Pathophysiology of the Aerodigestive Reflex in Infants: GERD Management Trial
Phase: NA
Conditions: Gastroesophageal Reflux Disease
Sponsor: Sudarshan Jadcherla

Cover Page 
 
We are submitting the protocol and statistical methods for the below study: 
 
 
Identifiers: NCT02486263    
Unique Protocol ID: 11-00734    
Secondary IDs: R01DK068158   
 
Brief Title: 
Neonatal Gastro-Esophageal Reflux Disease (GERD) Management Trial (GMT)  
 
This includes the manuscript published in Pediatric Research with a copy of the IRB protocol 
included. 
The date of the most recent IRB protocol with all revisions listed is 6/6/2019. 
 
Sincerely, 
 
 
 
SUDARSHAN R. JADCHERLA, MD, FRCP (Irel), DCH, AGAF 
Professor of Pediatrics & Associate Division Chief of Neonatology, Academics 
Divisions of Neonatology, Pediatric Gastroenterology and Nutrition 
Director, The Neonatal and Infant Feeding Disorders Program 
Director, Neonatal Aerodigestive Pulmonary Research Program 
Principal Investigator, Innovative Feeding Disorders Research Program 
Center for Perinatal Research, WB 5211 
The Research Institute at Nationwide Children’s Hospital 
575 Children’s Cross Roads 
Columbus, OH 43215, USA 
Phone: 614-355-6643 
Fax: 614-355-5899 
E-Mail: Sudarshan.Jadcherla@nationwidechildrens.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

TITLE: Role of Feeding Strategy Bundle with Acid-Suppressive Therapy in Infants with 
Esophageal Acid Reflux Exposure: A Randomized Controlled Trial 
RUNNING TITLE: Infant GERD Management and Therapy Trial 
AUTHORS: *Sudarshan R. Jadcherla1-5; Kathryn A. Hasenstab1,2; Lai Wei6; Erika K. Osborn1,2; 
Sreekanth Viswanathan1-4; Ish K. Gulati1-4; Jonathan L. Slaughter2,3,4,7; Carlo Di Lorenzo4,5 
AUTHOR AFFILIATIONS: 
1Innovative Infant Feeding Disorders Research Program, 
Nationwide Children’s Hospital, Columbus, OH; 2Center for Perinatal Research, Abigail Wexner 
Research Institute at Nationwide Children’s Hospital, Columbus, OH; 3Division of Neonatology, 
Nationwide Children’s Hospital, Columbus, OH; 4Department of Pediatrics, College of Medicine, 
The Ohio State University College of Medicine, Columbus, OH; 5Division Pediatric 
Gastroenterology, Hepatology and Nutrition; Department of Pediatrics, Nationwide Children’s 
Hospital, Columbus, OH; 6Center for Biostatistics, Department of Biomedical Informatics, The 
Ohio State University College of Medicine, Columbus, OH; 7Division of Epidemiology, College 
of Public Health, The Ohio State University, Columbus, OH 
CORRESPONDING AUTHOR: Sudarshan R. Jadcherla, 575 Children’s Crossroads, Columbus, 
OH 43215 [Sudarshan.Jadcherla@nationwidechildrens.org], 614-355-6643  
STATEMENT OF FINANCIAL SUPPORT: Supported by the National Institutes of Health 
(RO1 DK 068158 [to SRJ]) and the National Center for Advancing Translational Sciences 
(UL1TR002733 [to The Ohio State University Center for Clinical and Translational Science for 
REDCap support]).  
DISCLOSURE STATEMENT: The authors have no disclosures (financial, professional, or 
personal) to declare. 
CATEGORY OF STUDY: Clinical Research 

AUTHOR CONTRIBUTIONS: Dr. Sudarshan R. Jadcherla obtained funding, conceptualized 
and designed the study, performed procedures and data acquisition, supervised data analysis, 
interpreted data, drafted the initial manuscript, and reviewed and revised the manuscript. Ms. 
Kathryn A. Hasenstab performed data acquisition, analysis, and interpretation of data, drafted the 
initial manuscript, and reviewed and revised the manuscript. Dr. Lai Wei designed the study, 
performed statistical analysis, interpreted data, and reviewed and revised the manuscript. Ms. Erika 
K. Osborn performed data acquisition, analysis, and interpretation of data, and reviewed and 
revised the manuscript. Drs. Sreekanth Viswanathan and Ish K. Gulati performed procedures and 
data acquisition, interpretation of data, and reviewed and revised the manuscript. Drs. Jonathan L. 
Slaughter and Carlo Di Lorenzo provided additional intellectual input, interpreted data, and 
reviewed and revised the manuscript. All authors approved the final manuscript as submitted and 
agree to be accountable for all aspects of the work. 
 
 
 

KEY POINTS 
 Conservative feeding therapies are thought to modify GERD symptoms and its consequences. 
However, in this randomized controlled trial in convalescing neonatal ICU infants with GERD 
symptoms, when controlling for preterm or full-term birth and severity of esophageal acid 
reflux index, the effectiveness of acid suppression plus a feeding modification bundle (volume 
restriction, intra- and post- prandial body positions, and prolonged feeding periods) vs. acid 
suppression alone, administered over a 4-week period was not superior in improving symptom 
scores or feeding outcomes.   
 Restrictive feeding strategies are of no impact in modifying GERD symptoms or clinically 
meaningful outcomes. Further studies are needed to define true GERD and to identify effective 
therapies in modifying pathophysiology and outcomes.   
 The improvement in symptoms and feeding outcomes over time irrespective of feeding 
modifications may suggest a maturational effect. This study justifies the use of placebo 
controlled randomized clinical trial among NICU infants with objectively defined GERD.   
 
 

ABSTRACT 
OBJECTIVE: To test the hypothesis that a feeding-bundle concurrent with acid-suppression is 
superior to acid-suppression alone in improving gastroesophageal reflux disease (GERD) 
attributed-symptom scores and feeding outcomes in neonatal ICU infants.    
METHODS: Infants (N=76) between 34-60 weeks’ postmenstrual age with acid reflux index>3% 
were randomly allocated to study (acid suppressive therapy + feeding bundle) or conventional 
(acid suppressive therapy only) arms for 4 weeks. Feeding bundle included: total fluid volume 
<140 ml/kg/day, fed over 30 min in right lateral position, and supine postprandial position. Primary 
outcome was independent oral feeding and/or ≥6-point decrease in symptom score (I-GERQ-R). 
Secondary outcomes included growth (weight, length, head circumference), length of hospital stay 
(LOHS, days), airway (oxygen at discharge), and developmental (Bayley scores) milestones. 
RESULTS: Of 688 screened: 76 infants were randomized and used for the primary outcome as 
intent-to-treat, and secondary outcomes analyzed for 72 infants (N=35 conventional, N=37 study). 
For study vs conventional groups, respectively: a) 33%(95% CI, 19%-49%) vs 44%(95% CI, 28%-
62%), p=0.28 achieved primary outcome success, and b) secondary outcomes did not significantly 
differ (p>0.05).  
CONCLUSIONS: Feeding strategy modifications concurrent with acid suppression are not 
superior to PPI alone in improving GERD symptoms or discharge feeding, short-term and long-
term outcomes.  
 
 

INTRODUCTION 
Differentiating gastroesophageal reflux (physiological, GER) from GER disease 
(pathological, GERD) remains a challenge in ICU infants (1-5).  Troublesome symptoms (6) often 
trigger a battery of empiric therapies, such as acid-suppression, feeding modifications, and 
positional changes (7-10).  Prevalence of GERD ranges from 2–30% across neonatal intensive care 
unit(NICU)s in the United States, along with a 13-fold variation in therapies, imposing an 
additional economic burden of over $70K per admission and 30 hospital days (9-13).  
The infant GER questionnaire-revised (I-GERQ-R) is a survey of parental/provider 
perception of symptom burden thought to be due to GERD, with a 6 point decrease indicating 
clinical improvement (14). Although, prior clinical trials for GERD pharmacotherapy have used 
symptom-based criteria (15-18), few have evaluated the effectiveness of a bundled holistic 
approach, i.e., a combination of pharmacologic-, feeding-, and positional approaches in NICU 
patients. Improvement of parental perception of symptoms and total GER events with left lateral 
position and proton pump inhibitor (PPI) (8), reduction of GER events with infants in  prone or 
left lateral post-prandially (19), and conservative strategies for 2 weeks showed improvement with 
I-GERQ-R scores among one to ten months age (20). We observed that decreased feeding volume 
and prolonged feeding duration were associated with reduced GER events (21). However, a 
bundled approach combining targeted acid suppression (limited duration), feeding modifications 
(volume, position, duration) and postprandial positions has not been rigorously examined in infants 
with proven esophageal acid reflux index (ARI) severity.    
Based on this rationale, we have undertaken this clinical trial to determine the effective 
therapeutic strategies on the clinically meaningful primary outcomes in infants presenting with 
GERD symptoms who have qualifying ARI criteria. The objective of this RCT was to examine the 

short- and long-term clinical outcomes among infants treated concurrently over 4 weeks with PPI 
with randomly assigned feeding strategy modifications while controlling for gestational maturity 
(pre-term or full-term at birth) and severity of esophageal ARI (3-7%, >7%). Our hypothesis was 
that the study approach (acid suppression, modified feeding volume, duration, and position) was 
superior in achieving independent oral feeding or a 6-point reduction in I-GERQ-R vs the 
conventional (acid suppression alone) feeding approach. 
PATIENTS AND METHODS  
STUDY DESIGN AND EXPERIMENTAL PROTOCOL  
This is a single center, single blinded RCT (Clinicaltrials.gov: NCT02486263) comparing 
the effectiveness of two feeding strategies combined with the use of a PPI (omeprazole) to manage 
acid-GERD [GERD Management and Therapy trial (GMT trial)]. This study was approved by the 
Institutional Research Board (IRB) at Nationwide Children’s Hospital, Columbus, OH (IRB # 11-
00734).  Omeprazole is commonly used off-label in this population within the standard of care (9). 
Data safety monitoring plan was implemented and monitored quarterly by the Data Safety 
Monitoring Board (DSMB). Written, signed, and informed parental consent was obtained. Health 
Insurance Portability & Accountability was followed. Study PI and RN coordinator were available 
24/7.   
Twenty-four-hour pH-impedance studies were performed (6, 22, 23) (Laborie Medical 
Technologies, Mississauga, ON, Canada). ARI (duration of esophageal acid exposure, %) was 
calculated (24). I-GERQ-R symptom score (14, 17, 25) was collected.  Demographic and clinical 
outcomes were managed using research electronic data capture tools (REDCap) tools (26) for up 
to 2 years from subject enrollment.    
PARTICIPANT SELECTION, RANDOMIZATION AND ALLOCATION 

Inclusion criteria were: a) infants admitted with clinical symptoms of GERD between 34-
60 weeks postmenstrual age, with physician’s intent to treat with acid-suppressive therapy, b) an 
intake volume of full enteral feeds ≥150 mL/kg/day, c) room air or supplemental oxygen ≤1 liter 
per minute, and d) ARI ≥3% (6, 22-24). Exclusion criteria were: a) infants with known genetic, 
metabolic or syndromic diseases; b) neurological diseases including ≥ grade III intraventricular 
hemorrhage or perinatal asphyxia, c) GI malformations or surgical GI conditions, and d) infants 
on acid suppressive medication at initial evaluation. Randomization was performed among 
consented subjects who were stratified 1:1 ratio by ARI severity (3%-7%: indeterminate acid 
reflux and >7%: severe acid reflux) and by birth gestation (preterm, full term) into study feeding 
approach or conventional approach. Permuted Block Randomization with block sizes of 2, 4, 6, 
and 8 was undertaken by the study statistician (OSU Center for Biostatistics) using a computer-
generated allocation and implemented in REDCap. Nurse coordinator enrolled subjects by 
verifying eligibility, obtaining parental consent, and entering demographic data into REDCap. PI 
and study staff who evaluated subject clinical outcomes were blinded to study allocation.   
STUDY INTERVENTIONS 
Interventions 
Providers employ uniform feeding and nutritional practices in our NICU infants as per our 
standardized guidelines, which applies to nutrient and volume modifications. However, upon 
randomization and allocation, individual protocols are complied with. Upon completion of 
screening, enrollment and randomization, the assigned feeding management strategy was relayed 
to parents and the medical team. Subjects in both arms received omeprazole off label, as a 
therapeutic choice (27, 28) at a recommended dose of 0.75 mg/kg/dose BID (15, 27, 29).   The 
conventional approach was to not adjust provider recommended feeding strategies (i.e. fed in any 

position, duration, volume, and postprandial position). The study approach utilized a modified 
feeding strategy including: a) feeding in the right lateral position to facilitate intra-prandial gastric 
emptying (30), b) feeding duration of at least 30 min utilizing pacing when orally fed to ensure 
completion of prescribed volumes or via pump to ensure steady delivery of milk if gavage-fed 
(21), c) supine postprandial position (31), and d) limiting total feeding volume to ≤140 ml/kg/day 
(21).  
OUTCOME MEASURES 
The a priori primary end-point was achieving independent oral feeds and/or a six-point 
decrease in I-GERQ-R score at 5 weeks or sooner, whichever was earliest at discharge. To clarify 
further, there were 2 scenarios: 1) Among infants who were transitioning to oral feeds (gavage 
fed) at inception: success was defined as achieving full oral feeds or a >6-point decrease from 
baseline I-GERQ-R. 2) Among infants who were on full oral feeds at inception, success was 
determined if full oral feeds were maintained plus a ≥ 6-points decrease from baseline I-GERQ-R. 
Secondary end-points included growth metrics (weight, length and head circumference), 
supplemental oxygen, economic metrics (LOHS), long-term feeding outcomes at 6 months and 1 
year, and developmental outcomes at 2 years (32, 33).    
STUDY OVERSIGHT 
Compliance to protocol and Data Integrity were maintained. Patient care data were stored 
and secured. Study recruitment criteria were reported to DSMB quarterly and IRB annually. 
Compliance measurements were documented as intake volumes, feeding durations, feeding 
positions, postprandial positions and symptom scores, growth metrics and nutritional status. 
Compliance to administration of omeprazole was confirmed using electronic medical records 

(Epic, Epic Systems Corporation, Verona, WI, USA) and or parental validation. Trial protocol and 
important changes to methods after trial commencement are listed in Supplement 1. 
STATISTICAL METHODS  
Based on our preliminary data, we had planned to enroll 100 patients (50 per group) to 
detect 27% or higher increase in proportion of success of study group compared to the conventional 
group with 80% power and overall one-sided α level of 0.025. One interim futility analysis was 
planned at about 50% information prior to the final analysis at 100% information, corresponding 
to 50 and 100 evaluable patients, respectively. The boundary was determined using Lan-DeMets 
spending functions to simulate O’Brein-Fleming boundaries(34). Using the target proportion of 
success, the boundary at the futility analysis was p>0.297.  
Seventy-six infants were randomly assigned till the end of funding for this study and were 
included in the analysis of demographics and clinical characteristics (Fig 1, Table 1) and primary 
outcome by intent-to-treat. If a patient dropped out before the end of study and no symptom score 
was evaluable, we treated the patient as a failure for the primary outcome by intention-to-treat.  
Secondary outcome analysis was performed for 72 subjects (Fig 1). Futility boundary was not 
reached at interim analysis of 50 patients (p=0.1 < 0.297) and accrual was continued with DSMB 
approval. Summary statistics were calculated for patient demographics and clinical characteristics 
for final analysis. Success rate in achieving PO or reduction in the I-GERQ-R by 6-points was 
calculated with 95% confidence interval and compared using chi-square test between the 
conventional and study groups (primary outcomes) for the intention-to-treat and treat-as-treated 
analyses. Fisher’s exact or chi-square test were used to compare other categorical secondary 
outcomes including feeding method and supplemental oxygen between the groups. Shapiro-Wilk 
test for normality was used for the continuous outcomes. Paired t-tests or Wilcoxon singed-rank 

tests were used to assess changes in growth velocity and feeding therapy characteristics between 
time-1 and time-2. Two sample t-tests or Wilcoxon rank-sum tests were used to compare these 
continuous outcomes between conventional and study groups. Median (interquartile range [IQR]), 
mean (SD), or % was reported, unless stated otherwise. P values <0.05 were considered 
statistically significant, and SAS version 9.4 (SAS, Inc, an IBM Company, Chicago, IL) was used.  
RESULTS 
Participant Characteristics 
Screening, recruitment and follow-up of subjects occurred between August 2012 to 
October 2018, and data was locked May 2019. Recruitment ended to allow for clinical outcome 
analysis. From the 688 infants assessed for eligibility, ARI was: normal (<3%) in 246 (36%), 
indeterminate (3-7%) in 169 (25%), and abnormal (>7%) in 273 (40%). Study enrollment, 
randomization, and primary outcome analysis are described in the CONSORT diagram (Fig 1). 
Demographic and clinical characteristics at allocation were not significantly different in both 
groups (Table 1). Frequency (%) of GERD referral reasons were for respiratory concerns 
(apnea/bradycardia/desaturation, airway management, or suspected aspiration) in 54%, feeding 
concerns (poor oral feeding or intolerance) in 47%, and GERD type symptoms (arching/irritability 
or emesis) in 25% (note proportions do not add to 100 due to providers being able to list multiple 
reasons for referral). Reasons for referral did not differ between conventional and study groups 
(all P>0.05). Proportion of milk types (exclusive breast milk: exclusive formula: combination of 
formula and breast milk, %) were not different between groups: 19: 67: 14 in conventional vs 18: 
53: 3 in study groups (P=0.24). Of those formula fed (28 in conventional group, and 29 in study 
group) proportion of formula types (hydrolyzed: gentle: low lactose: preterm: standard, %) were: 
4:7:4:75:10 in conventional vs 10:10:0:69:10 in study groups (P=0.84). Caloric density ranged 

from 19 cal/oz to 30 cal/oz, and the proportions (%) (19: 20: 22: 24: 27: 30 cal/oz) for conventional 
(11: 31: 33: 19: 6) and study groups (8: 20: 30: 35: 3) did not differ (P = 0.47). Breast milk intake 
in both groups was 40% at inception (P=1.0), and the caloric density (cal/oz) for the conventional 
vs. study groups was 24 [22-25] and 24 [22-27] respectively (P=0.41) For conventional and study 
groups respectively, acid suppressive dose (mg/kg/dose BID) was 0.75 [0.75 – 0.75] vs 0.75 [0.75 
– 0.75], p=0.27 upon initial dose, and 0.75 [0.75 – 1.0] vs 1.0 [0.75 – 1.0], p=0.09 at follow-up. 
STUDY OUTCOMES  
Primary and Secondary Clinical Outcomes 
The clinically meaningful primary and secondary outcomes did not differ significantly between 
groups (Table 2). I-GERQ-R scores for study and conventional groups are shown (Fig 2).  At 
inception: positive I-GERQ-R was 19/35 (54%) in the conventional group vs 24/37 (65%) in the 
study group, p=0.36. At Time-2: positive I-GERQ-R prevalence was 9/31 (29%) in the 
conventional group vs 13/34 (38%) in the study group, p=0.43. In the study group vs conventional 
group, respectively: a) primary outcome achieved in 33% (95% CI, 19% - 49%) vs 44% (95% CI, 
28% - 62%) (p=0.28),  b) secondary outcomes: independent oral feeding in 65% (95% CI, 48% - 
80%) vs 77% (95% CI, 60% - 90%), p=0.26, ≥6-point I-GERQ-R decrease in 38% (95% CI, 22% 
- 56%) vs 35% (95% CI, 19% - 55%), p=0.82, length of stay was 98 [81-132] days vs 108 [83-
125] days, p=0.89, and oxygen requirement at discharge in 19% (95% CI, 8% - 35%) vs 26% (95% 
CI, 13% - 43%), p=0.49. There were no significant differences in growth metrics (all p>0.05) or 
developmental scores at 2 years (all p>0.05). Feeding outcomes or I-GERQ-R scores did not 
significantly differ between conventional vs study groups based on feeding method at inception 
(Table 3).   Individual I-GERQ-R questions relating to vomiting, regurgitation, and crying (i.e. 
frequency of emesis, volume of emesis, symptoms with emesis, and crying more than usual in the 

past week) had no differences (P>0.05) within the group or between the groups across maturation 
for these individual symptoms, except for symptoms with emesis (never: rarely: sometimes: often: 
always, %) was 16:16:42:19:6 for conventional group at Time-1 vs 18:18:29:0:35 for study group 
at Time-1, p < 0.01. 
Compliance measures, side effects and adverse events 
Compliance to randomization, allocation and interventions, and drop outs are reported (Fig 
1, Table 2). Total fluid volume was identical at inception but both groups showed a reduction 
compared to baseline at time-2. However, as per the trial design, the study group showed 
significantly (all p < 0.05) lower volume intake, feeding in right side lying position, and 
postprandial supine position. Feeding duration of actual feeding was increased in the study group 
but not statistically different from the conventional group. No side effects or adverse events were 
reported in either group.  
DISCUSSION  
In this RCT, while controlling for birth gestation and severity of acidity, we compared the 
effectiveness of acid suppression with or without a systematic feeding modification bundle in 
modifying feeding outcomes and I-GERQ-R scores. We found no differences in our a priori 
primary outcome or pre-assigned secondary outcomes. Important clinical and research 
implications can be noted despite the non-superiority of the feeding bundle. 
Diagnostic conundrums and management issues with GERD in the NICU setting persist. 
Prior studies (8, 19, 20) used perceived clinical symptoms  as a basis for acid-suppression, but 
studies have shown lack of benefit on symptom improvement (35, 36). Recent work by us (6, 21, 
22), suggests that such symptoms are often due to pharyngo-esophageal provocation or cross-
systems activation of reflexes, and can occur during non-acid events or swallowing events, or 

during transient relaxation of lower esophageal sphincter (30). However, the inability to handle 
the refluxate determines the ‘troublesomeness of the symptoms’ rather than the esophageal acid 
exposure.   Clinical practice varies when pathophysiological reasoning is not commonly applied. 
Clinical practices can have unintended consequences (1, 37-40) resulting from acid suppression, 
undernutrition, delays with feeding milestones, decisional conflicts, discharge outcomes and 
prolonged hospitalization, all of which can escalate burden (9, 27).  
Salient features of our study include: 1) Allocations were unbiased and appropriately 
distributed between groups. 2) Among those presenting with GERD symptoms at inception, about 
36% of infants had normal esophageal acid exposure, while 40% had abnormal acid exposure, and 
the rest in the indeterminate range. 3) The study bundle was not superior to acid suppression alone 
in improving primary outcomes or secondary outcomes. 4) Restricted feeding volume, body 
positions (intra- and post-prandial), oral or gavage feeding methods, supplemental oxygen, birth 
gestation and postnatal maturation did not influence the primary or secondary outcomes. 5) 
Reliability of compliance among those discharged was based on parental trust and available 
information. 6) There were no reported adverse events. No differences in long term developmental 
outcomes or economic burden measures, such as, LOHS, feeding methods and respiratory support 
at discharge were noted. 7) Symptom scores (I-GERQ-R) were significantly lower in both groups, 
suggesting that maturation may play a role in symptom modification, and not the bundled 
approaches. 8) Feeding outcomes improved in both groups.  
GMT Trial strengths and clinical implications are several: 1) Random allocation, study 
design and protocol adherence were robust and rigorous. Although our strict inclusion criteria may 
have led to lower eligibility, our approach resulted in identifying infants carefully with true ARI 
as a marker of esophageal acid exposure.  Objective determination of GERD based on ARI >7% 

is justifiable in future trials, as nearly 40% of infants are in this severe range, and it is possible to 
study such a group in larger clinical trials based on pH and impedance criteria, while employing 
placebo for equipoise. Since time-limited PPI therapy concurrent with feeding strategies was 
neither shown to be beneficial or associated with adverse effects, we believe that, it is safe to 
include a completely untreated placebo group in future trials that enroll patients with objectively 
determined acid-GERD. 2) The management strategies were tightly regulated, as were feeding and 
testing guidelines, and the treatment was uniformly delivered across the two groups. The patient 
population was homogeneous and constituted a fair representation from the convalescing NICU 
population. In addition, the randomized controlled allocation accounted for premature or full-term 
birth, and the indeterminate or determinate acid-GERD per ARI. Furthermore, the prevalence of 
oxygen requirement or tube feeding at discharge was not different between groups. 3) Our study 
trial has many elements of objectivity. Determination of I-GERQ-R and ARI, as well as monitoring 
feeding methods during the trial are strengths. Thirty-six percent of those with aerodigestive and 
or cardiorespiratory symptoms perceived by their clinicians to be due to GERD prior to trial 
consent, were not randomized and were also never treated with a PPI as the esophageal acid 
exposure was normal (ARI < 3%).  In a purely symptom-based clinical trial, all those 688 infants 
screened would have likely been treated for presumed GERD. In the current study, only those that 
had true ARI exposure have been randomized and treated. Therefore, the symptom-based approach 
alone is not the solution to diagnose and treat GERD. Interestingly, perception of symptoms 
(IGERQR scores) decreased across time regardless of treatment group allocations (Fig 2). These 
findings strongly support maturational effect. As both groups were treated with PPI, placebo-
included RCTs are needed to determine if maturation alone will improve objectively determined 
acid- and non-acid-GERD.  4) Absence of pH-impedance testing to confirm true acid-GERD prior 

to randomization would have resulted in all patients being treated based on subjective, non-specific 
symptoms alone. Owing to the strict inclusion and exclusion criteria of this RCT, those with 
indeterminate and abnormal ARI were treated with a PPI. In the future, a careful RCT that tests 
the utility of PPI treatment for confirmed acid-GERD by allocating patients to either limited PPI 
treatment or placebo is indicated to determine whether PPI treatment is needed. The effectiveness 
of our short-term use of PPI for 4 weeks to improve GERD-attributable symptoms should be tested 
in future trials. Effect of esophageal acid exposure and therapies on primary mechanistic outcomes 
of esophageal motility and symptom causation will be addressed in future reports.  5) In routine 
clinical practice, feeding volumes are modified and alterations in feeding positions are used to 
manage symptoms. Our study did not show any differences in the outcomes with feeding- and 
position modifications. Furthermore, volume restriction had no influence on the study outcomes. 
The improvement in symptoms and feeding outcomes over time irrespective of PPI or feeding 
modifications may suggest a maturational effect.  
It is important to note that major mechanisms of GER, i.e. transient LES relaxation is the 
major reason for any reflux events- both acid or non-acid substrate. Our therapeutic target was acid 
reflux index in this study via PPI, feeding volumes, and positional changes. Given that acid GER 
can also have weakly or non-acid either before or after PPI therapy, and that there were no 
differences in outcomes between the two groups, we speculate that neither PPI, feeding volume, 
or positional changes modify the studied indices or symptoms. Maturation under optimal 
conditions of good nutrition along with placebo-controlled trials are needed to answer the 
importance of weakly acid or non-acid GER, which would require a multicenter trial with a large 
group of infants with appropriate physiologic diagnostic testing. 

 
Our study has limitations. 1) Parental and physician biases appeared to be a barrier to 
recruitment. Recruitment was slow despite the high prevalence of GERD-associated symptoms 
and a high eligibility rate. This is concerning, as many parents refused clinical trial participation.  
Many infants did not have true acid-GERD, and fluid restriction often occurred before testing. 
Interestingly, in some cases, parents and providers did not want to stop the PPI use. These barriers 
to recruitment can be mitigated in future larger trials with better parent-provider education, as no 
major effects on the primary or secondary outcomes were noted in our study with or without our 
allocated bundled GERD treatment. 2) Owing to the higher screening to eligibility ratio, rigorous 
inclusion criteria, and strict study protocols, we could not complete the recruitment as originally 
planned of 100 evaluable patients. Seventy-six infants were randomly assigned during the funding 
period. However, using this cumulative sample size of 72 patients for interim monitoring, we found 
that we would stop for futility at this time point even if the funding period was not ended. 3) Further 
studies are needed to correlate parental/provider perception of symptoms (I-GERQ-R) with true 
symptoms and symptom indices examined during pH-impedance testing.  Such studies should also 
address the severity of acid exposure index in relation to changes in symptom indices.   
CONCLUSION 
We addressed the current practice controversies in this clinical trial: 1) Screening and 
identifying acid-GERD objectively is possible in symptomatic infants prior to any 
pharmacotherapy. 2) Feeding strategy modification (fluid restriction, positional changes, 
prolonged feeding duration) has no role in decreasing reflux-type symptoms or in improving the 
primary outcome of achieving independent oral feeds and/or a six-point decrease in I-GERQ-R 
score.  3) No difference in the prevalence of chronic lung disease was noted between the groups. 
4) I-GERQ-R scores decreased across time regardless of treatment group allocations that strongly 

support maturational effect.  However, we did not detect an effect on a priori short-term or long-
term outcomes following randomized allocations. As restrictive feeding strategies do not make a 
difference, placebo-controlled clinical trials in a larger cohort of convalescing NICU infants with 
objectively determined newer GERD criteria must be addressed in future trials. 
 

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gastroesophageal reflux and gastric acidity in preterm infants with pathological acid 
reflux. J Pediatr Gastroenterol Nutr 44:41-44. 
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Pediatr 163:680-685 e681-683. 
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Neurodevelopmental Outcomes in Preterm Infants Referred for Gastrostomy Evaluation. 
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Biometrika 70:659-663. 
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Tighe M, et al. 2014 Pharmacological treatment of children with gastro-oesophageal 
reflux. Cochrane Database Syst Rev:CD008550. 
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irritability in infants: systematic review of randomized controlled trials. J Pediatr 
166:767-770.e763. 
37. 
Bell JC, et al. 2018 Acid suppressants for managing gastro-oesophageal reflux and 
gastro-oesophageal reflux disease in infants: a national survey. Arch Dis Child 103:660-
664. 
38. 
Malchodi L, et al. 2019 Early Acid Suppression Therapy Exposure and Fracture in 
Young Children. Pediatrics 144. 
39. 
Gold BD 2006 Is gastroesophageal reflux disease really a life-long disease: do babies 
who regurgitate grow up to be adults with GERD complications? Am J Gastroenterol 
101:641-644. 

40. 
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inhibitors: pharmacotherapy for gastroesophageal reflux in neonates. Clin Perinatol 
39:99-109. 
ACKNOWLEDGEMENTS: The authors would like to thank: 1) the infants and their parents 
who participated in this study 2) Rebecca Moore, MACPR, BSN, RN for clinical support, 3) the 
Data Safety Monitoring Board, IRB, and Audit departments at the Abigail Wexner Research 
Institute at Nationwide Children’s Hospital, Columbus, OH, USA.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

 

 
 
 

 
 
 
Figure 1. Study Enrollment and Randomization. Depicted is the CONSORT diagram 
describing participant flow and randomization into the conventional or study bundles, and subjects 
analyzed for outcomes. 
 
 

 
 
Figure 2. I-GERQ-R Outcomes. Depicted is a combination plot by group (boxplots) and 
individual I-GERQ-R scores (black line represents median). Note that parent perception scores (I-
GERQ-R) significantly decreased in both groups at Time-2.  
 
 
 
 
 
 
 

PROTOCOL TITLE: 
Pathophysiology of the Aerodigestive Reflex in Infants: GERD Management and Therapy Trial 
[GMT Trial] 
PRINCIPAL INVESTIGATOR: 
Name: Sudarshan Jadcherla, MD, FAAP, FRCP (Ireland) AGAF 
Department/Center: Center for Perinatal Research 
Telephone Number: (614) 655-6643 
Email Address: Sudarshan.Jadcherla@nationwidechildrens.org 
VERSION NUMBER/DATE: 
Version 9.0 6/6/2019 
Nationwide Children’s Hospital IRB REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
11/30/2012 
Because NICU infants have lower fluid 
prescriptions in general, revised allowable total 
fluid volume from ≥170 ml/kg/day to ≥150 
ml/kg/day at inception to be eligible for screening 
No 
2 
2/15/2013 
Because convalescing NICU infants with lung 
disease can have varying supplemental oxygen 
requirements, revised allowable respiratory support 
from Room air or ≤0.3 LPM via nasal cannula to 
≤1.0 LPM or Room air at inception to be eligible 
for screening 
No 
3 
12/9/2013 
Because parents and providers did not permit 
stopping the PPI at 4 weeks for clinical reasons, 
allowed the subject to remain on medication at the 
follow up evaluation  
No 
4 
3/24/2014 
Allowed Practitioners to increase permissible study 
medication dose as clinically indicated  
No 
5  
7/29/14 
Added the use of swallowing motility 
measurements to the mechanistic study protocol 
Yes 
6 
9/19/2014 
Convalescing subjects with Neonatal Abstinence 
syndrome admitted to NICU have feeding 
difficulties masquerading as GERD symptoms.  
No 

Changed inclusion criteria to permit these infants to 
be screened for eligibility into the study 
7 
5/1/2015 
To examine sucking, swallowing and motility 
measures, sucking-swallowing rhythms were 
measured for the mechanistic study protocol  
Yes 
8 
1/12/2018 
Added reciprocity with The Ohio State University 
and included biostatistician, Wei Lai into the study 
staff 
yes 
 
1.0 Study Summary 
 
Study Title 
Pathophysiology of Aerodigestive Reflex in Infants: GERD 
Management Trial 
Study Design 
Single center randomized control trial 
Primary Objective 
To compare two feeding approaches and their effect on clinical 
outcomes in infants with proven Gastroesophageal Reflux Disease 
(GERD) 
Secondary Objective(s) 
To determine the pathophysiological mechanism of success or 
failure to either therapy, we will test the hypothesis and validate 
results from the preliminary data by utilizing our diagnostic tools 
to identify differences between the two study arms in regards to: 
aerodigestive reflexes, esophageal clearance mechanisms, 
neuromotor markers of swallowing, and pH-Impedance-symptom 
indices.  
 
  
Research 
Intervention(s)/ 
Investigational Agent(s)  
Both groups will have esophageal manometry studies followed by 
randomization into two groups, Conventional and Study. The 
conventional group allows for unrestricted feeding volumes with 
no time limit, feeds given in any positon and random post prandial 
feeding positions. The study group will have permissive feeding 
volume restrictions, feeding duration of at least 30 minutes, 
feeding given in right side lying, and supine post prandial position. 
Both groups will be treated with omeprazole per NCH NICU 
guidelines 

IND/IDE #  
N/A 
Study Population 
Infants admitted to the NICU at NCH and referred to the Neonatal 
and Infant Feeding Disorders program for evaluation of 
Gastroesophageal reflux Disease (GERD) 
Sample Size 
120 
Study Duration for 
individual participants 
5 weeks  
Study Specific 
Abbreviations/ 
Definitions  
GMT (GERD Management and Therapy Trial)  
RSL- right side lying  
ARI –Acid reflux index 
PMA= (Gestational age at birth + chronologic age) 
 
2.0 
Objectives 
 
2.1 Purpose, specific aims or objectives 
 Clinical trial based on objective evaluation of symptoms scored by blinded 
independent rater during pH-Impedance studies (Aim 1). 
 Investigates the neuro-physiological aspects of the reflexes involved with 
GERD and its complications (Aim 2).  
 Unique to this proposal, we will apply physiologically rational, and safe, 
therapeutic strategies that have the real potential to ameliorate GERD 
symptoms/complications. If the proposed aims are achieved, we 
anticipate: 
o 
Finding that not only acid, but also feeding volume, position and 
maturational changes in adaptation underlie the pathogenesis of 
GERD, and in this way clearly identifying relevant new therapeutic 
targets for this disease.  
o 
Understanding the various stimulus-targets and provoked reflexes that 
lead to sensitization of afferents, and thereby symptoms associated 
with GERD.  
o 
Understanding the mechanism(s) underlying functional esophageal 
disorders in infants, thereby clarifying the pathophysiology of 
symptoms presumed to be GERD related.  
o 
Development of cost effective, efficacious methods for the diagnosis 
and management of GERD in infants.  
o 
Establishing objective criteria for evaluating the need for anti-reflux 
surgical procedures in infants.  
 
 2.2 Hypothesis 

 Aim 1 
o The innovative feeding strategy provided over 4 wks is more 
effective than standard therapy for the acquisition of safe feeding 
skills by improved symptom scores (Primary), improved individual 
I-GERQ-R measures, growth measures, reduced lengths of stay 
and resource utilization (Secondary).  
 Aim 2 
o The sensory-motor characteristics of aerodigestive reflexes evoked 
with induced esophageal stimulation or upon spontaneous 
esophageal provocation as in GER, improve in the innovative 
therapy group with regards to: sensory thresholds, response latency 
and duration, frequency and magnitude of reflexes, TLESRs, 
spatial-temporal-physical- chemical characteristics of GER events 
with associated symptom indices.  
3.0 
Background 
 
3.1 Relevant prior experience and gaps in knowledge 
 
The NASPGHAN-2009 guidelines define GERD as reflux of gastric contents   in the 
presence of troublesome symptoms and/or complications.  The prevalence of GERD in 
premature infants is estimated to be 10.6 %. Premature infants have pathologic 
reflux with esophageal manifestations (e.g. irritability, feeding refusal, arching, 
dysphagia) and extra- esophageal manifestations (e.g. arousals, cardiorespiratory-, 
sensory-, and physical symptoms, chronic lung disease, impaired growth). Such high 
risk infants suffer chronic morbidity, longer hospitalizations, re- admissions, and account 
for an unacceptable health care burden. 
 
Current treatment approaches in infants are likely to fail because of lack of clear 
therapeutic targets. Furthermore, GERD symptoms are non-specific and heterogeneous 
such that designing effective approaches to symptom based management is very 
difficult.  
 
Exact economic burden of premature infant GERD is lacking. 12.7% (525,000) out of 
4,131,019 births in 2009 were born at < 37 wks. Assuming that half (263,000) of these 
infants are in NICUs, and given our estimated prevalence of GERD as 10.6% (27,900) 
and the estimated cost per admission attributable to GERD was $76,796; we project an 
estimated economic burden attributable to GERD as over $2.1 billion. Others have 
estimated that 48% of ICU discharges are treated for presumed GERD. Clinical 
significance of GERD is also evident from the 7-fold increase in the use of acid 
suppressive medications, and indeed about 45% of anti-reflux procedures are performed 
in infants (15). These numbers ignore the quality of life issues for both the patients and 
the parents. 
 
Extensive developments with the mechanisms, physiology, pharmacotherapy and clinical 
approach to GERD in the human adult, as well as therapeutic limitations in infants are 
well recognized Specifically for infants, there are no available safe or FDA-
approved prokinetics that regulate esophageal motility and suppress transient lower 
esophageal sphincter (LES) relaxations.    
 
3.2 Relevant Preliminary Data 

 
In an observational study in infants (N=35) referred for GERD management, we studied 
the impact of feeding methods (volumes, duration, flow rates, caloric density, 
osmolality) on pH-Impedance variables of GER. The conclusions were: longer feeding 
duration, less feeding volume, and slower flow rate led to less total GER events, fewer 
nonacid GER events and shorter bolus clearance time; whereas, caloric density and 
osmolality of feeds has no impact on the characteristics of GER. 
o Jadcherla  SR,  Chan  CY,  Moore  R,  Malkar  M,  Timan  CJ,  Valentine CJ  2011  
Impact  of  Feeding Strategies on the Frequency and Clearance of Acid and Nonacid 
Gastroesophageal Reflux events in dysphagic Neonates. JPEN J Parenter Enteral 
Nutr.  
o Malkar M, Chan CY, Peng J, Moore R, Jadcherla SR 2011 Effect of osmolality and 
caloric density of feeds on the frequency and characteristics of gastroesophageal 
reflux in infants. Neurogastroenterol Motil. 
 
The effect of right lateral position on accelerated gastric emptying has been described by 
others (107, 108, 114), and the effect of supine posture in the prevention of ALTEs or 
SIDS is recognized in the AAP guidelines. 
o 2003 Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 
111:914-917. 
o Omari TI, Rommel N, Staunton E, Lontis R, Goodchild L, Haslam RR, Dent J, 
Davidson GP 2004. Paradoxical impact of  body  positioning  on  gastroesophageal  
reflux  and  gastric  emptying  in  the premature neonate. J Pediatr 145:194-200. 
o Corvaglia L, Rotatori R, Ferlini M, Aceti A, Ancora G, Faldella G 2007 The effect 
of body positioning on gastroesophageal reflux in premature infants: evaluation by 
combined impedance and pH monitoring. J Pediatr 151:591-596, 596 e591. 
o Van Wijk MP, Benninga MA, Dent J, Lontis R, Goodchild L, McCall LM, Haslam 
R, Davidson GP, Omari T 2007 Effect of body position changes on postprandial 
gastroesophageal reflux and gastric emptying in the healthy premature neonate. J 
Pediatr 151:585-590, 590 e581-582. 
 
We  used  state-of-the-art  methods  including,  multimodal esophageal  sensory  
provocation  concurrent with  video,  pH-Impedance  and  symptom  indices  in  the 
investigation of sensory-motor aspects (sensory thresholds, reflex frequency, response 
latency, duration and magnitude) of Vago-vagal reflexes (Primary and Secondary 
Peristalsis, Upper esophageal sphincter contractile reflex-UESCR, Lower esophageal 
sphincter relaxation reflex-LESRR and Pharyngeal reflexive swallowing) that facilitate 
swallowing and esophageal clearance to maintain airway protection in neonates. Twelve 
pharyngo esophageal motility studies were done in 6 subjects, 3 in each group, at 
inception (test-1) and again at completion of therapy (test-2).  With innovative strategy, 
the response onset to esophageal stimulation induced LESRR is decreased at T2 in 
addition to a greater LES relaxation magnitude compared to T1; in contrast, response 
onset to LESRR and LESRR magnitude are similar at T1 and T2 for standard therapy. 
This finding supports the hypothesis that LES relaxation governed by inhibitory vagal 
effects mediated by nitrergic neurons is rapidly restored with innovative feeding 
strategy, similar to those changes tested during maturation. 
o Pena EM, Parks VN, Peng J, Fernandez SA, Di Lorenzo C, Shaker R, Jadcherla SR 
2010 Lower esophageal sphincter relaxation reflex kinetics: effects of peristaltic 
reflexes and maturation in human premature neonates. Am J Physiol Gastrointest 
Liver Physiol 299:G1386-1395. 
 
 
Clinical outcomes from 44 subjects that had reflux index >3% were measured; 24 infants 
had lower feeding volumes, longer feeding duration, greater compliance to supine 
postprandial posture (innovative feeding strategy); 20 infants had standard feeding 

therapy, all received acid suppressive therapy. This trial supported the hypothesis that 
the innovative feeding strategy is superior to standard feeding therapy. 
 
3.3 Statistical procedures 
 Statistical Analyses:  
o Aim I: Outcomes: We will test the hypothesis that the innovative feeding strategy 
provided over 4 wks is more effective than standard therapy for the acquisition of 
safe feeding skills by improved symptom scores (Primary), improved individual I-
GERQ-R measures, growth measures, reduced lengths of stay and resource 
utilization (Secondary).  Linear mixed models will be used to study the associations 
between the primary endpoints for Aim 1 (symptom scores) and treatment, and trend 
across time. The interaction term “group x time” will be included in the model to 
study whether the two treatment groups have different “behavior” across time. 
Confounder variables, such as medications, feeding position or volume, will be 
included in the models. Logistic regression models will be used to assess success of 
the treatment vs. standard of care. Also, potential confounders (e.g. feeding method: 
oral vs. tube) will be included and studied in these models. Holm’s method will be 
used to adjust for multiple comparisons (150). All the secondary variables listed 
above, will be analyzed using either linear mixed models or logistic regression 
models. Model goodness of fit tests and residual analyses will be performed to 
assess the models. Interaction terms and potential confounder variables will be 
included. 
o Aim II: Mechanistic Hypothesis: We will test the hypothesis that the sensory-motor 
characteristics of aerodigestive reflexes evoked with induced esophageal stimulation 
or upon spontaneous esophageal provocation as in GER, improve in the innovative 
therapy group with regards to: sensory thresholds, response latency and duration, 
frequency and magnitude of reflexes, TLESRs, spatial-temporal-physical- chemical 
characteristics of GER events with associated symptom indices. Based on the 
preliminary data, we will have at least 80% power to detect the above differences of 
pre and post therapy between the two groups. Linear mixed models or logistic 
regression models (depending on the nature of the outcome variable) will be used to 
study the associations of interest within sensory motor components of aerodigestive 
reflexes within and between study groups and their outcomes. Potential confounders 
as well as interaction between groups and type of infusion will be included in the 
models. We have utilized similar models previously. Correlation between symptom 
indices (SI, SSI, SAP) and reflexes will be calculated. 
 Sample Size Determination:  
o From the more recent preliminary data analysis, 83.3% (20/24, 95% CI: 62.6%-
95.2%) of patients had success based on symptoms and feeding methods in the 
innovative strategy group, while only 35% (7/20, 95% CI: 15.4%-59.2%) had 
success in the standard therapy group. In order to provide greater assurance than 
afforded by comparing to historical control of the standard therapy, a total of 
evaluable 100 patients will be randomized into the innovative feeding strategy or 
standard therapy group. The chi- square test yields 80% power to detect 27% or 
higher increase in proportion of success while maintaining an overall one-sided α 
level of 0.025. This conservative power calculation is supported by the preliminary 
data and assumes the proportion of success for the standard therapy is around 40% 
and a group-sequential design with O’Brien-Fleming error spending function. 
 Interim Analysis:  

o One interim futility analysis will be undertaken at about 50% information prior to 
the final analysis at 100% information, corresponding to 50 and 100 evaluable 
patients, respectively. The boundary is determined using Lan-DeMets spending 
functions to simulate O’Brien-Fleming boundaries with an overall one-sided α level 
of 0.025. Using the target proportion of success, the boundary at the futility analysis 
expressed as a p-value is 0.297. We plan to enroll 120 patients to allow for 20% of 
attrition. 
 Intention to treat analysis:  
o Every patient who had been randomized will be included in the analysis. If a patient 
drops off before end of study and no symptom score has been measured, we will 
treat the patient as a failure. Beside the intention to treat analysis, we will also 
perform the analysis with only those patients that complete the study. Linear mixed 
models will be used to study the associations between the primary endpoints for Aim 
1 (symptom scores) and treatment, and trend across time. The interaction term 
“group x time” will be included in the model to study whether the two treatment 
groups have different “behavior” across time. Confounder variables, such as 
medications, feeding position or volume, will be included in the models. Logistic 
regression models will be used to assess success of the treatment vs. standard of 
care. Also, potential confounders (e.g. feeding method: oral vs. tube) will be 
included and studied in these models. Holm’s method will be used to adjust for 
multiple comparisons. All the secondary variables listed above, will be analyzed 
using either linear mixed models or logistic regression models. Model goodness of 
fit tests and residual analyses will be performed to assess the models. Interaction 
terms and potential confounder variables will be included. 
o The proposed projects will focus on esophageal provoking stimuli in designing 
multi-faceted innovative therapies, that will be studied in a prospective single center 
randomized blinded controlled trial. The pH- Impedance data with associated 
symptom indices will be analyzed. This trial will advance our knowledge of GER 
and GERD in infants. These studies will likely mandate the development of infant-
specific diagnostic and treatment paradigms to manage not only GERD but also 
other diseases where GERD is a co-morbidity. 
 
3.4 Scientific or scholarly background for, rationale for, and signficance of the research 
based on the existing literature and how will it add to existing knowledge 
 This proposal is a logical extension of our current R01 and is built on Novel 
Concepts, and State-Of-The-Art Methods. Previously we have developed, 
validated, and safely used the approaches and equipment necessary to assess GER 
and GERD in infants including: a) novel multimodal esophageal sensory-motor 
testing using manometry provocation methods, b) respiratory inductance 
plethysmography, c) ultrasonography of glottal motion, d) video-manometry, e) 
pH-Impedance with direct observation/video correlation of symptoms, and f) 
robust analytical and statistical paradigms. We are translating these methods to 
improve outcomes in infants with feeding problems, e.g., improving successful 
feeding outcomes and avoidance of gastrostomy in those referred for G-tube 
placement.  
 We will explore the sensory-motor mechanisms leading to symptoms in infants 
with GERD. GERD symptoms can be attributed to: a) refluxate properties: 

physical (gas, mixed, liquid), chemical (acid, non-acid), spatial (high or low) or 
temporal (acid or bolus clearance time); or b) luminal clearance mechanisms: 
esophageal mechano-distention and chemo-sensitive stimulation induced 
aerodigestive reflexes. The mechanisms for symptoms may underlie in stimulus 
thresholds, response-frequency, response-latency and response-magnitude of the 
aerodigestive protective reflexes. Therefore, to test the effects of different 
treatment strategies on these aerodigestive reflexes, we will interrogate the 
sensory-motor components before and after proposed therapies. 
 Publication history and references pertinent to this proposal are as follows: 
 
o Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, Sondheimer J, 
Staiano A, Thomson M, Veereman-Wauters G, Wenzl TG, North American Society for 
Pediatric Gastroenterology H, Nutrition, European Society for Pediatric Gastroenterology H 
2009 Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of 
the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition 
(NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and 
Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 49:498-547. 
o Jadcherla SR, Chisolm D, Gardner W 2011 Economic burden of gastroesophageal 
reflux disease (GERD) in convalescing ICU Neonates. Neurogastroenterol Motil. (Accepted 
abstract) 
o Jadcherla SR, Peng J, Moore R, Saavedra J, Shepherd E, Fernandez S, Erdman SH, Di 
Lorenzo C 2011 Impact of personalized feeding program in 100 NICU infants: A novel 
pathophysiology-based approach for better outcomes. J Pediatr Gastroenterol Nutr. (In press) 
o Jadcherla  SR,  Chan  CY,  Moore  R,  Malkar  M,  Timan  CJ,  Valentine CJ  2011  Impact  
of  feeding Strategies on the Frequency and Clearance of Acid and Nonacid 
Gastroesophageal Reflux events in dysphagic Neonates. JPEN J Parenter Enteral Nutr. (In 
press) 
o Malkar M, Chan CY, Peng J, Moore R, Jadcherla SR 2011 Effect of osmolality and 
caloric density of feeds on the frequency and characteristics of gastroesophageal reflux in 
infants. Neurogastroenterol Motil. (Accepted abstract) 
o 1976 Commentary on breast-feeding and infant formulas, including proposed standards for 
formulas. Pediatrics 57:278-285. 
o Kleinman RE 2009 Pediatric Nutrition Handbook 6th  ed. Elk Grove Village, IL: 
American Academy Of Pediatrics Committee on Nutrition. 
o Jadcherla SR, Gupta A, Fernandez S, Nelin LD, Castile R, Gest AL, Welty S 2008 
Spatiotemporal characteristics of  acid refluxate and relationship to symptoms in 
premature and term infants with chronic lung disease. Am J Gastroenterol 103:720-728. 
o Jadcherla SR, Peng J, Chan CY, Moore R, Wei L, Fernandez S, Di Lorenzo C 2011 
Significance of Gastroesophageal Refluxate in Relation to Physical, Chemical and Spatio-
temporal Characteristics in Symptomatic ICU Neonates. Pediatr Res.(In press; 
PMID:21505374) 
o Behrman RE, Butler AS 2007 Preterm birth: causes, consequences, and prevention. The 
National Academies of Sciences, Institute of Medicine, Washington DC, p 740.2008 Hospital 
discharge of the high-risk neonate. Pediatrics 122:1119-1126. 

o Clark RH, Bloom BT, Spitzer AR, Gerstmann DR 2006 Reported medication use in 
the neonatal intensive care unit: data from a large national data set. Pediatrics 117:1979-
1987. 
o Jadcherla SR, Wang M, Vijayapal AS, Leuthner SR 2010 Impact of prematurity and co-
morbidities on feeding milestones in neonates: a retrospective study. J Perinatol 30:201-208. 
o Lasser MS, Liao JG, Burd RS 2006 National trends in the use of antireflux procedures 
for children. Pediatrics 118:1828-1835. 
o Malcolm WF, Gantz M, Martin RJ, Goldstein RF, Goldberg RN, Cotten CM 2008 Use of 
medications for gastroesophageal reflux at discharge among extremely low birth weight 
infants. Pediatrics 121:22-27. 
o Gupta  A,  Jadcherla  SR  2006  The  relationship  between  somatic  growth  and  in  vivo  
esophageal segmental and sphincteric growth in human neonates. J Pediatr Gastroenterol 
Nutr 43:35-41. 
o Jadcherla SR 2006 Esophageal Motility in the Human Neonate. NeoReviews 7:e7-e12. 
o Jadcherla SR 2006 Upstream effect of esophageal distention: effect on airway. Curr 
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esophageal pH data. Gastroenterology 107:1741-1745. 
o Jadcherla SR, Shaker R 2001 Esophageal and upper esophageal sphincter motor function 
in babies. Am J Med 111 Suppl 8A:64S-68S. 
o Jadcherla SR 2002 Gastroesophageal reflux in the neonate. Clin Perinatol 29:135-158. 
o Jadcherla SR 2003 Manometric evaluation of esophageal-protective reflexes in infants 
and children. Am J Med 115 Suppl 3A:157S-160S. 
o Holm S 1979 A simple sequentially rejective multiple test procedure Scan J Statist 6:65-70 
o Lan KKG, Demets DL 1983 Discrete Sequential Boundaries for Clinical Trials. Biometrika 
70:659-663. 
 
4.0 
Study Endpoints 
 
Primary Outcome 
o Clinical outcome of feeding success for those infants transitioning to oral feeds 
at inception.  
 
The primary endpoint is the feeding success defined as achieving full oral 
feeds (defined as no need for tube feeds to maintain hydration and nutrition) 
and/or a >/= 6-point decrease from baseline I-GERQ-R. The time frame is up 
to 5 weeks after enrollment.  
o Clinical outcome of feeding success for those infants on full oral feeds at 
inception.  
 
The primary endpoint is the feeding success defined as maintaining full oral 
feeds and a >/= 6-point decrease from baseline I-GERQ-R. The time frame is 
up to 5 weeks after enrollment.  
 
Secondary Outcomes 
o Clinical Outcomes 
 
Length of hospital stay 
 
Growth outcomes during the study period and up to 1 year 
 
Independent feeding skills over time up to 1 year 
 
Respiratory support during the study period and at discharge 
 
Developmental outcomes with Bayley’s scores at 2 years 
 
Individual differences in I-GERQ-R questionnaire 
o  Motility Outcomes 
 
Mechanisms of aerodigestive clearance and esophageal provocation are 
evaluated based on esophageal motility studies at inception and after 5 
weeks. 
o pH Impedance outcomes  
 24-hour pH impedance results at inception of study and then 5 
weeks later after treatment completed 
 

5.0 
Study Intervention/Investigational Agent 
 Those subjects randomized into the study group will follow innovative 
feeding strategy for 5 weeks. The innovative feeding strategy is as 
follows:  
o Feeding Volume <140 ml/kg/d  
o Feeding duration over 30 minutes 
o Right lateral feeding position 
o Supine position postprandial 
 
6.0 
Procedures Involved* 
6.1 Study design: 
 Study design and setting: This is a Single Center Prospective 
Randomized, Blinded Controlled Trial.  Consented subjects will undergo 
1:1 randomization into either innovative feeding strategy and standard 
therapy arms.  
 Patient Population: Potential study subjects are those that are referred by 
their attending physician for evaluation and management of potential 
GERD, the key symptoms being irritability and arching, gagging, 
choking, coughing, aspiration, life threatening events, swallowing 
problems, and/or failure to thrive. I-GERQ-R questionnaire will be 
completed as per guidelines. Each patient must have a signed consent 
from parent/legal guardian prior to initiation of screening for the trial. 
 Inclusion Criteria: Hospitalized convalescing infants with aerodigestive 
symptoms or admitted for GERD symptoms, < 42 weeks GA. Infants 
will be included if PMA at time of study is ≥ 34 wks age and < 60 wks.  
Subjects must be on full enteral feeds defined as ≥ 150mL/k/day. Infants 
must be breathing unaided, and nasal cannula oxygen up to 1 LPM is 
allowed. In subjects receiving empiric prokinetics or acid suppressive 
agents, the medications need to be stopped for ≥ 72 hr prior to 
evaluation. 
 Exclusion Criteria: Infants with known genetic, metabolic or syndromic 
disease, neurological diseases such as Grade III or IV intra ventricular 
hemorrhage or perinatal asphyxia, GI malformations and surgical GI 
conditions. 
 Tests and procedures 
o Twenty-four-hour pH and impedance ordered diagnostically 
for suspected GERD 
o If RI >3 and infant meets all above criteria, infant 
randomized into conventional or study group 
o Esophageal manometry performed 
o 4 weeks of the study intervention for the study group and 
standard treatment for the conventional group while 
collecting data on symptoms, feeding position, duration and 
volume 

o Omeprazole stopped after 4-week course. 
o Repeat esophageal manometry and pH impedance testing 
done after 1 week off omeprazole (at week 5). If the 
providers/parents are resistant or refuse to stop the 
medication, repeat testing will still be done, and the alteration 
will be noted. 
 Overall Study Endpoints: Primary clinical outcome occurs at time 2 
study or at discharge if time 2 study not completed. Secondary study 
outcomes occur at time 2 studies. Secondary clinical outcome measures 
(growth characteristics, development and long term feeding outcomes) 
will be collected up to 24 months. 
 Methods to overcome potential confounders: Data will be collected from 
EPIC documentation, feeding diaries, parent interviews and follow up 
appointments. While inpatient, these are documented regularly. After 
discharge, we will be dependent on parents to provide the data.  
 
Removal and management of subject(s) from protocol: The investigator and/or the 
parent(s) have the right to withdraw from study at any time and opt for the standard of 
care. Parent(s) that withdraw their infants from the study therapy will be encouraged to 
continue to remain in the study for all follow up evaluations. Those who choose 
completely withdrawal from the study will be encouraged to follow the standard of 
care; wherein, response failures are followed for secondary outcomes until 18 months. 
 
Secondary Outcome Measures: (up to 24 months, for Bayleys developmental score) 
Secondary outcome measures (growth characteristics, development and long term 
feeding outcomes) will be collected up to 12 months. 
 
6.2 Describe: 
 24-hour Esophageal pH/impedance testing and calculation of acid reflux 
index (ARI) is a standard clinical test. Subjects will be monitored 1:1 by 
trained staff not associated with the study for the duration of the test. 
This allows us to quantify the components of refluxate and associated 
symptom indices while assuring subject safety.  
 Manometry methods have been used concurrent with video, submental 
EMG, RIP, ECG, pulse-oximetry and nasal air flow to test basal and 
adaptive pharyngo-esophageal reflexes and sensory-motor 
characteristics of motility and to monitor safety Concurrent 
synchronized video recordings will be performed to further validate 
symptoms based on objective definition of the esophageal reflexes. 
Documentation of symptom markers can be validated by integrating 
manometry with respiratory inductance plethysmography and video. 
 Manometry and pH/impedance testing are both performed on a routine 
basis for clinical diagnostic purposes. The catheters needed to perform 
these studies are placed under strict guidelines by, in the instance of 
pH/impedance testing, a trained Registered Nurse or, in the case of 
manometry testing, a trained physician. The pH/impedance catheter 
placement is confirmed by x-ray.  

 For the duration of both of these procedures, the subject is monitored by 
a trained RN, and vital signs (heart rate, breathing and oxygen 
saturation) are monitored by both visualization of subject and electronic 
monitoring.  
 Equipment used to perform these procedures are commonly used in 
clinical diagnostic testing and are being used for FDA approved 
purposes.  
 Omeprazole is prescribed to both groups and is the standard of care in 
the NICU.  
 The source records that will be used to collect data about subjects will be 
EPIC records, patient diary logs for symptoms, I-GERQ-R 
questionnaires, feeding process, medication compliance, physician visits 
and clinical data.  
 
6.3 Data to be collected 
 Patient diary logs for symptoms, feeding process, medication 
compliance, physician visits and clinical data.  
 24-hr pH data will be collected to characterize the frequency, acid 
reflux index, Vandenplas score, longest reflux event duration, and 
number longer than 5 min 
 Basal manometry data will be collected to assess swallow frequency, 
resting UES and LES pressure, swallow propagation types, peristaltic 
velocity, frequency of symptoms and the causative mechanisms.  
 Multimodal sensory motor testing involves mid-esophageal provocation 
with graded infusions (0.1 to 5 ml) of air (to stimulate 
mechanoreceptors), apple juice (pH 3.7, to stimulate acid-sensitive 
receptors), and sterile water (pH 7.0, as control stimulus), and examine 
the changes in sensory-motor characteristics of aerodigestive reflexes 
pertinent to secondary peristalsis or deglutition response, esophago-UES 
contractile reflex, LES-relaxation reflex, and symptoms during the 
stimulation. This protocol will be performed in both experimental and 
standard therapy groups at time-1 and time-2 (where feasible).  
 Basal and adaptive pharyngeal reflexes with air and water infusions are 
measured at time-1 and time-2 (where feasible). 
 Subjects will be monitored up to one year through electronic medical 
records (EPIC) for number of hospital readmissions, number of clinic 
visits, growth metrics and medication use.  
 
6.4    Long term follow up 
 
Long term follow-up will include feeding method, growth characteristics and 
development up to 18 months of age. 
 
7.0 
Sharing of Results with Subjects* 
Results of pH/impedance testing will be shared with care team and/or parents at 
the time of testing. Results of manometry testing will be conveyed verbally to 

parents and/or the care team at the time of testing along with any incidental 
findings that may impact subject’s care.  
 
8.0 
Study Timelines* 
The study procedures (pH/impedance and manometry) will be performed two 
times with 5 weeks between.  
Omeprazole will be given for 4 weeks, with a 1-week washout period prior to the 
performance of the second studies.  
 
9.0 
Inclusion and Exclusion Criteria* 
            Inclusion criteria: 
 Hospitalized infants with aero-digestive symptoms or were admitted for 
GERD symptoms 
 ≥ 34 weeks PMA and ≤ 60 weeks PMA (PMA= GA+ Chronological age)  
 Enterally fed infants (PO or NG) 
 Average daily fluid of 150 to 170 ml/kg/day at time of study 
 Supplemental oxygen of ≤ 1 LPM by nasal cannula 
  Subjects receiving empiric prokinetics or acid suppressive agents, the 
medications will be stopped for ≥ 72 hr prior to evaluation 
Exclusion criteria: 
 Known genetic, metabolic or syndromic disease 
 Grade III or IV IVH or intra-cranial hemorrhage, perinatal asphyxia  
 GI malformations or surgical GI conditions 
Infants who are hospitalized in the NICU at NCH main campus and have 
undergone pH/impedance testing will be screened for the above inclusion and 
exclusion criteria. Our population will include individuals who are not yet adults 
(infants) 
 
10.0 Vulnerable Populations: 
10.1 
This research complies with 45 CFR 46, as it includes only human infants up to 6 months 
old. As this study involves slightly greater than minimal risk, as regulated in 45 CFR 46 Subpart D, 
all subjects for this study will have consent of at least one parent. 
 
The Neonatal and Infant Feeding Disorders (NIFD) Program is directed by the PI, Dr. 
Sudarshan Jadcherla who is a Neonatologist with Pediatric GI experience and is a 
recognized GI motility expert.  The NIFD program is a nationally recognized clinical 
program supported by the NIH and is well equipped to conduct clinical studies such 
as proposed in this application. In addition, there is a team of dedicated trained 
nurse coordinators who are competent and comfortable with performing these 
procedures on preterm infants as well as a neonatal nurse practitioner. The team 

also includes trained technical personnel affiliated to this program who perform 
these studies on a regular basis for diagnostic purposes in this same population. 
11.0 Local Number of Subjects 
 N=120 subjects 
 This is a single center trial, all subjects will be recruited at Nationwide 
Children’s Hospital 
 
12.0 Recruitment Methods 
6.4 Infant’s referred to the Neonatal and Infant Feeding Disorders Program at 
Nationwide Children’s Hospital who have a pH/impedance study will be 
screened. 
6.5 RN Coordinators will identify and screen potential subjects 
6.6 Parents of infants will be offered $20.00 for each study visit completed. 
Payment is made in the form a debit card with payment loaded to it 
following the visit.  
 
13.0 Withdrawal of Subjects* 
 If a subject develops any condition outlined in the exclusion criteria (i.e. 
surgical or neurological conditions) they will be withdrawn 
 Subjects will be withdrawn if there are any safety concerns 
 Parents can choose to withdraw their infant at any time during the study 
period, but some data collection will continue.  
 
14.0 Risks to Subjects* 
This study includes the risk associated with the nasal placement of the manometry 
probe and pH/impedance catheter. These risks are similar to the risks associated 
with the placement of a nasogastric feeding tube in infants which is frequently 
done for tube feeding infants both in the hospital and sometimes at home 
15.0 Potential Benefits to Subjects* 
Infants can benefit from evaluation careful observation of GERD feeding and 
breathing problems. The esophageal manometry may provide added information 
about the infant’s feeding problem and those results will be reported to the parents 
and providers.  
 
16.0 Data Management* and Confidentiality 
 
16.1  Data analysis plan: See above statistical analysis 
 
16.2  Data safety plan: 

 All data will be stored on password protected computers accessible by 
trained Research assistants within the lab. Redcap will be used to store 
data. All paper CRFs are stored in locked cabinets with access limited to 
lab staff.  
 Data will be verified by at least two specially trained study team 
members.  
 
17.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
 
Subjects are monitored throughout study procedures by a trained Registered 
nurse 
 
Meetings of the Data Safety Monitoring Board will take place on a quarterly 
basis.  
 
The study is overseen by the IRB at NCH and annual reports will be 
submitted 
 
A Data safety monitoring plan will be implemented with reports given to the 
DSMB and the IRB and NIDDK when appropriate. 
 
Subjects who remain hospitalized throughout the study period will be 
monitored by lab staff via review of their electronic medical record and 
review of bedside documentation 
 
Subjects who have been discharged to home will be monitored by weekly 
telephone communication with parents and caregivers 
 
Parents will be told whom to contact in case of concerns 
  
18.0 Provisions to Protect the Privacy Interests of Subjects 
 
Parents will have the choice of whether to participate and share information 
about their child. 
 
The research team will access electronic records for follow up data. 
 
19.0 Compensation for Research-Related Injury 
 
Research related injury will not be compensated 
 
Language from consent: 
 If your child is hurt by the procedures that are part of the Study, 
you should seek medical treatment for the injuries and tell the 
Study Doctor as soon as possible at the number on the first page of 
this form.  If it is an emergency, call 911 or go to the nearest 
emergency department. In most cases, this care will be billed to 
your health insurance company or whoever usually pays for your 
health care at the usual charges, but some insurance companies 
will not pay for care related to a study.  If the care is provided at 
Nationwide Children's Hospital, we make no commitment to pay 
for the medical care provided to you.  No funds have been set aside 
to compensate you in the event of injury.  If no one else pays for 
your care, you may have to pay for the cost of this care.  This does 

not mean that you give up any of your legal rights to seek 
compensation for your injuries 
20.0 Economic Burden to Subjects 
 
None 
21.0 Consent Process 
 
Consent 
 
Consent will take place in person with one parent (risk level 2) prior to 
the study taking place.  
 
We will be following “SOP: Informed Consent Process for Research 
(HRP-090).”  
 
Non-English Speaking Subjects – if known, skip if not known 
 
If subjects do not speak English are enrolled, the consent form will be 
translated in person by an interpreter speaking the language of the 
parent. 
 
Subjects who are not yet adults (infants, children, teenagers) 
 
All subjects enrolled in this study will be infants.  
 
Parental permission will can be obtained from one parent only as this 
study is level 2 risk. 
 
Consent will not be obtained from individuals other than parents (i.e. 
foster parents, custodial agencies) 
 
Consent will be obtained in person 
           
22.0 Process to Document Consent in Writing 
21.1 We will be following “SOP: Written Documentation of Consent     (HRP-
091). 
 
23.0 Setting 
 
This research will be conducted at Nationwide Children’s Hospital, Columbus, Ohio 
 
Research procedures will be performed at Nationwide Children’s Hospital 
 
Safety monitoring will be conducted through the NCH IRB 
 
24.0 Multi-Site Research* 
24.1 
This is a single site study with collaboration from The Ohio State University Department 
of Biostatistics for assistance with data analysis. Dr. Wei is a Research Assistant Professor at the 
Department of Biostatistics at The Ohio State University College of Medicine and Public Health. 
She has expertise in clinical statistical modeling techniques. She has worked with the PI with 
sample size and statistical design for this study. She will provide consultation with analysis and 
design support. Dr. Wei works with the PI closely with regards to statistical outputs and 
manuscript writing.  

24.2 
 Data is stored in REDCap where all of the study staff including Dr. Wei can access the 
data. Subject identifiers include Names, Birth Date, Discharge Date and Medical Record 
Numbers as identified in the consent form. 
 
24.0  Protected Health Information Recording 
 
1.0 
Indicate which subject identifiers will be recorded for this research. 
☒  Name 
☐  Complete Address 
☐  Telephone or Fax Number 
☐  Social Security Number (do not check if only used for ClinCard) 
☒  Dates (treatment dates, birth date, date of death) 
☐  Email address, IP address or URL 
☒  Medical Record Number or other account number 
☐  Health Plan Beneficiary Identification Number 
☒  Full face photographic images and/or any comparable images (x-rays) 
☐  Account Numbers 
☐  Certificate/License Numbers 
☐  Vehicle Identifiers and Serial Numbers (e.g. VINs, License Plate Numbers) 
☐  Device Identifiers and Serial Numbers 
☐  Biometric identifiers, including finger and voice prints 
☐  Other number, characteristic or code that could be used to identify an individual 
☐  None (Complete De-identification Certification Form) 
 
2.0   
Check the appropriate category and attach the required form* on the Local Site 
Documents, #3. Other Documents, page of the application.  (Choose one.) 
☒  Patient Authorization will be obtained. (Include the appropriate HIPAA language (see 
Section 14 of consent template) in the consent form OR attach the HRP-900, HIPAA 
AUTHORIZATION form.) 
☐  Protocol meets the criteria for waiver of authorization. (Attach the HRP-901, 
WAIVER OF HIPAA AUTHORIZATION REQUEST form.) 
☐  Protocol is using de-identified information. (Attach the HRP-902, DE-
IDENTIFICATION CERTIFICATION form.) (Checked "None" in 1.0 above) 
☐  Protocol involves research on decedents. (Attach the HRP-903, RESEARCH ON 
DECEDENTS REQUEST form.) 
☐  Protocol is using a limited data set and data use agreement. (Contact the Office of 
Technology Commercialization to initiate a Limited Data Use Agreement. 
 
*Find the HIPAA forms in the IRB Website Library, Templates. 
 

Attach the appropriate HIPAA form on the “Local Site Documents, #3. Other Documents”, 
page of the application. 
 
3.0    How long will identifying information on each participant be maintained? 
       
       3.1 Throughout the study period and 18 months of follow up follow up, plus 10 
years.  
 
4.0 
Describe any plans to code identifiable information collected about each participant.  
Each subject will be given a code known only to study staff and identifiable information 
will be kept   separate from study data. Both will be stored in a secure area in a locked 
cabinet or in a computer database accessible only by study staff.   
 
Check each box that describes steps that will be taken to safeguard the confidentiality of 
information collected for this research: 
X Research records will be stored in a locked cabinet in a secure location 
X Research records will be stored in a password-protected computer file 
X The list linking the assigned code number to the individual subject will be 
maintained separately from the other research data 
X Only certified research personnel will be given access to identifiable subject 
information 
 
5.0 
Describe the provisions included in the protocol to protect the privacy interests of 
subjects, where "privacy interests" refer to the interest of individuals in being left 
alone, limiting access to them, and limiting access to their information. (This is not 
the same provision to maintain the confidentiality of data. 
              
25.0 Confidential Health Information 
1.0 
Please mark all categories that reflect the nature of health information to be 
accessed and used as part of this research. 
 
☒  Demographics (age, gender, educational level) 
☒  Diagnosis 
☒  Laboratory reports 
☐  Radiology reports 
☒  Discharge summaries 
☒  Procedures/Treatments received 
☒  Dates related to course of treatment (admission, surgery, discharge) 
☐  Billing information 
☐  Names of drugs and/or devices used as part of treatment 
☐  Location of treatment 
☐  Name of treatment provider 
☐  Surgical reports 
☒  Other information related to course of treatment 

☐  None 
 
2.0 
Please discuss why it is necessary to access and review the health information noted in 
your response above. 
                   2.1 We will be looking at outcome variables for the first 18 months of life. 
 
3.0 
Is the health information to be accessed and reviewed the minimal necessary to achieve 
the goals of this research?  ☒ Yes    ☐ No 
 
4.0 
Will it be necessary to record information of a sensitive nature?  ☐ Yes   ☒ No 
 
5.0 
Do you plan to obtain a federally-issued Certificate of Confidentiality as a means of 
protecting the confidentiality of the information collected?  ☐ Yes   ☒ No