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
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All trials for Hospitalized Neonates and Infants, Expected to Require Parenteral Nutrition for 28 Days All trials of Smoflipid 20% (investigational lipid for parenteral nutrition) All trials of Intralipid® 20%
-Summary
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.
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+Arms and interventions
| Arm | Type | Interventions | Description |
|---|
| Smoflipid 20% | Experimental | Drug: Smoflipid 20% (investigational lipid for parenteral nutrition) | 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". |
| Intralipid® 20% | Active comparator | Drug: Intralipid® 20% | 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". |
- Smoflipid 20% (investigational lipid for parenteral nutrition) (Drug), also known as Smoflipid 20% (lipid injectable emulsion): 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.
- Intralipid® 20% (Drug), also known as Intralipid® 20% (a 20% intravenous fat emulsion): 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.
+Outcome measures
Primary outcomes
- 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 [Screening, Day 8, 15, 22, 29/end of treatment + confirmatory sample: 7 days after conjugated bilirubin level exceeds 2 mg/dl]: 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.
Secondary outcomes
- Body Weight (Change From Baseline) [Day 1-29, and at Follow-up (+7 days) (if continued: until Day 85 + at Follow up)]: 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).
- Body Length (Change From Baseline) [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]: 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).
- Head Circumference (Change From Baseline) [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]: 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).
- Time to Full Enteral or Oral Feeds [Day 29/end of treatment, if continued: Day 85/end of treatment]: 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.
- Fatty Acids in Plasma and Red Blood Cell Membranes (Change From Baseline) [Day 1, Day 29/end of treatment, if continued: Day 57, 85/end of treatment]: RBC refers to red blood cells. Timepoints >10% of Subjects (overall) are displayed.
- Length of Stay in Hospital [Day 1- Follow up (7 days after end of treatment)]: Length of stay in hospital (time from randomization to discharge) was be calculated.
NA=Not available
- Ratio of Independent Bloodstream Infections to Number of Days on Study Medication [Day 1-29 or -85 if continued + Follow-up]: The Ratio is the incidence of bloodstream infection by numbers of day on study medication.
- 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 [Day 1-29 or -85 if continued + Follow-up]: The Analysis was conducted over all study phases.
- 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 [Day 1-29 or -85 if continued + Follow-up]: 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
- Cumulative Number of Days Patients Are Administered a Lipid Dose Without Lipid Minimization [Day 1-29 or -85 if continued + Follow-up]: The Analysis was performed over the entire study period.
- 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 [Day 1, Day 29/end of treatment, if continued: Day 57, 85/end of treatment]: 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.
+Eligibility
Sex: All, ages: 0 Weeks to any
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
+Posted results
Participant flow
| Milestone | Smoflipid 20% | Intralipid® 20% |
|---|
| Started | 83 | 78 |
| Completed | 33 | 33 |
| Not completed | 50 | 45 |
Outcome results
- 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 (Primary), Count of participants, Participants: Intralipid® 20% 3; Smoflipid 20% 2
- Body Weight (Change From Baseline) (Secondary), Count of participants, Participants: Intralipid® 20% 12; Smoflipid 20% 20
- Body Length (Change From Baseline) (Secondary), Count of participants, Participants: Intralipid® 20% 12; Smoflipid 20% 25
- Head Circumference (Change From Baseline) (Secondary), Count of participants, Participants: Intralipid® 20% 9; Smoflipid 20% 20
- Time to Full Enteral or Oral Feeds (Secondary), Median, Time to event in days: Intralipid® 20% 21.95 (NA to NA); Smoflipid 20% 23.29 (NA to NA)
- Fatty Acids in Plasma and Red Blood Cell Membranes (Change From Baseline) (Secondary), Mean, ug/mL: Intralipid® 20% 7.36 +/- 6.545; Smoflipid 20% 14.52 +/- 16.480
- Length of Stay in Hospital (Secondary), Median, Median time (days) until discharge: Intralipid® 20% 65.0 (NA to NA); Smoflipid 20% 50.5 (NA to NA)
- Ratio of Independent Bloodstream Infections to Number of Days on Study Medication (Secondary), Mean, ratio: Intralipid® 20% 0.002 +/- 0.0105; Smoflipid 20% 0.003 +/- 0.0123
- Number of Patients With 1 or More Bloodstream Infections to Number of Patients on Study Medication (Secondary), Count of participants, Participants: Intralipid® 20% 5; Smoflipid 20% 6
- Number of Patients Who Complete PN Treatment Without Lipid Minimization (Secondary), Count of participants, Participants: Intralipid® 20% 73; Smoflipid 20% 79
- Number of Patients Needing to be Withdrawn From the Study Due to Elevated Conjugated Bilirubin Levels (Secondary), Count of participants, Participants: Intralipid® 20% 0; Smoflipid 20% 1
- 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 (Secondary), Mean, mg/dl*days: Intralipid® 20% 0.587 +/- 2.6620; Smoflipid 20% 0.804 +/- 3.4700
- Cumulative Number of Days Patients Are Administered a Lipid Dose Without Lipid Minimization (Secondary), Mean, Cumulative days: Intralipid® 20% 27.8 +/- 21.98; Smoflipid 20% 26.7 +/- 19.94
- Time to Conjugated Bilirubin > 2 mg/dL (Confirmed by a Second Sample Collected 7 Days After the First) (Secondary), Mean, Number of days: Intralipid® 20% NA (NA to NA); Smoflipid 20% NA (NA to NA)
- Blood Sampling for Special Analysis (Sterols Including Phytosterols, α-tocopherol) (Secondary), Mean, ug/mL: Intralipid® 20% 45.076 +/- 28.8520; Smoflipid 20% 41.900 +/- 28.7879
- Holman Index (Secondary), Count of participants, Participants: Intralipid® 20% 61; Smoflipid 20% 72
Adverse events
Time frame: Monitoring of AEs, including SAEs, was conducted throughout the study. The Investigator or designee recorded all AEs after informed consent and until the patient's last follow-up visit. The minimum monitoring period was 7 days after first treatment and the maximum period was up to day 92 after first treatment.
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|
| Intralipid® 20% | 1/78 (1.3%) | 5/78 (6.4%) | 55/78 (70.5%) |
| Smoflipid 20% | 1/83 (1.2%) | 8/83 (9.6%) | 59/83 (71.1%) |
Serious adverse events by term
| Term | Organ system | Intralipid® 20% | Smoflipid 20% |
|---|
| Cardiogenic shock | Cardiac disorders | 1/78 | 0/83 |
| Intestinal obstruction | Gastrointestinal disorders | 0/78 | 1/83 |
| Necrotising colitis | Gastrointestinal disorders | 1/78 | 1/83 |
| Cholestasis | Hepatobiliary disorders | 0/78 | 1/83 |
| Escherichia bacteraemia | Infections and infestations | 1/78 | 0/83 |
| Escherichia sepsis | Infections and infestations | 0/78 | 1/83 |
| Escherichia urinary tract infection | Infections and infestations | 1/78 | 0/83 |
| Meningitis | Infections and infestations | 0/78 | 1/83 |
| Sepsis | Infections and infestations | 0/78 | 1/83 |
| Sepsis neonatal | Infections and infestations | 0/78 | 1/83 |
| Accidental overdose | Injury, poisoning and procedural complications | 0/78 | 1/83 |
| Tracheal injury | Injury, poisoning and procedural complications | 1/78 | 0/83 |
| Candida test positive | Investigations | 1/78 | 0/83 |
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | 1/78 | 0/83 |
| Pulmonary vein stenosis | Respiratory, thoracic and mediastinal disorders | 1/78 | 0/83 |
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | 1/78 | 0/83 |
Other adverse events by term
| Term | Organ system | Intralipid® 20% | Smoflipid 20% |
|---|
| Anemia | Blood and lymphatic system disorders | 8/78 | 4/83 |
| Anemia neonatal | Blood and lymphatic system disorders | 17/78 | 15/83 |
| Tachycardia | Cardiac disorders | 4/78 | 3/83 |
| Abdominal distension | Gastrointestinal disorders | 3/78 | 7/83 |
| Abdominal pain | Gastrointestinal disorders | 5/78 | 4/83 |
| Constipation | Gastrointestinal disorders | 7/78 | 7/83 |
| Diarrhea | Gastrointestinal disorders | 4/78 | 3/83 |
| Gastroesophageal reflux disease | Gastrointestinal disorders | 7/78 | 5/83 |
| Vomiting | Gastrointestinal disorders | 16/78 | 15/83 |
| Cholestasis | Hepatobiliary disorders | 9/78 | 7/83 |
| Bilirubin conjugated increased | Investigations | 7/78 | 3/83 |
| Blood alkaline phosphatase increased | Investigations | 6/78 | 1/83 |
| C-reactive protein increased | Investigations | 7/78 | 6/83 |
| Cardiac murmur | Investigations | 4/78 | 1/83 |
| Gamma-glutamyltransferase increased | Investigations | 11/78 | 10/83 |
| Hematocrit decreased | Investigations | 5/78 | 2/83 |
| Hyperkalemia | Metabolism and nutrition disorders | 2/78 | 5/83 |
| Hyponatremia | Metabolism and nutrition disorders | 2/78 | 5/83 |
| Tachypnea | Respiratory, thoracic and mediastinal disorders | 2/78 | 6/83 |
+Locations (13)
| Facility | City | Country | Status |
|---|
| Lucile Packard Children's Hospital | Palo Alto, California | United States | |
| UC San Diego Medical Center | San Diego, California | United States | |
| Rady Children's Hospital San Diego | San Diego, California | United States | |
| Yale - New Haven Children's Hospital | New Haven, Connecticut | United States | |
| Ann & Robert H. Lurie Children's Hospital of Chicago | Chicago, Illinois | United States | |
| University of Nebraska Medical Center | Omaha, Nebraska | United States | |
| Mount Sinai Hospital | New York, New York | United States | |
| Steven & Alexandra Cohen Children's Medical Center of NY | New York, New York | United States | |
| The Children's Hospital at OU Medical Center | Oklahoma City, Oklahoma | United States | |
| Children's Hospital of Philadelphia | Philadelphia, Pennsylvania | United States | |
| Children's Hospital of Pittsburgh of UPMC | Pittsburgh, Pennsylvania | United States | |
| Vanderbilt Children's Hospital | Nashville, Tennessee | United States | |
| Texas Children's Hospital | Houston, Texas | United States | |
+Publications
- Results publication: Abrams SA, Ernst KD, Weitkamp JH, Mascarenhas M, Anderson-Berry A, Rudolph J, Ling CY, Robinson DT, Shores D, Hair AB, Lai J, Lane B, McCallie KR, Levit O, Kim JH. Safety and Efficacy of a Composite Lipid Emulsion with Fish Oil in Hospitalized Neonates and Infants Requiring Prolonged Parenteral Nutrition - A Randomized, Double-Blind, Multicenter, Controlled Trial. J Nutr. 2024 Dec;154(12):3615-3625. doi: 10.1016/j.tjnut.2024.10.005. Epub 2024 Oct 5. PMID 39374788
+Study documents
+Investigators