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Bridging the Docosahexaenoic Acid (DHA) Gap: The Effects of Omega-3 Fatty Acid Supplementation in Premature Infants

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ClinicalTrials.gov Identifier: NCT01908907
Recruitment Status : Completed
First Posted : July 26, 2013
Results First Posted : April 2, 2018
Last Update Posted : March 21, 2019
Sponsor:
Collaborator:
The Gerber Foundation
Information provided by (Responsible Party):
Sanford Health

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Prematurity
Interventions Dietary Supplement: DHA oil
Dietary Supplement: (MCT) Control oil
Enrollment 60
Recruitment Details Ninety infants, less than or equal to one week of age, were recruited from the Sanford Health Boekelheide Neonatal Intensive Care Unit (NICU) between October 2012 and March 2014.
Pre-assignment Details Preterm infants were between 24 and 33 6/7 weeks gestational age (GA) at birth. Adaptive enrollment was used to assure that infants <28 weeks GA were enrolled over the same time period as more commonly admitted preterm infants >28 weeks GA.
Arm/Group Title DHA Oil Medium Chain Triglyceride (MCT) Control Oil
Hide Arm/Group Description

DHA oil administered 50 mg/d (0.18ml)as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

DHA oil administered at 50 mg/d (0.18ml) Or MCT oil administered at 0.18 ml

MCT oil administered 0.18ml as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

Placebo Group:MCT oil administered at 0.18 ml as an oil emulsion

Period Title: Overall Study
Started 31 29
Completed 29 29
Not Completed 2 0
Reason Not Completed
Physician Decision             1             0
Protocol Violation             1             0
Arm/Group Title DHA Supplemented Placebo Supplemented Total
Hide Arm/Group Description Preterm infants (31) randomized to receive 50mg/d of enteral DHA supplementation Preterm infants (29) randomized to receive placebo study oil Total of all reporting groups
Overall Number of Baseline Participants 31 29 60
Hide Baseline Analysis Population Description
Preterm infants less than one week of age and born between 24 and 33 6/7 week GA were randomized to receive 50mg/d of enteral DHA
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Weeks of GA
Number Analyzed 31 participants 29 participants 60 participants
30.69  (2.42) 30.35  (2.46) 30.52  (2.43)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants 29 participants 60 participants
Female
15
  48.4%
15
  51.7%
30
  50.0%
Male
16
  51.6%
14
  48.3%
30
  50.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants 29 participants 60 participants
Hispanic
0
   0.0%
0
   0.0%
0
   0.0%
Non-Hispanic
28
  90.3%
25
  86.2%
53
  88.3%
Unknown
3
   9.7%
4
  13.8%
7
  11.7%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 31 participants 29 participants 60 participants
31
 100.0%
29
 100.0%
60
 100.0%
1.Primary Outcome
Title Days to Reach Full Enteral Feedings and Days on Study Oil.
Hide Description This study was designed to determine feasibility and tolerability of enteral DHA supplementation, but was not intended to determine the effects of DHA on health related outcomes. Tolerability was measured by days to reach full enteral feedings, days on study oil, GA at completion of the study and postnatal growth. The days to reach full enteral feedings was defined as enteral intake of 100kcal/kg/d. Safety and tolerability was closely monitored under the oversight of an independent DSMB.
Time Frame From enrollment until the infant reaches full feed or is discharged from the NICU, whichever comes first, assessed up to 50 days.
Hide Outcome Measure Data
Hide Analysis Population Description
Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made.
Arm/Group Title DHA Oil (MCT) Control Oil
Hide Arm/Group Description:

DHA oil administered 50 mg/d (0.18ml)as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

DHA oil administered at 50 mg/d (0.18ml) Or MCT oil administered at 0.18 ml

MCT oil administered 0.18ml as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

Placebo Group:MCT oil administered at 0.18 ml as an oil emulsion

Overall Number of Participants Analyzed 31 29
Mean (Standard Deviation)
Unit of Measure: days
Days to reach full enteral feedings 20.00  (8.32) 16.21  (7.41)
Days on Study oil 34.00  (19.2) 33.71  (16.32)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DHA Oil, (MCT) Control Oil
Comments All analyses used the intent-to-treat study population. A linear mixed model was used to assess differences in time to full feeds, days on study drug, and gestational age at discharge. These models included a random effect for multiples, which was maintained in the model after testing. Fixed effects included treatment and GA group for time to full feeds and days on study drug and treatment effect for gestational age at discharge.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.07
Comments [Not Specified]
Method Regression, Linear
Comments Outcome was transformed using a natural logarithm transformation. Models included gestational age group since the randomization was blocked.
Method of Estimation Estimation Parameter Median Difference (Net)
Estimated Value 13.5
Confidence Interval (2-Sided) 95%
0.2 to 28.7
Parameter Dispersion
Type: Standard Error of the Mean
Value: 6.5
Estimation Comments Since analyzed on the log scale, estimates provide are % change rather than absolute change between group.
2.Primary Outcome
Title Feasibility and Tolerability of Daily Enteral DHA Oil - Weight Change
Hide Description A linear mixed model was used to explore weight over time.
Time Frame 30 days from birth
Hide Outcome Measure Data
Hide Analysis Population Description
Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:
Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.
Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.
Overall Number of Participants Analyzed 31 29
Mean (Standard Error)
Unit of Measure: Grams per day
18.4  (0.57) 18.4  (0.57)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DHA Supplemented, MCT (Placebo Control Group)
Comments Linear mixed models were used to explore growth over time (weight, length and head circumference). These models included a random effect for intercepts and slopes to account for subject specific growth over time as well as a random effect for possible correlation between twins and triplets present in the data set. Fixed effects included both a linear and quadratic time effect, GA at birth, treatment group, full feeds (yes/no), and interactions. Non-significant interactions were eliminated.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.048
Comments [Not Specified]
Method Regression, Linear
Comments This is a complex regression model including linear and quadratic growth and interactions as specified above.
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.016
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.008
Estimation Comments [Not Specified]
3.Primary Outcome
Title Long Chain Polyunsaturated Fatty Acid (LCPUFA) Levels - Docosahexaenoic Acid (DHA) Levels in Whole Blood
Hide Description Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time Frame At baseline (enrollment, < 1 week of age), full feedings, discharge
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:

Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Overall Number of Participants Analyzed 31 29
Mean (Standard Deviation)
Unit of Measure: mol% (composition) of fat
Baseline Comparisons 2.91  (0.45) 2.88  (0.68)
Full Enteral Feedings 2.83  (0.50) 3.03  (0.54)
Discharge 2.87  (0.50) 3.55  (0.44)
4.Primary Outcome
Title Feasibility and Tolerability of Daily Enteral DHA Oil - Length Change
Hide Description A linear mixed model was used to explore length over time.
Time Frame 30 days from birth
Hide Outcome Measure Data
Hide Analysis Population Description
Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:
Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.
Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.
Overall Number of Participants Analyzed 31 29
Mean (Standard Error)
Unit of Measure: Centimeters per day
0.13  (0.006) 0.12  (0.004)
5.Primary Outcome
Title Feasibility and Tolerability of Daily Enteral DHA Oil - Head Circumference
Hide Description A linear mixed model was used to explore head circumference over time.
Time Frame 30 days from birth
Hide Outcome Measure Data
Hide Analysis Population Description
Comparison between preterm groups that received either DHA oil or MCT (placebo control) oil were made. They had DHA levels measured to be used as a reference population in our NICU.
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:
Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.
Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.
Overall Number of Participants Analyzed 31 29
Mean (Standard Error)
Unit of Measure: Centimeters per day
0.10  (0.004) 0.10  (0.004)
6.Secondary Outcome
Title LCPUFA Levels - Arachidonic Acid (ARA) in Whole Blood
Hide Description Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time Frame At baseline (enrollment, <1 week of age), full feedings and discharge
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:

Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Overall Number of Participants Analyzed 31 29
Mean (Standard Deviation)
Unit of Measure: wt:wt% of total fat in sample
Baseline 13.21  (2.22) 14.89  (1.89)
Full Enteral Feedings 14.35  (1.51) 14.87  (1.50)
Discharge 14.31  (1.26) 13.94  (1.67)
7.Other Pre-specified Outcome
Title LCPUFA Levels - Alpha-linolenic Acid (ALA) in Whole Blood
Hide Description Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time Frame Baseline (<1 week of age), full enteral feedings and discharge
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:

Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Overall Number of Participants Analyzed 31 29
Mean (Standard Deviation)
Unit of Measure: wt:wt% (composition) of total fat
Baseline 0.74  (0.50) 0.55  (0.33)
Full enteral feedings 0.21  (0.13) 0.20  (0.11)
Discharge 0.24  (0.13) 0.26  (0.13)
8.Other Pre-specified Outcome
Title LCPUFA Levels - Linoleic Acid (LNA)
Hide Description Linear mixed models were also used to examine the association between each FA of interest and treatment group over time. Since only three time points were available for FA measurement, only a random intercept was included in the models. For these models, the random effect for multiples was again found to be not needed and removed. Primary outcome variables for this analysis included LNA, ALA, ARA and DHA. Only early/late preterm status was included in the model as a covariate since this was a stratification variable. Continuous dependent variables were transformed using the natural logarithm as needed to meet the assumptions of the regression model (this included LNA and ALA).
Time Frame Baseline, full feedings and discharge
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title DHA Supplemented MCT (Placebo Control Group)
Hide Arm/Group Description:

Preterm infants supplemented with 50mg/d (0.18ml) of enteral DHA from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Preterm infants receiving 0.18 ml of MCT (control oil) from the first week of life until term GA or discharge, whichever came first.

LCPUFA levels were measured at baseline, after reaching full enteral feedings and at discharge or term GA, whichever came first.

Overall Number of Participants Analyzed 31 29
Mean (Standard Deviation)
Unit of Measure: wt:wt% (composition) of fat in sample
Baseline 18.45  (4.51) 16.45  (3.39)
Full feedings 14.72  (2.05) 14.95  (2.04)
Discharge 15.37  (2.39) 16.64  (3.18)
Time Frame Monitored for 30 days after last dose of study medication.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title DHA Oil (MCT) Control Oil
Hide Arm/Group Description

DHA oil administered 50 mg/d (0.18ml)as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

DHA oil administered at 50 mg/d (0.18ml) Or MCT oil administered at 0.18 ml

MCT oil administered 0.18ml as an oil emulsion enterally with feedings or by gavage tube if the infant has one.

Placebo Group:MCT oil administered at 0.18 ml as an oil emulsion

All-Cause Mortality
DHA Oil (MCT) Control Oil
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
DHA Oil (MCT) Control Oil
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/31 (3.23%)      0/29 (0.00%)    
General disorders     
Death *  1/31 (3.23%)  1 0/29 (0.00%)  0
Infections and infestations     
Sepsis   1/31 (3.23%)  1 0/29 (0.00%)  0
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
DHA Oil (MCT) Control Oil
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   31/31 (100.00%)      29/29 (100.00%)    
Blood and lymphatic system disorders     
Thrombocytopenia   1/31 (3.23%)  1 0/29 (0.00%)  0
Anemia   20/31 (64.52%)  20 14/29 (48.28%)  14
Other Blood and lymphatic disorders   0/31 (0.00%)  0 4/29 (13.79%)  5
Cardiac disorders     
Periventricular Leukomalacia   0/31 (0.00%)  0 1/29 (3.45%)  1
Other Cardiac Disorders   1/31 (3.23%)  1 1/29 (3.45%)  1
Congenital heart defect   0/31 (0.00%)  0 1/29 (3.45%)  1
Patent Ductus Arteriosus   3/31 (9.68%)  3 3/29 (10.34%)  3
Physiologic murmur   13/31 (41.94%)  15 6/29 (20.69%)  7
Endocrine disorders     
Adrenal insufficiency   1/31 (3.23%)  1 0/29 (0.00%)  0
Other Endocrine Disorders   1/31 (3.23%)  1 0/29 (0.00%)  0
Hypothyroidism   0/31 (0.00%)  0 1/29 (3.45%)  1
Eye disorders     
Retinopathy of Prematurity   7/31 (22.58%)  7 5/29 (17.24%)  5
Gastrointestinal disorders     
Gastro-esophageal Reflux Disease   6/31 (19.35%)  6 4/29 (13.79%)  4
Constipation   0/31 (0.00%)  0 2/29 (6.90%)  2
Dysfunctional bottling/swallowing   7/31 (22.58%)  7 1/29 (3.45%)  1
Gastritis   0/31 (0.00%)  0 1/29 (3.45%)  1
Gastrointestinal Disorder NOS   0/31 (0.00%)  0 1/29 (3.45%)  1
General disorders     
Other General Disorder   2/31 (6.45%)  2 2/29 (6.90%)  2
Pain   0/31 (0.00%)  0 1/29 (3.45%)  1
Hepatobiliary disorders     
Cholecystitis   1/31 (3.23%)  1 1/29 (3.45%)  2
Infections and infestations     
Sepsis (Grade 4)   3/31 (9.68%)  3 3/29 (10.34%)  3
Conjunctivitis   1/31 (3.23%)  1 2/29 (6.90%)  2
Other Infections and Infestations   0/31 (0.00%)  0 1/29 (3.45%)  1
Meningitis   0/31 (0.00%)  0 1/29 (3.45%)  1
Pneumonia   2/31 (6.45%)  2 0/29 (0.00%)  0
Tracheitis   0/31 (0.00%)  0 2/29 (6.90%)  2
Urinary Tract Infection   1/31 (3.23%)  1 1/29 (3.45%)  1
Investigations     
Blood bilirubin increased   2/31 (6.45%)  2 1/29 (3.45%)  1
Metabolism and nutrition disorders     
Milk Soy Protein Intolerance   4/31 (12.90%)  5 4/29 (13.79%)  4
Hypercalcemia   1/31 (3.23%)  1 0/29 (0.00%)  0
Other Metabolism and Nutrition Disorders   1/31 (3.23%)  1 0/29 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Other Musculoskeletal Disorders   0/31 (0.00%)  0 1/29 (3.45%)  3
Osteoporosis   1/31 (3.23%)  1 0/29 (0.00%)  0
Scoliosis   0/31 (0.00%)  0 1/29 (3.45%)  1
Nervous system disorders     
Intraventricular Hemorrhage   0/31 (0.00%)  0 1/29 (3.45%)  1
Psychiatric disorders     
Irritability   2/31 (6.45%)  2 0/29 (0.00%)  0
Renal and urinary disorders     
Other Renal and Urinary Disorders   1/31 (3.23%)  1 2/29 (6.90%)  2
Urinary Tract Obstruction   0/31 (0.00%)  0 1/29 (3.45%)  1
Respiratory, thoracic and mediastinal disorders     
Bronchopulmonary Dysplasia   2/31 (6.45%)  2 3/29 (10.34%)  3
Apnea   6/31 (19.35%)  6 9/29 (31.03%)  9
Hypoxia   1/31 (3.23%)  1 0/29 (0.00%)  0
Periodic Breathing   2/31 (6.45%)  2 5/29 (17.24%)  5
Pneumothorax   1/31 (3.23%)  1 0/29 (0.00%)  0
Respiratory Failure   1/31 (3.23%)  1 0/29 (0.00%)  0
Other Respiratory Disorder   5/31 (16.13%)  5 3/29 (10.34%)  3
Skin and subcutaneous tissue disorders     
Rash   5/31 (16.13%)  5 4/29 (13.79%)  4
Other Skin Disorders   2/31 (6.45%)  2 0/29 (0.00%)  0
Vascular disorders     
Thromboembolic Event   1/31 (3.23%)  1 0/29 (0.00%)  0
Other Vascular Disorders   1/31 (3.23%)  1 0/29 (0.00%)  0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Lora Black, Senior Director of Clinical Research
Organization: Sanford Health
Phone: 605-328-1368
Responsible Party: Sanford Health
ClinicalTrials.gov Identifier: NCT01908907     History of Changes
Other Study ID Numbers: DHA Gap
First Submitted: July 2, 2013
First Posted: July 26, 2013
Results First Submitted: April 28, 2017
Results First Posted: April 2, 2018
Last Update Posted: March 21, 2019