aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyl transferase (GGT) exceeding 2.5x upper limit of normal range Active bloodstream infection demonstrated by positive blood culture at screening Cystic fibrosis Meconium ileus Serum triglyceride levels > 250 mg/dL Cyanotic congenital heart defect Severe renal failure with serum creatinine > 2.0 mg/dL History of shock requiring vasopressors Anasarca Extracorporeal Membrane Oxygenation (ECMO) Known inborn errors of metabolism Known congenital viral infection Unlikely to survive longer than 28 days Known hypersensitivity to fish-, egg-, soya- or peanut protein or to any of the active substances or excipients

Ages Eligible for Study
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Minimum Age: 0 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Smoflipid 20%<br>Smoflipid is a lipid emulsion containing soybean oil, MCTs (medium-chain triglycerides), olive oil, and fish oil. Smoflipid belongs to the pharmacotherapeutic group: Solutions for parenteral nutrition, fat emulsions. | Drug: Smoflipid 20% (investigational lipid for parenteral nutrition)<br>* Dose: The targeted maximal dose is 3.0 g/kg/day. In patients already receiving parenteral nutrition (PN) before starting study treatment, the dose will either stay at 3.0 g/kg/day or be increased by 1.0 g/kg/day steps to a maximum of 3.0 g/kg/day. Smoflipid 20% will be infused over 20 - 24 hours, as per hospital policy, at a weight based infusion rate. Smoflipid 20% will be infused into a central or a peripheral vein.<br>* Other names: Smoflipid 20% (lipid injectable emulsion);|
| Active Comparator: Intralipid® 20%<br>Intralipid is a long-chain triglyceride emulsion derived from purified soybean oil and egg yolk phospholipids. Intralipid belongs to the pharmacotherapeutic group: Solutions for parenteral nutrition, fat emulsions. | Drug: Intralipid® 20%<br>* Dose: The targeted maximal dose is 3.0 g/kg/day. In patients already receiving parenteral nutrition (PN) before starting study treatment, the dose will either stay at 3.0 g/kg/day or be increased by 1.0 g/kg/day steps to a maximum of 3.0 g/kg/day. Intralipid® 20% will be infused over 20 - 24 hours, as per hospital policy, at a weight based infusion rate. Intralipid® 20% will be infused into a central or peripheral vein.<br>* Other names: Intralipid® 20% (a 20% intravenous fat emulsion);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Patients in Each Treatment Group With Conjugated Bilirubin Levels > 2 mg/dL During the First 28 Days of Study Treatment, Confirmed by a Second Sample Collected 7 Days After the First Sample | Analysis of patients with Event at any timepoint of sampling (i.e. Day 8, 15, 22, 29/end of Treatment) and subsequent (i.e. +7 days) confirmation. | Screening, Day 8, 15, 22, 29/end of treatment + confirmatory sample: 7 days after conjugated bilirubin level exceeds 2 mg/dl | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body Weight (Change From Baseline) | Data were age-standardized using growth charts as suggested by Fenton (Fenton et al., 2013) and the World Health Organization (WHO) Multicenter Growth Reference Study (MGRS; WHO 2006, 2007). | Day 1-29, and at Follow-up (+7 days) (if continued: until Day 85 + at Follow up) | 
| Body Length (Change From Baseline) | Data were age-standardized using growth charts as suggested by Fenton (Fenton et al., 2013) and the World Health Organization (WHO) Multicenter Growth Reference Study (MGRS; WHO 2006, 2007). | Day 1, 8, 15, 22, 29/end of treatment, if continued: Day 36, 43, 50, 57, 64, 71, 78, 85/end of treatment, Follow-up | 
| Head Circumference (Change From Baseline) | Data were age-standardized using growth charts as suggested by Fenton (Fenton et al., 2013) and the World Health Organization (WHO) Multicenter Growth Reference Study (MGRS; WHO 2006, 2007). | Day 1, 8, 15, 22, 29/end of treatment, if continued: Day 36, 43, 50, 57, 64, 71, 78, 85/end of treatment, Follow-up | 
| Time to Full Enteral or Oral Feeds | Time to full enteral or oral feeds (i.e. PN weaning) is the time from the randomization date to the date of the first full enteral or oral Feeds. | Day 29/end of treatment, if continued: Day 85/end of treatment | 
| Fatty Acids in Plasma and Red Blood Cell Membranes (Change From Baseline) | RBC refers to red blood cells. Timepoints >10% of Subjects (overall) are displayed. | Day 1, Day 29/end of treatment, if continued: Day 57, 85/end of treatment | 
| Length of Stay in Hospital | Length of stay in hospital (time from randomization to discharge) was be calculated. NA=Not available | Day 1- Follow up (7 days after end of treatment) | 
| Ratio of Independent Bloodstream Infections to Number of Days on Study Medication | The Ratio is the incidence of bloodstream infection by numbers of day on study medication. | Day 1-29 or -85 if continued + Follow-up | 
| Number of Patients With 1 or More Bloodstream Infections to Number of Patients on Study Medication |  | Day 1-29 or -85 if continued + Follow-up | 
| Number of Patients Who Complete PN Treatment Without Lipid Minimization | The Analysis was conducted over all study phases. | Day 1-29 or -85 if continued + Follow-up | 
| Number of Patients Needing to be Withdrawn From the Study Due to Elevated Conjugated Bilirubin Levels |  | Day 1-29 or -85 if continued + Follow-up | 
| Area Under the Curve for Time Period in Which Conjugated Bilirubin Levels Are > 1.5 mg/dL in Patients Who Are Not Withdrawn From the Study | The area under the curve (AUC>1.5) is defined as the area between conjugated bilirubin concentrations > 1.5 mg/dL and the horizontal line at 1.5 mg/dL, restricted by the time point of study withdrawal, if applicable. Analysis displays the summary of Area Under the Curve of Bilirubin Levels for the Time Period in Which Conjugated are >1.5 mg/dL | Day 1-29 or -85 if continued + Follow-up | 
| Cumulative Number of Days Patients Are Administered a Lipid Dose Without Lipid Minimization | The Analysis was performed over the entire study period. | Day 1-29 or -85 if continued + Follow-up | 
| Time to Conjugated Bilirubin > 2 mg/dL (Confirmed by a Second Sample Collected 7 Days After the First) |  | Day 1-29 or -85 if continued + Follow-up | 
| Blood Sampling for Special Analysis (Sterols Including Phytosterols, α-tocopherol) |  | Day 1, Day 29/end of treatment, if continued: Day 57, 85/end of treatment | 
| Holman Index | Essential fatty acid deficiency is based on the ratio of Mead acid and Arachidonic acid (also called the triene/tetraene ratio or Holman index; Holman, 1960). A ratio of > 0.2 was considered abnormal (=essential fatty acid deficiency; Holman et al., 1979). Timepoints with >10% of patients are displayed. | Day 1, Day 29/end of treatment, if continued: Day 57, 85/end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parenteral nutrition, Neonates, Infants, Lipid emulsions, Intravenous