SMOFlipid and Incidence of BPD in Preterm Infants

Does Parenteral Omega-3 Enriched Lipid Emulsion Reduce Incidence of Bronchopulmonary Dysplasia in Preterm Infants

Despite many advances in neonatal care in the recent years, bronchopulmonary dysplasia (BPD) continues to be the major cause of chronic lung morbidity in infants. The pathogenesis of BPD is multifactorial; however, inflammation remains the central pathway for all risk factors. Omega-3 long chain polyunsaturated fatty acids (n3-LCPUFAs) from fish oil are known to down-regulate systemic inflammation and oxidative stress. Currently used soybean-based fatty acid emulsion (Intralipid) contains mainly n6-LCPUFA. Intralipid does not maintain the in-utero balanced LCPUFA accretion. Furthermore, Intralipid has been shown to increase free radical production and to be associated with BPD. A new fatty acid emulsion enriched with n3-LCPUFA (SMOFlipid) improves the fatty acid profile and reduces pro-inflammatory agents.

This project aims primarily to study whether SMOFlipid can lower the rate of BPD in preterm infants compared to Intralipid.

Study Overview

• Status: Recruiting
• Conditions: Bronchopulmonary Dysplasia; Very Low Birth Weight Infant
• Intervention / Treatment: Other: n3-LCPUFA enriched Intravenous Lipid Emulsion

Detailed Description

Intravenous lipid emulsions (IVLEs) is a core component of parenteral nutrition (PN) for providing calories and essential fatty acids. Until recently, Intralipid was the only available IVLE in North America. For a long time now, the use of Intralipid has been described to be associated with the development of BPD. Lack of sufficient lipid clearance in premature infants, augmented oxidative stress, deficiency of anti-inflammatory agents, and elevated pulmonary artery pressure have all shown to be potential causes for lung injury during the use of Intralipid.

Intralipid, made mainly of soybean oil, contains high amounts of n6-LCPUFA and low amounts of n3-LCPUFA. This results in prostaglandin synthesis favoring pro-inflammatory products and amplified oxidative stress. Current evidence indicates that well-balanced fatty acid supply is a crucial factor to reduce inflammation and oxidative stress. The concern about unbalanced n6:n3 ratio has led to the development of novel IVLEs, like SMOFlipid. SMOFlipid is composed of a mixture of soybean oil (30%), medium-chain triglycerides (MCT) (30%), olive oil (25%) and fish oil (15%). The combination of soybean oil and fish oil allows delivering balanced LCPUFA with n6:n3 ratio of 2.5:1 and provides sufficient amounts of the preformed n3-LCPUFA.

Interventions that improve n3-LCPUFA status have been shown to reduce pulmonary inflammation in animal models.

In humans, a study on extremely preterm infants has revealed a rapid decline in the n3-LCPUFA in the first week of life despite the use of Intralipid. Early restoration of an adequate ratio of LCPUFA to inhibit inflammation has gained interest in recent years. In an observational study by Skouroliakou et al., very low birth weight infants receiving SMOFlipid within 48 hours of birth and for at least 7 days had a lower incidence of BPD compared to the Intralipid control group. A recent systematic review and meta-analysis of 8 randomized control trials (7 compared SMOFlipid to Intralipid) was conducted to evaluate safety and efficacy of fish oil-enriched IVLEs in preterm infants. Infants who received fish oil-enriched IVLEs had significantly higher RBC membrane DHA and EPA. The meta-analysis showed no difference in all-cause mortality and overall complication rate in 238 infants receiving fish oil-enriched IVLEs. However, all the studies included in this meta-analysis were small. Furthermore, the studies focused mainly on laboratory findings, and did not aim to study effect on inflammation, oxidative stress or clinical outcomes. Studies from critically ill adults in intensive care units exhibited a reduction in the duration of hospitalization and ventilator days, a risk factor for lung injury, when using n3-LCPUFA enriched IVLEs.

• Study Type: Interventional
• Enrollment (Anticipated): 384
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Belal Alshaikh, MD, MSc; Phone Number: (403) 956 1588; Email: belal.alshaikh@ahs.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Recruiting
      • Foothills Medical Centre
      • Contact: Belal Alshaikh, MD; Email: belal.alshaikh@ahs.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 2 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Preterm infants born <30 weeks and admitted to NICU at Foothills Medical Centre in the first 24 hours of life.
• Anticipated duration of PN for >7 days

Exclusion Criteria:

• Infants with congenital anomalies
• Infants with suspected inborn errors of metabolism or family history of inborn error of metabolism
• Perinatal asphyxia
• Evidence of congenital infection
• Primary biliary atresia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Conventional IVLE (Intralipid) from D0 at 1g/kg/day and increase by 1 g/kg daily till reaching 3 g/kg/day.
Experimental: Experimental group; n3-LCPUFA enriched IVLE (SMOFlipid) from D0 at 1g/kg/day and increase by 1 g/kg daily till reaching 3 g/kg/day.	Other: n3-LCPUFA enriched Intravenous Lipid Emulsion; To start from D0 at 1g/kg/day and increase by 1 g/kg daily till reaching 3 g/kg/day.; Other Names: SMOFlipid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of Bronchopulmonary Disease	According to Child Health and Human Development with classification to mild, moderate and severe.	36 weeks corrected gestational age
Fatty acid profile	Determine serum fatty acids levels (μmol/L).	First 3 weeks of life
Pro-inflammatory cytokine response	Compare pro-inflammatory cytokine levels (pg/mL)	First 3 weeks of life
Lipid peroxidation measure 1	Malondialdehyde (MDA, μmol/L) in blood	First 3 weeks of life
Lipid peroxidation measure 2	8-isoprostane levels (pg/mL) in blood	First 3 weeks of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Cholestasis	Direct bilirubin more than 34 mmol/L	Up to 36 weeks corrected gestational age or discharge
Weight gain velocity	Change in weight Z scores	Up to 36 weeks corrected gestational age or discharge
Incidence of retinopathy of prematurity	Defined as stage 2 or higher according to the international classification or requiring treatment.	Up to 36 weeks corrected gestational age or discharge
Incidence of moderate to severe neurodevelopmental disability	Defined by 1 or more of the following: moderate to severe motor impairment cerebral palsy (CP) or non-CP) with a GMFCS level ≥2, a BSID III cognitive score of <70, severe visual impairment (bilateral blindness with vision <20/200), or severe hearing impairment (permanent hearing loss that interferes with ability to understand or communicate with or without amplification).	18-22 months corrected gestational
Incidence of severe intraventricular hemorrhage (IVH)	Defined as grade 3 or higher	Up to 36 weeks corrected gestational age or discharge

Collaborators and Investigators

• Sponsor: University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2019
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: August 27, 2019
• First Submitted That Met QC Criteria: September 3, 2019
• First Posted (Actual): September 6, 2019

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Preterm Infants; Intravenous lipid emulsions; SMOF
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Body Weight; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Birth Weight; Bronchopulmonary Dysplasia; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; SMOFlipid
• Other Study ID Numbers: REB19-1088

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No