Clinical trial NCT03630770
Conditions: Candida Infection Premature Infant
Sponsor: Joseph Bliss
Start date: 2014-06-05; Completion date: 2021-11-02
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates whether adding a dietary supplement similar to coconut oil (MCT oil) to feedings in premature infants will reduce the amount of yeast (Candida) detectable in their stool. Infants who have Candida in their stool are eligible to participate. Half of the enrolled infants will have additional MCT oil added to their feedings and half will not.

Detailed description:

Arms: arm 1: This group receives no feeding supplement. arm 2: This group is supplemented with MCT oil
Interventions: intervention 1: Medium-Chain Triglyceride (MCT) Oil
Intervention descriptions: intervention 1: Infants receive 0.5 ml/oz of MCT oil to their prescribed feedings for 21 days or until hospital discharge.

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
 
 
Effect of Medium Chain Triglyceride Intake on Colonization of Preterm 
Infants with Candida 
 
 
January 12, 2018 


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I. Purpose and Background 
 
Systemic candidiasis has become the fourth leading cause of hospital acquired sepsis in 
the United States, making these infections as common as those caused by enteric Gram-negative 
bacilli.[1]  Premature neonates are an immunocompromised population that has seen a 
concurrent increase in the incidence of these serious fungal infections.  A report of neonatal late-
onset sepsis in the NICHD neonatal network identified fungi as the cause of 12% of these 
infections, with Candida species being the 2nd most common etiologic agent overall (after 
coagulase-negative Staphylococcus).2  Further, infections with C. albicans carried a mortality 
rate of 44%.[2]  Thus, despite the dramatic advances in neonatal intensive care and the 
availability of antifungal drug therapies, these infections still carry an unacceptably high cost in 
terms of morbidity and mortality.   
Antifungal prophylaxis has been shown to reduce invasive fungal infections in neonatal 
intensive care units; indeed, it has been suggested that all NICUs caring for extremely preterm 
infants should use antifungal prophylaxis.[3]  However, this strategy is associated with risks of 
drug toxicity and emergence of resistance to antifungal drugs.  Alternative strategies to reduce 
colonization and invasive disease are therefore warranted.  Colonization with C. albicans 
generally precedes the development of invasive infection, and the gastrointestinal tract is a 
common site of colonization.[4] In an adult mouse model of colonization, dietary fatty acids 
impact the level of C. albicans colonization.  Crucially, dietary medium chain triglyceride 
(MCT) oil decreases C. albicans colonization.[5]  MCT oil has been an ingredient in infant 
formula since the 1950’s.  In a pilot study, we found that dietary supplementation of preterm 
infants with MCT oil for 7 days reduced colonization in infants who received it but not in control 
infants (Arsenault, et al., submitted). This is the first evidence that MCT oil can decrease 
colonization in preterm infants who are at risk for invasive disease with this organism.   
This protocol describes an observational, follow-up study in which we will examine 
whether  the suppression of Candida colonization with dietary MCT supplementation will be 
maintained over a longer time period of supplementation.  Data collected in this study will be 
used to further inform a future interventional trial in which MCT oil can be formally tested for its 
ability to reduce Candida colonization in premature infants at risk for disseminated candidiasis. 
 
Specific Aims:  1. To determine the frequency, timing, level, and dietary risk factors of 
Candida species colonization in the gastrointestinal tracts of preterm infants.   
2. To examine whether dietary supplementation with MCT oil reduces gastrointestinal 
colonization by Candida species.   
 
 
II. Characteristics of the Research Population 
 
 
Any premature infant admitted to the Neonatal Intensive Care Unit (NICU) at Women 
and Infants Hospital will be eligible for this study.  There will be no distinction based on gender 
or ethnicity.  We anticipate that 800 different individuals will be adequate to provide the number 
of samples required for these experiments.  Because we are interested in supplementing infants 
colonized with Candida with MCT oil, we will restrict the targeted group to those infants who 
are already receiving dietary supplements through either preterm or transitional formula or 
fortified breast milk. These infants are generally under 2000 grams birth weight. 


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Inclusion criteria: Any premature infant admitted to the NICU at Women & Infants 
Hospital who is on full enteral feeds of either preterm or transitional formula or fortified breast 
milk and who is anticipated to have a minimum stay of two weeks. 
 
Exclusion criteria:  Infants not on full enteral feeds with preterm formula or fortified 
breast milk or whose NICU stay is anticipated to be less than two weeks. 
 
 
III. Methods and Procedures 
 
1. 
Obtaining Specimens:  Preterm infants admitted to the NICU will be screened for 
inclusion.  Each medical record will be reviewed to confirm that the standard hospital consent 
form was signed on admission and that there were no exclusions indicated for the collection of 
stool for research purposes. A subject ID number will be assigned. Stool samples identified only 
by subject ID number will be collected and processed to determine whether they contain 
Candida species by standard laboratory methods in the Bliss research laboratory. Because 
colonization with Candida may develop over time, we will collect stool samples from eligible 
patients weekly throughout their hospital stay.  Parent(s) of colonized infants will be approached 
for informed consent. Once consent is obtained, infants will be randomized into control and 
supplementation groups.  After baseline sample collection, infants in the supplementation group 
will receive 0.5 ml/oz additional MCT oil (4 kcal/oz) as a nutritional supplement for 21 days or 
until hospital discharge.  Sample collection from enrolled infants will include a stool sample and 
0.5 ml of maternal breast milk obtained from a bottle provided to the patient’s room.  Samples 
will be collected three times during the study period: before supplementation is started, 1 week 
after supplementation is started, and at the conclusion of the supplementation period..  The 
following information will be extracted from the medical record of consented infants: gestational 
age, birth weight, day of life, gender, admitting diagnosis, prenatal infection screening labs, 
method of delivery, antibiotic use (duration and drug class), corticosteroid use, presence of 
central lines, amount and types of feeds (breast milk only, breast milk and formula, formula only; 
formula brand; type and amount of fortifiers and other nutritional supplements) and feeding 
modality (breast, bottle, NG, G-tube) will be recorded.  If any infant subsequently develops an 
invasive fungal infection or oral thrush, that will also be noted.  All information extraction will 
conform to HIPAA and institutional standards for protected health information.           
 
2.  
Data Analysis:  Stool samples from preterm infants admitted to the ICU will be 
processed by standard laboratory methods in the Bliss research laboratory to determine whether 
they contain Candida species.  The presence and concentration of organisms will be recorded.  
Once infants are enrolled, stool samples and breast milk will be collected and stored for later 
testing at Tufts University.  The presence and concentration of microbes in stool samples will be 
quantified, and the fatty acid content of breast milk samples will be analyzed.  All identifiers 
will be removed from all samples collected for this study; they will be identified only by subject 
study ID number. No PHI will be provided to Tufts.  Laboratory data generated from these 
studies will be maintained independent from any patient identifying information.  Patient 
identifiers will be maintained in coded fashion secured in Dr. Bliss’ office at Women & Infants 
Hospital.  This office is in a building distinct from that of the laboratory. 
 


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Microbiological Methods: Stool samples will be weighed and suspended in 10 ml of sterile 
saline. Serial dilutions will be cultured on YPD agar media (1% yeast extract, 2% peptone, 2% 
dextrose, 2% agar) containing 100 μg/mL streptomycin and 50 μg/mL ampicillin to inhibit 
bacterial growth and to allow quantification of the yeast content per gram of stool. Colonies will 
be evaluated by light microscopy to confirm that they are comprised of yeast. Yeast will be 
speciated using the FDA-approved Vitek-2 system. 
 
3. Safety Assessments: Because MCT oil is already a component of infant formulas and 
breast milk, and because recommended dietary intakes will not be exceeded, there are no 
specific procedures, laboratory evaluations, or measures required to monitor infants receiving 
the supplement.  Routine clinical care and assessments will be undertaken, with the option to 
discontinue the supplement in the unlikely event that there is any clinical suspicion of 
intolerance.  In particular, enrolled patients receiving supplemental MCT oil will be monitored 
for the following signs/symptoms: 
1. Feeding intolerance – defined as any clinical event related to feeding (gastric aspirates, 
emesis, abdominal distension) that results in a reduction or withholding of enteral 
feedings for a period of 24 hours or more. 
2. Diarrhea 
3. Necrotizing enterocolitis 
4. Poor weight gain 
5. Excessive weight gain 
 
Adverse event 
An adverse event is any untoward medical occurrence in a patient or trial subject 
administered a pharmaceutical product; the event does not necessarily have a causal relationship 
with the treatment or usage.  Adverse events include the following: 
• Abnormal test findings, as specified below. 
• Clinically significant signs and symptoms. 
• Changes in physical examination findings. 
• Progression/worsening of underlying disease. 
Abnormal test findings 
An abnormal test finding, e.g., abnormal laboratory analysis results or vital signs, should be 
recorded as an adverse event in any of the following situations: 
• The investigator considers the test result to be clinically significant. 
• The test is associated with accompanying symptoms. Note, that the symptom, not the test 
result, should be recorded as an adverse event. 
• The test result leads to a medical/surgical intervention including withdrawal of 
investigational product or discontinuation from the study. Repeat/confirmatory testing is not 
considered a medical intervention. 
 
 
Serious adverse event (SAE) 
An adverse event that meets one or more of the following criteria/outcomes is classified as 
serious: 
• Results in death. 
• Is life-threatening (i.e., at immediate risk of death). 


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• Requires prolongation of hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Other medically important adverse event that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or may require medical or surgical intervention to 
prevent one of the outcomes listed above.  
 
Adverse Event Grading Scale 
The adjectives MILD, MODERATE, or SEVERE will be used to describe the maximum 
severity of the adverse event. For the purpose of consistency, these intensity grades are defined 
as follows: 
 
MILD: Does not interfere with patient's usual function. 
 
MODERATE: Interferes to some extent with patient's usual function. 
 
SEVERE: Interferes significantly with patient's usual function. 
Note the distinction between the gravity (seriousness) and the intensity (severity) of an 
adverse event. Severe is a measure of intensity; thus, a severe reaction is not necessarily a 
serious reaction. For example, a headache may be severe in intensity, but would not be 
classified as serious unless it met one of the criteria for serious events listed above. 
 
Causality assessment 
For each adverse event, a causality assessment will be made to determine if there is a 
reasonable possibility that the investigational product caused the adverse event. The adverse 
event is assessed using the following classification and criteria: 
Not related: This relationship suggests that there is no association between the 
investigational product and the reported event. 
Unlikely: This relationship suggests that the temporal sequence of the clinical event, 
including a laboratory test abnormality, with investigational product administration makes a 
causal relationship improbable, and that other drugs or underlying diseases provide plausible 
explanations. 
Possible: This relationship suggests that treatment with the investigational product caused 
or contributed to the adverse event, i.e., the event follows a reasonable temporal sequence from 
the time of drug administration or follows a known response pattern to the investigational 
product, but could also have been produced by other factors. 
Probable: This relationship suggests that a reasonable temporal sequence of the event with 
investigational product administration exists and, based upon the known pharmacological action 
of the drug, known or previously reported adverse reactions to the drug or class of drugs, or 
judgment based on the investigator’s clinical experience, the association of the event with the 
investigational product seems likely. 
Definite: This relationship suggests that a definite causal relationship exists between 
investigational product administration and the adverse event, and other conditions (concurrent 
illness, progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event. 
“Not related” and “unlikely” will be included in the category “unrelated” (i.e., not having 
a reasonable suspected causal relationship to the investigational product). 
“Possible”, “probable” and “definite” will be included in the category “related” (i.e., 
having a reasonable causal relationship to the investigational product). 


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IV. Risk/Benefit Assessment 
 
 
This is a minimal risk study. Collection of stool samples presents no risk to the patient. 
The very small volume of breast milk that is required for research purposes will not impact that 
which is available to the baby, but in the event that there is any concern about breast milk 
supply, the samples will not be collected.  Some babies will receive a supplement of MCT oil to 
their feedings.  MCT oil is already a component of preterm formulas and is present to varying 
degrees in breast milk as well.  It is commercially available and in routine use as a caloric 
supplement in premature infants.  The amount of MCT oil that will be supplemented (4 kcal/oz) 
is within the range recommended and maintains the appropriate fat:total calorie ratio for infant 
feeding. Because colonization with Candida is a recognized risk factor for invasive candidiasis 
in premature infants, if MCT oil supplementation reduces colonization with this potential 
pathogen, the subjects could potentially benefit from participation. 
 
Colonization of the gastrointestinal tract with Candida species is a very common 
occurrence in premature infants, occurring in 30-60% of infants in recent series.  Determination 
of colonization status for Candida is not a part of routine clinical care.  Although colonization 
has been defined as a risk factor in research settings, the vast majority of infants who are 
colonized with Candida species will not develop invasive disease.  The infants who are found to 
have Candida in their stool therefore do not exceed a risk threshold that would warrant any 
specific treatment for this condition in current clinical practice. 
 
 
V. Subject Identification, Recruitment, and Consent/Assent 
 
 
Subjects will be identified by the investigators.  The subject’s hospital admission consent 
form will be reviewed to confirm that it has been signed and that the patient has not indicated 
any restrictions on the use of stool samples for research purposes.   
 
There are no costs to the patient or financial incentives for the patient for participation in 
this study. 
 
 
VI. References 
 
1. 
Calderone, R.A., Candida and Candidiasis, 2002, ASM Press: Washington D.C. 
2. 
Stoll, B.J., et al., Late-onset sepsis in very low birth weight neonates: the experience of 
the NICHD Neonatal Research Network. Pediatrics, 2002. 110(2 Pt 1): p. 285-91. 
3. 
Kaufman, D.A., "Getting to Zero": preventing invasive Candida infections and 
eliminating infection-related mortality and morbidity in extremely preterm infants. Early 
Human Development, 2012. 88 Suppl 2: p. S45-9. 
4. 
Huang, Y.C., et al., Association of fungal colonization and invasive disease in very low 
birth weight infants. Pediatr Infect Dis J, 1998. 17(9): p. 819-22. 
5. 
Gunsalus, K.T., et al., Manipulation of host diet to reduce gastrointestinal colonization 
by the opportunistic pathogen Candida albicans. mSphere, 2016. 1(1).