Cold Milk as a Novel Therapy for Dysphagia in Preterm Infants
Phase: NA
Conditions: Dysphagia of Newborn
Sponsor: NYU Langone Health

 
 
Official Title: 
Cold milk as a novel therapy for dysphagia in preterm infants 
NCT Number: 
NCT04421482 
Study Number: 
s20-00876 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
June 13, 2022 
 
 

Study #:  i20-00876 
 
 
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Cold milk as a novel therapy for dysphagia in preterm infants 
 
Principal Investigator: 
 
Nazeeh Hanna, MD 
Department of Pediatrics 
Chief, Division of Neonatology 
NYU- Langone Long Island Hospital Tel. (516) 663-8450 
E-mail: Nazeeh.Hanna@NYULangone.org  
 
Additional Investigators: 
 
Louisa Ferrara, PhD, CCC-SLP, BCS-S, CNT 
Researcher, Feeding/Swallowing Specialist 
Department of Pediatrics 
Division of Neonatology 
NYU- Langone Long Island Hospital Tel. (516) 779-9647 
E-mail: Louisa.Ferrara@NYULangone.org 
 
Ranjith Kamity, MD 
Attending Neonatologist 
Department of Pediatrics 
Division of Neonatology 
NYU- Langone Long Island Hospital Tel. (516) 663-8453 
E-mail: Ranjith.Kamity@NYULangone.org 
 
Vikramaditya Dumpa, MD 
Attending Neonatologist 
Department of Pediatrics 
Division of Neonatology 
NYU- Langone Long Island Hospital Tel. (516) 663-9371 
E-mail: Vikramaditya.Dumpa@NYULangone.org 
 
NYULMC Study Number: 
 
Funding Sponsor: 
Department of Pediatrics and 
NIH, 1R21HD100653-01 (Pending) 
 
Title 
Cold milk as a novel therapy for dysphagia in preterm infants  
Short Title 
Cold milk for dysphagia in preterm infants 

Study #:  i20-00876 
 
 
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Brief 
Summary 
It is estimated that 30-70% of very low birth weight (VLBW) preterm infants will be diagnosed 
with swallowing dysfunction (dysphagia), which often leads to airway compromise in the form 
of laryngeal penetration and/or tracheal aspiration during oral feeding attempts. Chronic airway 
compromise results in a persistent inflammatory state, with disease progression that can be 
devastating for already fragile and developmentally immature lungs in preterm infants. At this 
time, there are limited therapeutic options for dysphagia in VLBW infants during oral feeding. 
In a recent publication, our research group was the first to demonstrate that short-duration of 
oral feeding with cold liquid reduces dysphagia occurrence from 71% to 26%. However, these 
data must be further validated for the effectiveness and safety of a full duration feeding before 
being recommended for routine clinical practice.  
 
The objective is to identify preliminary evidence for the efficacy and safety of feeding full oral 
cold milk for dysphagia management in preterm infants. We hypothesize that oral feeding of 
cold milk in preterm infants with dysphagia will improve suck/swallow/breathe coordination and 
decrease penetration/ aspiration to the airway. We further hypothesize that cold milk 
intervention will have no adverse effects on intestinal blood flow, as assessed by Doppler 
Ultrasound. This is significant because there is a critical need to identify effective and safe 
evidence-based treatment options for dysphagia management in preterm infants. 
 
This prospective study will seek to enroll Subjects who meet the following inclusion criteria: 1) 
preterm infants less than 34 weeks gestation), 2) admitted to NYU- Langone Long Island 
Hospital NICU, 3) Post-menstrual age (PMA) > 35 weeks at the time of the study, 4) receiving 
no or minimum respiratory support (<2 lit/min low-flow nasal cannula), 5) tolerating at least 
50% of their enteral feeding orally, 6) having symptoms of swallowing dysfunction during oral 
feeding (clinical dysphagia) and 7) referred by the medical team for video fluoroscopic swallow 
study (VFSS) and/or fiberoptic endoscopic evaluation of swallowing (FEES).  
 
To assess the efficacy of cold milk in treating dysphagia, study subjects will first have an oral 
motor feeding assessment using an FDA approved device called the nFant® Feeding 
Solution (510k cleared, # K143507), used routinely in many NICUs as well as VFSS and/or 
FEES. To assess the safety of using cold milk, subjects will receive a doppler ultrasound 
before and after the ingestion of cold liquid feeding to assess the mesenteric blood flow.  
 
Objectives 
Evaluate the effectiveness of cold milk to improve penetration/aspiration in preterm infants 
with dysphagia, as well as to evaluate the safety of oral feeding of cold milk in preterm 
infants 
Methodology Prospective Study 

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Endpoint 
1. Evaluate the effectiveness of cold milk to improve penetration/aspiration in preterm 
infants. 
The primary outcome will be the percentage of swallows with aspiration and/or 
penetration for cold milk compared with room temp milk (a total of 15 swallows will be 
assessed by VFSS and FEES). Based on our preliminary results, we expect to find a 
significant decrease in penetration and aspiration during the initial cold swallows (5 
swallows). We expect this improvement to be sustained on the subsequent cold swallows 
(10 swallows) following the 15-minute cold liquid feeding. A decrease of 30% in penetration 
and/or aspiration with cold milk will be considered significant. Similarly, a 30% improvement 
of feeding coordination as assessed by nFant device will be considered significant. 
 
2. Evaluate the safety of feeding cold milk in preterm infants. 
We will evaluate whether cold milk will cause hypothermia (assessed by measuring Axillary 
temperatures), change in vital signs  (respiratory rate, heart rate, and oxygen saturation) as 
well as change in mesenteric blood flow indices (assessed by abdominal ultrasound). . 
These changes with cold milk feeding will be expressed as % change compared to base line 
(room temp milk). 
Study 
Duration 
2 years 
Participant 
Duration 
The subjects will participate in the study for approximately 48 hours during their NICU 
hospital stay  
Population 
Preterm Infants less than 34 weeks gestation admitted to NYU- Langone Long Island 
Hospital NICU. (n=42) 
Study Sites 
NYU- Langone Long Island Hospital 
Number of 
participants 
42 
 
1. Introduction, Background Information and Scientific Rationale 
Approximately half a million preterm infants are born every year in the USA.1,2 It is estimated that 30-70% of very 
low birth weight (VLBW) preterm infants will be diagnosed with swallowing dysfunction (dysphagia), with an inverse 
relationship between the severity of dysphagia and gestational age (GA).3-6 Although the pathophysiology of 
dysphagia is multifactorial,4,7-9 the discoordination between swallowing and breathing is the most prevalent cause 
of dysphagia in preterm infants,10 which often leads to airway compromise in the form of laryngeal penetration 
and/or tracheal aspiration into the lungs.7,11 Chronic airway compromise results in a persistent inflammatory state, 
with disease progression to chronic lung injury and bronchopulmonary dysplasia (BPD) that can be devastating for 
already fragile and developmentally immature lungs in preterm infants.4,7  
 
A challenge facing clinicians is the limited therapeutic options for dysphagia in VLBW infants during oral feeding. 
Currently, the most widely used option for this population is the thickening of feedings to alter the bolus flow and 
maneuverability in the oropharynx to improve airway protection.12-15 However, such an option has limited efficacy, 
especially if feeding breast milk, since human milk enzymes can interfere with the desired milk consistency.16 One 
alternate technique in adults is to use cold foods to stimulate a safer swallow.17 The theoretical basis for this 
technique is to provide increased sensory information to the sensory receptors within the pharynx, to trigger more 
efficient swallowing movements.14,15,18-21 Cold temperature stimulates the sensory thermo-receptors in the 
pharyngeal area via cation channels expressed in the visceral afferents of the cranial nerves. Animal studies have 
demonstrated that these channels are activated by cold stimulus leading to thermoregulatory responses and 
protective reflexes.22 the use of cold stimulation has proven to reduce airway compromise in adults with 
dysphagia.17,23,24 However, for preterm infants, the use of cold feeds has not been well investigated, leaving 

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clinicians with very limited therapeutic options. The significant lack of dysphagia research in preterm infants hinders 
any evidence-based approach to this frequent problem.  
 
In a recent publication, our research group was the first to demonstrate that short-duration of oral feedings with cold 
liquid (5 swallows) reduces dysphagia occurrence from 71% to 26% as assessed by VFSS.25 Our preliminary data 
further confirms that oral cold milk feeding significantly improves suck/swallow/breathe coordination as evident by 
bedside oral feeding scoring scales. However, these data must be further validated for the effectiveness and safety 
of a full duration feeding before being recommended for routine clinical practice.  
 
The objective of this application is to identify evidence for the efficacy and safety of feeding full oral cold milk for 
dysphagia management in preterm infants. We hypothesize that oral feeding of cold milk in preterm infants with 
dysphagia will improve suck/swallow/breathe coordination and decrease penetration/aspiration to the airway. We 
further hypothesize that cold milk intervention will have no adverse effects. 
 
2. Potential Risks & Benefits 
For the study purpose, the FEES will be used to assess swallowing coordination with cold milk for a total of 15 
swallows only.   
 
Risks associated with FEES- FEES is a routine procedure done in the NICU and is ordered by the medical team. It 
is also possible that FEES will cause epistaxis, or respiratory distress during the FEES. Although it is unlikely given 
the previous reports in using it in preterm babies, as well as in adults and pediatrics. The diameter of the FEES 
scope is similar in size to the nasal gastric tube that most preterm infants have already, which is commonly well 
tolerated in preterm infants, even during oral feedings. Several studies demonstrated its safety in children. However 
the procedures will only be conducted in the presence of an attending Neonatologist to ensure airway safety in case 
of any adverse events. The FEES will be ordered by the medical team as clinically indicated (the clinician can do 
the FEES for the entire feeding or portion of the feeding).  
 
Development of cold stress in response to cold liquids- It is possible that infants feeding cold liquids will develop 
cold stress. Several studies have assessed the effects of cold feeds in healthy term and healthy preterm infants but 
not in the context of dysphagia. These studies revealed no significant adverse effects including no difference in 
sleep pattern, vocalizations, motility, intake, feeding behavior, weight gain, temperature or regurgitation.26 
Blumenthal and colleagues27 reported that cold feeds were well tolerated and produced no obvious clinical effects. 
Other studies found no significant differences in gastric residuals in preterm infants (28-30 weeks gestation age) 
fed cold (0-4°C) versus room temperature (25°C) milk,28 as well as no effect regarding gastric emptying time.27,29 
Based on the current literature in preterm infants, the 15-minute exposure to cold liquid is expected to result in little 
risk.30 
 
Cold Stress Prevention - As part of our study design, we are employing frequent axillary and gastric content 
temperature checks to ensure participant safety. Furthermore, infants’ vital signs (blood pressure, respiratory rate, 
heart rate, and oxygen saturation), and evidence of any respiratory compromise, will be monitored and recorded. 
 
Radiation Exposure - For this study, we aim to visualize 15 swallows, which will take approximately 18 seconds. Compared 
to the typical range of radiation time of 90-180 seconds in routine VFSS. The radiation exposure related to this research equals 
10-20% of what an infant would be exposed to during a typical routine VFSS. 
Radiation Exposure Prevention – Our study design will include various radiation sparing techniques: 1) 
Commination, which restricts the x-rays to a smaller area on the subject; 2) Pulsed fluoroscopy, which takes 30 
frames/second, instead of the continuous fluoroscopy of 60 frames/second; 3) The radiologist will utilize intermittent 
fluoroscopy to turn the radiation on only at the time of swallowing; 4) A lead shield will be placed on the subjects’ 
lap to protect reproductive organs from radiation scatter. 
 
Known Potential Benefits 
The subjects may or may not personally benefit from being in this study. The results of this research (the safety and 
effectiveness of cold milk for each subject) will be disclosed to the medical team for further consideration. If the 

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results confirm safety and efficacy for that infant, the medical team can consider using cold milk to treat the infant’s 
dysphagia which can be a significant benefit to the subject.   
 
3. Objectives  
The first objective is to identify preliminary evidence for the efficacy of feeding full oral cold milk for dysphagia 
management in preterm infants. We hypothesize that oral feeding of cold milk in preterm infants with dysphagia will 
improve suck/swallow/breathe coordination and decrease penetration/aspiration to the airway. Our second 
objective is to confirm the safety of this practice. We hypothesize that cold milk intervention will have no adverse 
effects on intestinal blood flow as assessed by Doppler Ultrasound. These objectives are significant because there 
is a critical need to identify effective and safe evidence-based treatment options for dysphagia management in 
preterm infants. 
 
4. Study Design  
This will be a prospective study, with each infant serving as their own control. All study subjects will meet the 
inclusion/exclusion criteria listed in Section 5 of this proposal and informed consent will be obtained. The subject will 
be considered for the study if the medical team diagnosed the infant with clinical dysphagia and decided to obtain  
Video Fluoroscopic Swallow Study (VFSS), or Fiberoptic Endoscopic Evaluation of Swallowing [FEES) or both to 
help manage the dysphagia (such as delay oral feeding till the child is more mature or use feeds thickeners). The 
VFSS and FEES are not a requirement for step 1 however abnormal VFSS and FEES are requirement for step 2.  
 
The following study procedures will be done before the routine VFSS/FEES testing ordered by the medical team: 
 
 
 
 
 
o 
Step 1 (bedside procedures):  
 
• 
We will evaluate the infant’s sucking, swallowing, and breathing patterns using a non-invasive FDA 
approved equipment (nFant® Feeding Solution). This device is in clinical use for several years and routinely 
used in several NICUs. The nFant has a wireless sensor within the nipple to assess sucking and swallowing 
coordination during feeding. This machine is not routinely used in NYU- Langone Long Island Hospital NICU 
because of costs but will be available only for infants enrolled in this research study. The nfant assessments 
will be performed by the research team under two separate feeding conditions, standard room temperature 
(RTS) and cold temperature (CS, at 4-9°C) of milk/formula for an entire feeding (15-20 minutes). The two 
feedings will be done on the same day but may not necessarily be two consecutive feedings (depending 
on the baby’s eagerness to feed orally). The order of each condition will be randomized to control for fatigue. 
Inter- and intra-rater reliability measures will be calculated. The nfant assessments will include the following 
measurements: 
 peak amplitude - the displacement of the nipple during compression phase normalized from a calibrated 
0% to 100%; 
 duration - how long or drawn out sucking events are from onset to end in seconds;  

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 frequency - the rate at which consecutive suck events are occurring in Hertz;  
 suck bursts - number of sucks per burst, duration and number of bursts, and active time spent sucking; 
 suck smoothness - the number of velocity changes in a nipple amplitude trace during a suck.  
 
• 
The axillary temperature will be measured immediately prior to and after each feeding condition. It will also 
be measured at 10, and 30 minutes after the CS feed, at the same time the gastric content temperatures are 
taken. Infants’ vital signs will be recorded (blood pressure, respiratory rate, heart rate, and oxygen 
saturation), as well as evidence of bronchospasm, lethargy, respiratory distress, apnea, tachypnea, 
cyanosis, bradycardia, or tachycardia.  
 
• 
Doppler ultrasound (Sonosite Edge Ultrasound system, Sonosite, Inc, WA) will be used to measure 
intestinal blood flow indices including the superior mesenteric artery flow (SMA), peak systolic velocity, 
SMA mean velocity, SMA end-diastolic velocity, resistive index, pulsatility index, portal vein volumetric 
blood flow, as well as heart rate and mean arterial blood pressure. Intestinal blood flow monitoring via 
Doppler ultrasound will be performed 6 times for each participant, performed one hour before and at 30 and 
60 minutes after both bedside feeding conditions (RTS and CS). Measurements will be taken at the bedside 
in the supine position.  
 
o 
Step 2 (done 24-48 hours after step 1):  
• 
Infants will be transported to the radiology suite and undergo VFSS and or FEES, as ordered by the treating 
medical team (Figure1: the blue boxes indicate procedures done for research purpose only. None of the 
research procedures are experimental and are approved tests for neonates including VFSS, FEES, nfant 
test and abdominal ultrasound).  
• 
Routine procedure for VFSS or FEES will be followed as ordered by the medical team. This procedure is 
part of the routine clinical care and not considered part of the research study. 
 
• 
If no dysfunction is noted, the procedure will end, and the child will no longer be eligible for further 
participation in this research study. If dysfunction (penetration/aspiration) either on the VFSS or FEES study 
is noted, the child will be eligible to participate in the next phase of the study. 
 
• 
Immediately following the initial VFSS-FEES assessment, the infants will remain in the same seated 
position with the FEES scope in place. While keeping all variables from the standard VFSS-FEES the 
same, the infant will be fed cold barium (4-9°C) using the same nipple. A total of 5 swallows will be 
visualized using VFSS and FEES, labeled “Cold Swallows-1 (CS1).” These 5 swallows assessment are 
done for the research purpose only. 
 
• 
If the dysphagia didn’t improve, the study would end, and the child will no longer be eligible for participation 
further in this research study. 
 
• 
If the dysphagia improves with cold liquid, VFSS will then be turned off and the infants will then be fed their 
regular feeds (formula or expressed breast milk as indicated by the medical team) chilled to an approximate 
temperature of 4-9°C for a total of 15 minutes, or until the infant shows signs of feeding completion. The 
cold feeding will be replaced every 5 minutes to make sure that the temperature is maintained at 4-9°C to 
minimize habituation effect.30  
 
• 
After the 15 minute period, the infant will be re-assessed by VFSS-FEES using cold barium from the same 
bottle (10 swallows, labeled “Cold Swallows-2” [CS2]). This design evaluates whether a full feeding of cold 
liquid will result in decreased penetration or aspiration compared to RTS condition. These 10 swallows 
assessment are done for the research purpose only). 
 
 
• 
The axillary temperature will be monitored every 10 minutes. Infants’ vital signs (blood pressure, respiratory 
rate, heart rate, and oxygen saturation), as well as evidence of any respiratory compromise, will be 
recorded. A neonatologist will be next to the baby at all times. The baby will return to the NICU after the 
study accompanied by the NICU team, including the neonatologist.  

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Depending on the scheduling of the VFSS/FEES testing by the infant’s medical team, the research team might need 
to do Step 2 before Step 1, as described above. There will be at least 24 hours period between the two steps. 
 
The results of the testing with cold milk will be disclosed to the medical team. The research team is ethically 
obliged to disclose the results of efficacy and safety of cold milk use in each child to their treating team.  The 
medical team can decide if that will be an option for dysphagia treatment. The research team will not interfere with 
that decision. Of note, the results of this research requires enrollment of 42 infants to test the hypothesis that cold 
milk is effective and safe for dysphagia in preterm infants. If efficacy and safety are demonstrated, clinicians can 
use cold milk without the need to do all the safety and efficacy measures detailed in this study for each child in the 
future. However, for the participants in this study, if efficacy and safety is demonstrated for that particular child, it 
will be safe to use cold milk for that specific child if the medical team desires. However again, the medical team 
will decide to use this information or not to treat dysphagia. We also changed the protocol so the results of this 
research can be disclosed to the family by the clinical team only. 
 
Data collection sheets will be immediately labeled with a unique identifier with no identifying or protected 
information. Consent forms and data collection sheets will be kept in a secure location for up to six years in 
accordance with institutional policies. Digital images obtained from VFSS and FEES procedures will be saved onto 
a writable DVD and immediately labeled with a unique identifier with no link to identifying or protected information. 
In order to minimize loss of patient confidentiality, all participant data forms will be coded with a subject ID number 
and will not contain the name, medical record number, date of birth, or other identifiable information. A master 
spreadsheet that links the study number to the medical record number will reside on REDCap.  
 
Chart Review – For this study patient data will be collected including date of birth, gestational age at birth, birth 
weight, gender, and ethnicity. Furthermore, patient charts will be reviewed to track infants’ clinical courses and 
diagnoses (such as respiratory distress, BPD, NEC, incidence of infections, retinopathy of prematurity, and 
intraventricular hemorrhage, etc.). All patient records will be assigned unique numerical codes and study records 
will be kept in a secure database. Coded sheets linking a subject’s name to a subject’s identification number will be 
stored separately in a password protected document only accessible to research personnel. 
Data Sources and Case Ascertainment: 
Cases will be obtained through a search for inclusion criteria using EPIC. 
 
Statistical Considerations- 
 
Statistical Analysis and Estimated Sample Size:  To evaluate whether cold liquid will improve aspiration and 
penetration, event rates during CS compared to RTS, as well as corresponding 95% confidence intervals, will be 
computed. Aspiration and Penetration variables will be assessed for normality using histograms and the 
Kolmogorov-Smirnov (K-S) test. Wilcoxon Signed-Rank test will be used to evaluate the specific aim 1, i.e., compare 
changes in aspiration and penetration between RTS and CS.  Aspiration and penetration will be evaluated using 
different methods (FEES and VFSS). Power and Sample Size: Our preliminary data showed a mean change of 
44 and 36% in aspiration and penetration, respectively. For power computation, we conservatively assumed an 
average change of 30% and a common standard deviation of 25 in both aspiration and penetration. We simulated 
data using a two-sided Wilcoxon Signed-Rank Test (the non-parametric equivalent of the paired t-test) with 
alpha=0.05 significance level and a pre-post correlation of 0.20, which revealed that a sample size of N=25 subjects 
would provide us more than 95% power to detect a large effect size both in aspiration and penetration. These 
simulation results are based on 10000 Monte Carlo samples. Assuming a conservative estimate that 60% of infants 
with clinical dysphagia will have a positive VFSS or FEES test, we expect that we will need to enroll 42 subjects to 
have 30 subjects with a positive dysphagia test. NYU- Langone Long Island Hospital Hospital NICU is a Regional 
Perinatal Center (one of 17 NICUs in the state of New York designated to provide the highest level of care to 
neonates in NY State). The average number of VLBW infants admitted is 90-100/year and a t  l e a s t  40-
45 infants/year will have clinical dysphagia referred for VFSS-FEES testing (3-4 patients/month). Therefore, we 
are confident that we will have sufficient sample size over the 2-year grant period to conduct the proposed aims. 
 
 

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2: Evaluate the safety of feeding cold milk in preterm infants. 
Axillary temperatures, as well as mesenteric blood flow indices, will be compared between the CS and RTS feeds. 
A Two One-Sided Test (TOST) will be used to evaluate whether the body temperature and blood flow indices are 
equivalent before and after the cold liquid swallow. Equivalence will be determined if the 90% confidence interval 
of pre-post change is contained within the predefined margin of ±0.5. Power and sample size: The study subjects 
are the same subjects enrolled in Aim 1 (n=42). We have simulated data assuming a margin of equivalence from -
0.5° C to 0.5° C, significance level 0.05, TOST and 10000 Monte Carlo samples. With the planned sample size for 
aim 1 (N=42), we will have sufficient power (>80%) to detect equivalence when the margin of equivalence is from -
0.5° C to 0.5° C and the actual mean difference is zero. 
5. Study Enrollment  
Inclusion Criteria 
1) Viable preterm infants less than 34 weeks gestation), 2) admitted to NYU- Langone Long Island Hospital 
NICU, 3) PMA > 35 weeks at the time of the study, 4) receiving no or minimum respiratory support (<2 
lit/min low-flow nasal cannula), 5) tolerating at least 50% of their enteral feeding orally and 6) having 
symptoms of swallowing dysfunction during oral feeding (clinical dysphagia). 7) referred by the medical 
team for VFSS and/or FEES assessments. 
 
Exclusion Criteria 
Exclusion criteria include children with other comorbidities, such as IUGR, upper airway anomalies, brain injury, 
neuromuscular disease, or life-threatening congenital disease. 
 
Total Number of Participants and Sites  
We will need 42 subjects over a 2 years period.  
 
Vulnerable Subjects 
Our population will include children by nature of the study objectives.  
 
The study has potentially greater than minimal risk, but there is possible direct benefit to the individual subject. 
Although previous studies as well as our preliminary study didn’t show any evidence of cold stress in response to 
cold milk feeding, it is a potential risk. In addition there will be minor increase in radiation exposure as described 
previously. Currently there is no effective treatment for dysphagia in preterm infants. The results of this research 
(the safety and effectiveness of cold milk for each subject) will be disclosed to the medical team. If the results 
confirm safety and efficacy for that infant, the medical team can consider using cold milk to treat the infant’s 
dysphagia which can be a significant benefit to the subject.  
 
Subjects Identification, Recruitment and Consent Process 
 
• 
Patients would already be admitted to NYU- Langone Long Island Hospital NICU due to premature birth. 
Physicians will refer patients for a feeding/swallowing consult with the clinical SLP when identified as having 
symptoms of swallowing dysfunction during oral feeding (clinical dysphagia). The research team will identify 
possible subject’s eligibility through EPIC query.  
 
• 
Our recruitment plan: All subjects will be infants admitted to the NYU- Langone Long Island Hospital 
neonatal intensive care unit. Subjects will be identified based on referral for feeding/swallowing consult, 
followed by confirmation of meeting all inclusion/exclusion criteria by the research team using EPIC query. 
There will be no restrictions regarding sex, race, or ethnic origin. After the consent is obtained, all study 
participants will be deemed medically stable to tolerate the study protocol by their attending neonatologist.  
 
• 
 This study will use a NYU Data Core generated list of patients meeting the inclusion criteria who have 
agreed to be approached for clinical research. 
 

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• 
Once potential subjects have been identified, the study team will notify the subject’s treating physician 
(TP) that they have patients eligible to participate using the following method: The treating physician will 
be contacted by secure messaging through EPIC, by phone, or in person and asked to permit study team 
to directly contact potential subjects. The treating physician may also contact study team for direct patient 
referrals. Once contact is made, patients will be told the reason they are being contacted and will be 
asked if they are interested in participating in this specific study. Should the potential subjects agree, the 
study team will provide the subjects with information regarding the next steps for participation. 
 
• 
The research team will approach the parents to discuss this research project during their visit to their infant 
in the NICU. Alternatively, the research team will call the parents on the phone to set a meeting time during 
their next visit to the NICU. The parents will be asked to meet in a private room in the NICU to explain all 
the details regarding the research and consent process and answer all their questions. The parents will be 
provided a copy of the consent form and will be given a chance to read the consent form privately (for at 
least a couple of hours or till next day if they wish). The research team will meet with the parents again in 
a private room to further answer any questions before signing the consent form if they agreed to participate 
in the study.  
• 
 
• 
Information contained within the consent will be written at an eighth-grade level to help ensure universal 
comprehension. All members of this research team have been trained in human subject research and will 
review the consent form in detail with the potential subject’s representatives. The subject’s representatives 
will be provided the opportunity to have all questions answered. Comprehension will be judged by the 
research team through the patient verbalizing understanding and asking appropriate questions. If English 
is not a primary language, a translator will be provided via telephone (Cyracom) to obtain consent in the 
subject’s representative’s primary language. The translator’s identification number will be recorded. A copy 
of the consent will be given to the patient, with the original maintained in a locked file cabinet. Coercion to 
obtain consent within this timeframe will not occur. Please see further details regarding informed consent 
process, in the section below titled: “Ethics/Protection of Human Subjects”. 
 
6. Sample Size Determination 
Our preliminary data (REF) showed a mean change of 44 and 36% in aspiration and penetration, respectively. For 
power computation, we conservatively assumed an average change of 30% and a common standard deviation of 
25 in both aspiration and penetration. We simulated data using a two-sided Wilcoxon Signed-Rank Test (the non-
parametric equivalent of the paired t-test) with alpha=0.05 significance level and a pre-post correlation of 0.20, 
which revealed that a sample size of N=25 subjects would provide us more than 95% power to detect a large effect 
size both in aspiration and penetration. These simulation results are based on 10000 Monte Carlo samples. 
Assuming a conservative estimate that 60% of infants with clinical dysphagia will have a positive VFSS or FEES 
test, we expect that we will need to enroll 42 subjects to have 30 subjects with a positive dysphagia test. 
 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Extensive discussion of risks and possible benefits of 
participation will be provided to the infants’ parents. Consent forms will be IRB-approved and the parents (defined 
as either the mom or dad if they are legally married) will be asked to read and review the document. The study 
investigators will explain the research study to the parents and answer any questions that may arise. All participants 
will receive a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants. Parents will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The parents should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate. The parents will sign the informed consent 
document prior to any procedures being done specifically for the study. The parents may withdraw consent at any 
time throughout the course of the study. A copy of the signed informed consent document will be given to the 
parents for their records. The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to participate in this study. 
 

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A copy of the signed informed consent document will be stored in the subject’s research record. The consent 
process, including the name of the individual obtaining consent, will be thoroughly documented in the subject’s 
research record. Any alteration to the standard consent process (e.g. use of a translator, consent from a legally 
authorized representative, consent document presented orally, etc.) and the justification for such alteration will 
likewise be documented.  
 
Participant and Data Confidentiality 
Data collected will be de-identified and stored into REDCap electronic data capture, according to NYU Langone 
Health policy on data storage. This database will be accessed through computers and network managed by NYU- 
Langone Long Island Hospital. All investigators and sub-investigators listed in this proposal will have access to the 
study data. Identifiable information will not be recorded; instead, each subject would have his or her own sequential 
identification number. Any paper record will be stored in a locked cabinet at NYU- Langone Long Island Hospital. 
Data will be stored for up to 5 years. Any paper records will be disposed through a confidential shredder. 
 
Participant confidentiality is strictly held in trust by the participating investigators and their staff. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party. Representatives of the IRB may 
inspect all documents and records required to be maintained by the investigator. The study participant’s contact 
information will be securely stored at each clinical site for internal use during the study. At the end of the study, all 
records will continue to be kept in a secure location for as long a period as dictated by local IRB and Institutional 
regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the NYU- Langone Long Island Hospital Hospital. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems by research staff will be secured 
and password protected. At the end of the study, all study databases will be de-identified and archived at NYU- 
Langone Long Island Hospital Hospital.  
 
Safety Monitoring Plan  
As requested by NIH, Safety Monitoring Plan is established as detailed below: 
 
This Safety Monitoring Plan is intended to describe processes in place for tracking and reporting Serious Adverse 
Events (SAE) and Adverse Events (AE), in compliance with NYU Institutional Review Board (IRB) and NICHD policy 
as well as ensuring the validity and integrity of the data obtained from this study. 
 
This trial will be submitted for approval to the NYU IRB. The research will not occur without NYU IRB prior approval. 
The PI will submit regular IRB updates as required by local IRB rules, including immediate IRB notifications of 
serious adverse events, protocol deviation/violations and annual continuing review. This trial will be registered at 
clinicaltrials.gov.  
 
All participant information will be secured in a database with password protection. The research nurse will receive 
only coded information that is entered into the database under those identification numbers. Electronic 
communication with outside collaborators will involve only unidentifiable information. 
 
Roles and Responsibilities 
 
Principal Investigator Responsibilities 
The Principal Investigator (PI) is responsible for study oversight, including ensuring human subjects’ research 
protections (HSP), by designating appropriately qualified, trained research staff, and medical clinicians to assess, 
report, and monitor Adverse Events (AEs). The PI, Sub-investigators, and study team members, will have current 
HSP certification and participate in research educational sessions, based on the current NIH and IRB guidelines. 
 
Drs. Hanna (PI), Dumpa and Kamity (Sub-Investigators) will have primary responsibility for monitoring participants’ 
well-being and ensuring that the information collected in this study remains confidential. Participants will be deemed 

Study #:  i20-00876 
 
 
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medically stable to be transported to the radiology suite and tolerate the study protocol by their attending 
neonatologist. The procedures (VFSS, FEES, nfant and IDFS) will be conducted in the presence of Dr. Hanna 
and/or Dr. Kamity and/or Dr. Dumpa (all staff neonatologists in addition to being study investigators) to ensure 
airway safety in case of any adverse events. 
 
 
Data Safety Monitoring Board (DSMB) Responsibilities 
• 
A Data Safety and Monitoring Committee (DSMB) will be created in accordance with established NIH policies. 
The members will be experts in neonatology (Teofilita Isaacson, MD, chair of the DSMB), pediatric pulmonary 
medicine (Melodi Pirzada, MD), pediatric nephrology (Manju Chandra, MD), pediatric gastroenterology and 
clinical trial design and ethics (Tuvia Marciano, DO) and biostatistics (Meredith Akerman, MS), who are not 
investigators in the trial.  
 
• 
The DSMB will meet regularly to review the protocols with respect to maintaining human subject protection, 
ethical and safety standards, monitor the safety of ongoing clinical trials, and advise the research team on this 
conduct. It will report to the PI and make recommendations if necessary. All data and deliberations of the DSMB 
will be strictly confidential. Decisions to alter or halt studies are the responsibility of the DSMB chair. The DSMB 
may recommend protocol modifications based on concerns for patient welfare or scientific integrity. The 
committee will be privy to statistical data and case report forms that it may require for its deliberations. It will 
review interim reports of patient accrual and outcome measures provided by the PI. Each report analyses will 
include treatment group and present all patients exits, mortality, and other major clinical events. After reviewing 
each such report, the DSMB will assess the need to perform further in-depth evaluation of the benefits and risks 
of continuing the study. If it is determined that the study objectives have not been satisfied based on data 
accrued to date, if patient safety would be compromised by continuation of the study, or if there are severe 
unanticipated problems with study conduct, the DSMB may recommend to the NICHD that the trial be 
terminated.  
 
• 
The DSMfB will meet quarterly as well as after each enrollment of 10 patients (an Interim Analysis of the results 
as well as all AEs will be presented). Emergency meetings will be scheduled immediately (maximum within 48 
hours) following any reported SAEs. Any death will requires expedited reporting by the DSMB chair (within 24 
hours of study’s knowledge of death). 
 
• 
DSMB report will be submitted to NIH within one week after each quarterly scheduled meeting. However, any 
action by the DSMB resulting in a temporary or permanent suspension of the clinical study will be reported to 
the NIH Program Official responsible for the grant within 48 hours. Any death will requires expedited reporting 
to NIH program officer within 24 hours of study’s knowledge of death. 
 
Reportable Adverse Events, including Serious Events 
 
Definitions 
Adverse Event (AE), also referred to as an adverse experience, is any untoward medical occurrence in humans, 
whether or not considered intervention related, which occurs during the conduct of a clinical trial. Any change in 
clinical status, routine labs, x-rays, physical examinations, etc., that is considered clinically significant by the study 
investigator is considered an AE. Adverse events will include: hypothermia (defined as temp less than 35.5 degree 
C) , abnormal changes in vital signs including  respiratory rate (apnic episodes or respiratory rate more than 70/min) 
, heart rate (less than 70/min or more than 220/min) , and oxygen saturation (less than 85%), . The staff nurses 
normally records any abnormal vital signs findings as part of their routine NICU care for all babies. These data will 
continuously be recorded during the cold feeding (usually around 15 minutes). Changes in vital signs can be a 
routine and frequent occurrences in preterm babies as part of their pathophysiology, The following AEs if occurred 
during the cold feeding will result in study termination for that baby and notification of the DSMB committee: 
1- Any incidence of hypothermia 
2- More than 2 episodes of apnea  
3- Tachypnea defined as increase respiratory rate more than 70/min for more than 2 minutes 
4- More than 2 episodes of bradycardia (defined as HR less than 70 for more than 10 seconds). 
5- Tachycardia (defined as HR more than 220) for more than one minute 

Study #:  i20-00876 
 
 
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6- More than 2 episodes of desaturation (defined as O2 saturation less than 85%) for more than 30 seconds 
 
Serious Adverse Events (SAEs), as determined by the PI, are any event that results in any of the following 
outcomes: 
1. Death 
2. Life-threatening SAE (life-threatening means that the study participant was, in the opinion of the 
investigator, at immediate risk of death from the reaction as it occurred) 
3. Inpatient hospitalization or prolongation of existing hospitalization 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life function. 
5. Important medical event that may not result in one of the above outcomes, but may jeopardize the 
health of the study participant or require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition of SAE. 
 
Participants in these studies will likely have pre-existing medical conditions, those pre-existing conditions will not 
be reported as adverse events. New events or the worsening through frequency or intensity of pre-existing 
conditions will be reported as adverse events within the context of the study. 
 
Elicitation of Adverse Events and Serious Adverse Events 
AEs and SAEs may be discovered through any of these methods: 
• 
Observing the participant by the research team 
• 
Observing the participant by the NICU team caring for the baby (which will be done in an objective 
manner)  
• 
Questioning the participant’s parent or legal guardian (which will be done in an objective manner) 
• 
Receiving an unsolicited complaint from the NICU medical team and/or participant’s parent or legal 
guardian 
• 
Reviewing of medical records/source documents 
 
The PI and study staff will review all data collection forms on an ongoing basis for data completeness and accuracy 
as well as protocol compliance. It is anticipated that data verification will be performed by someone other than the 
individual originally collecting the data, or by double-data entry. A statement reflecting the results of the ongoing 
data review will be incorporated into the Annual Report for the Independent Monitor 
 
Reportable AEs and SAEs will be documented on the Adverse Event Form first and will be recorded within the 
participant’s records. Source documents, including copies of electronic medical records may be attached to the 
record when requested. Only the participant’s study ID will be provided on source documentation, all other protected 
health information (PHI) must be redacted prior to report submission. 
 
Assessment of Severity: 
The PI will review all adverse events for seriousness (AE or SAE), severity (e.g. Grade 1-3) and causality during 
review of medical records, and will consult with other research personnel as needed. The investigator will document 
(signature/date) an assignment of severity (e.g., Grade 1-3) and make the initial determination of the causality of 
the event to the study intervention/procedures. The investigator may not delegate someone other than a clinician 
licensed to make diagnoses to this responsibility. The results will be submitted to the DSMB for review, verification 
and taking appropriate action as needed.  
 
Guidelines for Assessing Severity of an Adverse Event 
The PI/DSMBwill use the following definitions when assessing severity of an Adverse Event: 
• 
Grade-1/ MILD: Participant has minor findings, but tolerates them well and no or minimal intervention 
is required 
• 
Grade-2 / MODERATE: Participant experiences enough symptoms or findings to require intervention 
• 
Grade-3 / SEVERE: Participant experiences symptoms or findings that require significant intervention 
 
Guidelines for Determining Causality of an Adverse Event 

Study #:  i20-00876 
 
 
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The PI/DSMB will use the following question when assessing causality of an adverse event to the study 
product/intervention: Is there a reasonable possibility that the study product/intervention caused the event? 
“Reasonable possibility” means that there is evidence to suggest a causal relationship between the study 
intervention/procedures and the adverse event. An affirmative answer designates the event as a suspected adverse 
reaction.  
 
 
SAE Reporting and Management Procedures 
• 
Study staff will be trained to extract, evaluate, and report adverse events according to the protocol requirements 
and under the direct supervision of the PI. Unexpected, serious, and intervention-related serious adverse events 
(SAEs) will be reported to the DSMB, NYU IRB, and NIH immediately. Any adverse events, breaks of 
confidentiality, or any other data or safety issues that arise will be immediately brought to the attention of the 
NYU- IRB. All events will be reported within 24 hours of having received notice of the event. Dr. Kamity and Dr. 
Dumpa will be responsible for completing an Adverse Events Form should an event occur.  
 
• 
The following information will be reported for each event and must be reviewed by the investigator or designee: 
1) description of the event, 2) start date, 3) stop date, 4) severity of the event, 5) causal relationship to study 
product/intervention, 6) seriousness, 7) outcome of the event, and 8) if action with study product/intervention 
was required. 
 
• 
Drs. Hanna, Dumpa and Kamity will collaboratively gather any information needed to investigate the event and 
to determine subsequent action. Any subsequent action will be documented and reported to the NYU IRB and 
the Program Officer at NICHD. Adverse event reports will be reported in the annual continuing review report to 
the NYU IRB to ensure participant safety. Procedures to protect patient confidentiality and systems to ensure 
secure file transfer of sensitive data will be in place. 
 
Study Halting/Termination: 
 
The study will stop immediately if any of the following is to occur: 
1- Any Serious Adverse Events (SAEs), as detailed in the Data and Safety Monitoring Plan, will result in the 
immediate stopping of the study. The SAE will be reported immediately (within 48 hours) to the Data Safety 
Monitoring Board (DSMB) and the NIH program officer responsible for the study. Any death will requires 
expedited reporting (within 24 hours of study’s knowledge of death). No further enrollment will be allowed 
until the DSMB determines that this event was unrelated to the study procedures.  
2- Frequent AEs as a result of cold milk feeding that deemed to be excessive by the PI or the DSMB will trigger 
study halting. No further enrollment will be allowed until the DSMB determines that these events were 
unrelated to the study procedures. 
3-  The decision by the DSMB to halt the study at any time point at their discretion. Any action resulting in a 
temporary or permanent suspension of the clinical study will be reported to the NIH Program Official 
responsible for the grant. During the funding of this study, any action by the FDA (if applicable), NYU IRB 
or one of the study investigators that results in a temporary or permanent suspension of the study will be 
reported to the NIH Program Official immediately. 
 
Research Use of Stored Human Samples, Specimens, or Data 
 
Intended Use:  
Data collected under this protocol may be used to study efficacy and safety of cold liquid feedings. Human samples 
and/or specimens will  not be obtained. 
 
Storage:  
Data will be stored using codes assigned by the investigators. Data will be kept in REDCap.. Only investigators will 
have access to the data. 

Study #:  i20-00876 
 
 
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Data Handling and Record Keeping 
Once the data is collected on the data collection sheet, they will be immediately assigned a unique identifier. No 
link between this identifier and patient information will be made. No protected information or patient identifiers will 
be collected either. The data collected will be entered into RedCap within 2 days of collection. The original copies 
of the consent will be kept in a locked file cabinet. Consent forms will be kept in a secure location for up to six years 
in accordance with institutional policies. 
 
Future Use of Stored Specimens 
There will be no collected biospecimens to be stored.  
 
Study Finances 
 
Funding Source 
NIH R21 Grant  
 
Costs to the Participant 
None 
 
Participant Reimbursements or Payments 
None  
 
DISSEMINATION PLAN FOR CLINICAL TRIAL: 
This clinical trial does not meet the criteria for an “applicable clinical trial” since this study does not involve the use 
of any drug, biological or device products. The Principal investigator (PI) will assume the role of the responsible 
party and will ensure compliance to the NIH policy on dissemination of NIH-funded clinical trial information.  
 
Registering at ClinicalTrials.gov:  
This trial will be submitted for approval to the NYU- Langone Long Island Hospital University Hospital Institutional 
Review Board and no patient enrollment will occur without IRB prior approval. In accordance with the NIH policy 
on dissemination of NIH-funded research, this clinical trial will be registered at ClinicalTrials.gov not more than 21 
days of enrollment of the first study participant.  
 
Submitting results to ClinicalTrials.gov: 
The PI will be the responsible party to report the clinical trial information. Registration information including 
descriptive information, recruitment information, location and contact information of the study PI and 
administrative data will be submitted.  
The date of the last participant receiving an intervention will be reported as the primary completion date. In the 
event that the study enrollment is terminated prematurely, the study findings as well as reasons for early 
termination of the study will be made available on clinicaltrials.gov. All the results are submitted to 
clinicaltrials.gov within 12 months of primary completion date. 
 
Action 
Timeline 
1. 
Register on ClinicalTrials.gov 
Within 21 days of first patient enrollment 
2. 
Results information entered on ClinicalTrials.gov 
Within 12 months of primary completion date 
 
Making results publicly discoverable: 
The results of the study will be submitted to ClinicalTrials.gov for public posting, including inconclusive results that 
do not amount to a publication, thus ensuring that the research findings are publicly available. The results 
information reported will include participant baseline characteristics, outcomes and statistical analyses, the 
protocol and statistical analysis plan, and administrative information. Adverse events pertaining to the study 
interventions and protocol deviations will also be submitted to ClinicalTrials.gov.  In addition, all manuscripts 
published will be made publicly available on Pubmed Central.  
 
Informed consent:  

Study #:  i20-00876 
 
 
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We will include a specific statement in the informed consent documents about posting of the clinical trial 
information at Clinical Trials.gov. This information will be discussed with the study participants prior to obtaining 
consent for study enrollment. 
 
Monitor and manage data quality: 
We will conduct internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. The study staff will participate in a start-up meeting during which time the protocol will 
be reviewed and discussed and formal training will occur with regard to the assessments, rating scales being 
used, procedures for data entry and management.  
 
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