Dietary Carbohydrate Effects on GERD in Obese Veterans: Nutritional or Hormonal?
Phase: NA
Conditions: Gastroesophageal Reflux Disease, Obesity
Sponsor: VA Office of Research and Development

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Dietary Carbohydrate Effects on GERD in Obese Veterans:  
Nutritional or Hormonal? 
 
 
Principal Investigator: 
 
Kevin Niswender, MD, PhD 
Assistant Professor 
Diabetes, Endocrinology, and Metabolism Division 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Screening & Enrollment 
6.0 
Study Procedures 
7.0 
Risks  
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 
 
 
 

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1.0 
Background 
GERD, occurring in ≥ 25% of U.S. veterans, contributes substantially to health care 
costs as it is the most common inpatient GI discharge diagnosis and the most common 
indication for upper endoscopy (upper endoscopy procedures increased 54% from 2000 
to 2009 in commercially insured patients).1 GERD is also the most common outpatient 
diagnosis for GI disorders with > 9 million visits annually.1 Thus, the VA spends >$177 
million yearly on outpatient PPI prescriptions. Our local VA, the Tennessee Valley Health 
System (TVHS), has ~65,000 total patients and 19,094 (29.4%) of these patients are 
currently on PPIs. Furthermore, our TVHS endoscopy lab currently sees 3-4 patients 
weekly for GERD that is refractory to PPI treatment.     
A strong relationship has been demonstrated between the increasing prevalence of 
GERD and the rise of obesity in the U.S. population since the 1970’s.2,4,5,12 In fact, 
obesity increases the number of acid reflux episodes experienced and the percentage of 
time with esophageal pH < 4.0.6 Thus, the American Gastroenterological Association 
advises weight loss for obese persons with GERD.9 Yet, weight loss trials conducted 
over the past decade have not consistently demonstrated improvement in GERD 
symptoms, medication use, or related outcomes.10 In contrast, a recently completed 
structured weight loss program in obese adults showed significant decrease in the 
prevalence of GERD symptoms (from 37 to 15% of subjects) with a 13% (of baseline 
body weight) weight loss after 6 months of intervention.13 However, the intervention was 
highly structured as the primary component of the diet utilized was consumption of liquid 
shakes as meal replacements, not wholesome healthy foods. Beyond not being a 
method of training individuals how to eat in a healthful manner, the long term effects of 
such a strategy with regard to weight loss maintenance is unclear. It is notable that most 
alternative weight loss strategies are associated with a high degree of weight recidivism; 
a recent meta-analysis revealed that long-term weight maintenance at 4-5 years after a 
structured weight loss program averages about 23% of initial weight loss.14 The dietary 
strategy that we propose is not only a means of improving diet related behaviors with 
healthful foods but also does not appear to require substantial weight loss. Moreover, 
our preliminary data revealed resolution of GERD symptoms in 100% of subjects.                 
1.1 GERD Assessment: There is no one test for establishing a diagnosis of GERD 
either objectively or by subject report of symptoms. As initial management of GERD is 
provided with antisecretory drugs (PPIs and H2RAs), diagnostic testing for GERD is 
typically performed after initial treatment to evaluate drug treatment failures and to 
identify complications of GERD such as strictures or Barrett’s metaplasia. In these 
cases, endoscopy (with or without biopsy) is the first test used, typically for patients with 
dysphagia or those who have not responded to twice-daily PPI.9 The sensitivity of 
endoscopy as a diagnostic test is significantly reduced since drug therapy is initiated 
before testing. For patients who have normal findings with endoscopy, manometry is 
used to evaluate lower esophageal sphincter function as well as peristaltic functioning 
and motor disorders. Ambulatory pH monitoring is performed (while PPI therapy is 
withheld) to determine the frequency, severity and duration of reflux episodes. While 
wireless pH monitoring appears to have greater sensitivity than impedance, impedance 
monitoring allows evaluation of both acid and non-acid reflux events, and is conducted 
for a shorter period of time (24 vs 48 hours of monitoring). With impedance pH 
monitoring, a pH score (Johnson-DeMeester Score) is calculated from 6 parameters: 
percent total time pH <4.0, percent upright time pH <4.0, percent supine time pH <4.0, 

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number of reflux episodes, number of reflux episodes ≥ 5min., and minutes of longest 
reflux episode.15                  
As GERD is a chronic disease with persistent symptoms, the importance of subjective 
assessment of GERD symptoms and its impact on quality of life is well-recognized. As 
GERD is a complex condition with many presentations, there are about 20 instruments 
currently used in clinical practice and/or research to evaluate GERD symptoms, typically 
with heartburn and regurgitation being the primary symptoms assessed. A recent 
systematic review showed that 5 of these 20 are evaluative scales, with the others being 
either diagnostic tools or epidemiologic.16 The GERD Symptom Assessment Scale 
(GSAS),17 a 15-item scale developed with patient input, is considered the most 
comprehensive evaluative tool as it assesses both primary and associated symptoms. 
The GERDQ was developed to support health care providers in diagnosing GERD as 
well as monitoring the response to treatment over time.18 The GERDQ assesses 
frequency of symptoms and impact on life, and was based on results from a study that 
showed a positive correlation between the frequency of heartburn, regurgitation, sleep 
disturbances and use of over-the-counter medications for reflux and esophageal pH < 
4.0. A randomized trial showed that the GERDQ can identify patients with a high 
likelihood of GERD who are in need of drug therapy as well as those who are in need of 
objective testing.19      
1.2 Diet: Although avoidance of alcohol, caffeine, chocolate, acidic foods, spicy foods, 
mint, and high fat foods are typically recommended in treatment of GERD, there remains 
a lack of supporting evidence.20-23 In fact, meta- analysis showed no efficacy for these 
dietary factors.21 In contrast, a case report series and two small experiments suggest 
that low carbohydrate diet may improve esophageal acid exposure and symptoms. In the 
case series, 5 patients reported resolution of GERD symptoms within 2 weeks of 
following the Atkins diet which limits carbohydrate (CHO) intake to 20g per day.24 As 
patients also restricted coffee, caffeine and acidic fruit intakes, it is unclear whether 
reduced CHO intake was the primary factor responsible for symptom resolution. Another 
study utilizing a crossover design with 41 subjects, compared low fat to low CHO diet for 
3 months and  reported that 68% of subjects had symptom improvement on low CHO 
diet.25 However, the findings are subject to design bias as subjects were not randomized 
to treatment arm. Finally, a recent study evaluated esophageal pH in 8 obese females 
six days after carbohydrate restriction of 20 g/day.26 In this study, percent time with pH 
<4.0 in the distal esophagus dropped significantly from 5.1% to 2.5% (p = 0.02) and 
there was significant decrease in Johnson-DeMeester score from 34.7 to 14.0 (p = 0.02) 
– an effect similar to that expected with PPI treatment.27 Subjects also had significant 
improvement in symptom severity (GSAS score from 1.28 to 0.72, p = 0.0004). Notably, 
the published studies utilize a severe restriction of CHO at 20g/day which confounds 
applicability to the VA obese adult population who typically consume ~325g/day. 
Furthermore, our preliminary data suggest an effect not just of amount of CHO 
consumed, but type of CHO. With regard to type of CHO, it is intriguing that a study in 
healthy volunteers reported increased number of transient LES relaxations, esophageal 
acid exposures, reflux episodes and GERD symptoms with administration of lactose (a 
simple sugar).28  
1.3 GI Hormones and Insulin: Other studies have investigated hormones as a potential 
explanation for diet-induced GERD symptoms, particularly in relation to gastric motility or 
LES pressure. Most often studied has been the hormone gastrin, whose release is 
stimulated from digested food in the stomach as well as in response to gastric pH, and in 

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turn, is a factor influencing LES pressure postprandially.29 Further, the orexigenic 
hormone ghrelin influences upper GI motility30 and treatment with ghrelin has improved 
gastric emptying in rodent models.31 Ghrelin also has a role in regulation of glucose 
homeostasis via modulation of insulin secretion and sensitivity.32 Also influencing gastric 
emptying is the  anorexigenic hormone glucagon-like peptide-1 (GLP-1), which also 
influences postprandial plasma glucose, insulin and c-peptide levels.33 Finally, insulin 
resistance has been shown to strongly correlated with GERD symptoms,34 an effect that 
is likely also related to the close correlations between obesity and GERD as well as 
obesity and insulin resistance. Our data, however, suggest a direct relationship because 
large differences in body weight were not observed. There appears to be no published 
evidence delineating the effects of amount or type of dietary CHO in GERD on these 
potential hormonal mediators. Notably, our preliminary data showed a direct relationship 
between type of CHO consumed, ie, simple sugar intake, and insulin sensitivity - via 
HOMA-IR score, an indicator of insulin resistance identified as a significant predictor of 
more severe GERD symptoms as well as erosive esophagitis in normal weight adults.34           
 
 
 
 
 
 
 
 
 
 
1.4 Summary of the Problem: The VA spends >$177 million yearly on outpatient PPI 
prescriptions and total U.S. prescription drug spending for GERD is $10-20 billion 
annually. Currently, there are 19,094 patients on PPIs at our local VA, TVHS. However, 
PPIs do not prevent reflux of non-acidic material and do not completely eliminate 
esophageal acid exposure. Hence, GERD symptoms persist in ≥ 40% of patients treated 
with PPIs. Unresolved GERD leads to significant comorbidities - it appears ~25% of 
veterans age >50 years have Barrett’s Esophagus,35 a premalignant condition which 
leads to esophageal adenocarcinoma, the most rapidly rising type of tumor in the VA 
population. In addition, GERD increases risk for laryngeal and pharyngeal cancers in 
veterans.36  
Although a strong relationship has been demonstrated between the increasing 
prevalence of GERD and the rise of obesity in the U.S. population since the 1970’s, 
weight loss trials have not consistently demonstrated improvement in GERD symptoms, 
medication use, or related outcomes - there remains insufficient evidence for dietary 
recommendations for veterans with GERD. 

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1.5 Opportunity Presented Here: This study will rigorously test a compelling 
hypothesis regarding GERD pathophysiology and will provide evidence from a 
randomized controlled trial in this at-risk population for whom there is little evidence-
based insight with regard to readily modifiable dietary risk factors. Dietary intervention 
has been demonstrated and is predicted to have other salutary effects such as improved 
body weight, insulin sensitivity and lipid profiles.   
1.6 Innovation of Study: While it has long been thought that dietary factors play a role 
in promoting or exacerbating GERD symptoms, we are unaware of any evidence that 
effects of dietary macronutrients have been rigorously tested. Indeed, a PubMed search 
only returned 2 articles on diet and GERD in a veterans’ population. The very limited 
body of literature has targeted dietary fat and saturated fat intake. Yet, our preliminary 
data show a strong relationship between dietary simple carbohydrate (sugars) and 
GERD. In fact, our data show that obese subjects with GERD had complete resolution of 
their symptoms and medication use when following a low carbohydrate diet in which 
simple carbohydrate intake was strictly controlled. Obese individuals with GERD have 
rarely been studied beyond investigation of an association between body mass and 
GERD symptoms or between dietary fat intake and GERD symptoms. Our proposal to 
investigate the role of dietary carbohydrate is unique and the robustness of the proposed 
experimental design is novel in the GERD literature. Indeed a PUBMED search of 
carbohydrate and gastroesophageal reflux returned only a single citation; “Improvement 
of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief 
case reports” Altern Ther Health Med. 2001 Nov-Dec;7(6):120, 116-9.   
A lifestyle intervention that is novel in terms of GERD thinking, efficacious at improving 
insulin sensitivity, and that is likely to beneficially effect other common obesity co-
morbidities would represent a highly innovative approach to controlling GERD in the 
obese Veteran population.  
1.7 IMPACT: PPIs are one of the top 5 highest selling pharmaceuticals; the VA spends 
>$177 million yearly on outpatient PPI prescriptions and total U.S. prescription drug 
spending for GERD is $10-20 billion annually. Yet, ≥ 40% of individuals on PPIs or 
H2RAs fail to respond. Our local VA, the Tennessee Valley Health System (TVHS), has 
19,094 patients on PPIs currently. Aside from quality of life, GERD is a substantial 
source of morbidity, leading to esophagitis, strictures, Barrett’s esophagus and 
esophageal adenocarcinoma. The incidence of GERD and esophageal adenocarcinoma 
has increased >350% since the mid-1970’s, which parallels the increased prevalence of 
obesity during the past 3-4 decades. In addition, obesity is associated with a 2.5-fold 
increased risk of Barrett’s esophagus in veterans.37 The proposed dietary intervention, if 
deemed efficacious, can be directly implemented in daily clinical practice – without high 
costs or adverse side effects. It offers the potential to reduce symptom burden and 
medication use, and will provide evidence needed for future investigation of long-term 
sequellae of GERD. As 72% of the VA population is now overweight or obese,7,8 and at 
least 25% currently have GERD, we will generate significant information regarding a 
serious pathophysiology that not only fills a gap in the evidence base where only case 
reports exist, but will inform clinical practice and has potential to reduce health costs.  
 
 
 
 
 
 

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2.0 
Rationale and Specific Aims 
General Approach: We will use a randomized controlled trial design to rigorously test 
the hypotheses that low total carbohydrate and/or low simple (low sugars) carbohydrate 
dietary intake will reduce/resolve GERD in obese veterans. From our preliminary data of 
144 obese adults, we found that total carbohydrate was comprised of ~ 50% complex 
CHO and ~50% simple CHO (sugars) - prior to dietary intervention. Thus, that 
composition forms the definition for our control diet (below).  
2.1 Rationale and Strategy:   
Background PPI Use: Acid suppression therapy is commonly prescribed, particularly in 
the VA for symptomatic GERD relief. Our research team, which includes practicing 
clinicians and experienced GERD researchers (Drs. Vaezi and Smalley) debated a 
design wherein we would require research subjects to discontinue all acid suppression 
therapy for the duration of the study. It is clear that based upon symptom burden and for 
the purposes of adherence to study procedure that this would not be feasible. Further, 
we were concerned that if acid related damage were occurring off of acid suppression, 
then such a design may not be ethical. Thus, we have adapted a much more “clinical” or 
“intention-to-treat” mindset to the study design.  Indeed, in a clinical setting, patients are 
most often treated empirically. Thus, we will follow AGA guidelines9 and have subjects 
maintain acid suppression therapy during the intervention, with the exception of the 7-
day period prior to impedance and manometry testing. To determine the effect of acid 
suppression on the hormonal milieu we will now draw blood pre and post medication 
discontinuation. The only potential confounder to this approach would be if the efficacy 
of the dietary intervention were dependent upon having a highly acid and refluxing 
esophageal environment. This does not seem biologically plausible, and additionally the 
efficacy of the dietary intervention to reduce GERD in our preliminary data was not acid 
dependent given that all subjects self-discontinued use of acid suppression medications. 
We will perform secondary analysis in which changes in PPI use over time will be 
assessed. We will use the daily medication (type and dose) and diet checklist data and 
24hr diet recall data to conduct secondary analyses and verify the assumptions of our 
primary model. Summary statistics by diet group will be calculated to determine if weight 
loss, PPI use, total CHO, and simple CHO are consistent with the study design. We will 
also use the linear mixed effects model to determine if total and simple CHO are 
associated with total percent time pH < 4 by replacing the indicator variables in the 
primary model with these continuous covariates and their interaction. A secondary 
analysis of changes in PPI use over time will be considered. For this analysis, we will 
use the daily medication checklist (type, amount and dose) to create continuous 
variables of the weekly dose of PPI. PPI dose will be the outcome in a linear mixed 
effects regression model that includes time modeled flexibly using restricted and diet 
group indicators. An analogous model using weight as the outcome will be estimated. 
Choice of Objective Disease Measures: As described above in section 1.1, we will 
employ impedance pH monitoring to determine acid and non-acid reflux events over a 
24-hour period. This will allow data collection for our primary outcome, percent of time 
with pH < 4.0, as well as the other 5 measures that comprise the Johnson-DeMeester 
score.15 For motility, we will use the the SmartPill monitoring system, which measures 
whole and regional gut transit times. Kuo et al38and Sarosiek et al39 describe sensitivity 
and specificity for the SmartPill. SmartPill gastric emptying time was compared to gastric 
emptying scintigraphy (GES). Correlation between SmartPill and GES was 0.73, the 

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ROC curves between healthy subjects and gastroparetics was 0.83 for SmartPill and 
0.82 for GES, and the sensitivity/specificity for diagnosing gastroparetics for SmartPill 
was 0.65 / 0.87 and for GES was 0.44 / 0.93. In addition, Maqbool et al40 showed 
correlation between SmartPill transit time and scintigraphy was 0.95 at 120 mins and 
0.73 at 240 mins. Finally, Timm et al41 showed SmartPill assesses transit time in a 
within-subjects dietary crossover trial, where the amount of food was controlled but fiber 
source differed, indicating reliability for assessing dietary carbohydrate changes. 
Delayed gastric emptying is implicated in such disorders as idiopathic and diabetic 
gastroparesis and functional non-ulcer dyspepsia. The primary outcome measure from 
this test will be gastric emptying time. We recognize that a possible limitation of our 
proposed study is that we are not performing endoscopy to determine mucosal damage. 
While we will are using the clinical gold standard assessment of pH and reflux, it is well 
beyond the scope and capacity in this study to perform endoscopic assessments of 
mucosal health. Demonstration of a strong effect of the dietary intervention on GERD 
could prompt the development of future more invasive studies to examine such effects. 
Choice of Subjective Disease Measures: As there are ~20 instruments to assess 
GERD symptoms, most of which were evaluated in a systematic review,16 we have 
chosen two scales, the GSAS17 and the GERDQ,18 that have strong sensitivity and also 
have both item and context validity (both are more fully discussed above in section A.1., 
and in the Measures section i below).     
Duration of Intervention: Implementing a dietary intervention can present some 
challenges with regard to dietary compliance as well as subject retention for the duration 
of a study. Our preliminary data shows a significant effect of low carbohydrate diet after 
9 weeks of intervention – all subjects with GERD had resolution of their symptoms and 
GERD medication use. In the proposed study, we have chosen to continue to use a 9-
week intervention period as we would expect that obese adults may find it difficult to 
adhere to a longer term dietary change and this study is not designed to investigate 
behavioral issues. Attrition would be problematic as it may statistically underpower the 
study or bias the results and negatively affect internal validity of the study. Our aim is to 
minimize potential attrition, maximize statistical power, and minimize the time 
commitment while providing a dietary intervention of adequate duration to experience 
effects.  
Weight Loss: We recognize the benefits of weight loss in the obese veteran and are 
highly encouraged by the enormous resources dedicated to the MOVE! program. 
Interestingly, our preliminary data showed resolution of GERD symptoms and 
medication use, as well as improvement in insulin sensitivity – independent of weight 
loss. To clearly determine the effects of the modifying dietary carbohydrate intake per se 
and control for potential confounding (which would distort study findings) by changes in 
body weight during the course of the study, subjects will be prescribed diets in which the 
energy content will maintain body weight, not induce weight loss. Body weight will be 
monitored by the study dietitian. Body composition will be assessed at end of study 
weeks 1 and 9 by use of DEXA (described in Measures section below). Upon 
completion, the study dietitian will counsel subjects about unhealthy weight and provide 
a written handout on caloric reduction for weight loss.  
 
 

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2.2  Methods: 
Design: Randomized controlled dietary trial with 4 treatment arms comparing amount 
and type of CHO: 
 
• 
High total & high simple carbohydrate (HTHS):  
50% complex CHO + 50% simple CHO (control diet) 
• 
High total & low simple carbohydrate (HTLS): 
85% complex CHO + 15% simple CHO  
• 
Low total & high simple carbohydrate (LTHS):  
50% complex CHO + 50% simple CHO 
• 
Low total & low simple carbohydrate (LTLS):  
85% complex CHO + 15% simple CHO 
Diets: We have extensive experience designing, prescribing and assessing diets.42,43 At 
baseline, dietary intake will be assessed by the Vanderbilt Nutrition and Diet 
Assessment Core (full methods described under Measures below). Energy content of 
daily intake will be estimated based on the individual’s daily energy requirement using 
the Harris Benedict Equation with an activity factor of 1.2.44 By doing so, calorie level will 
be individualized to assure weight maintenance during the study. In addition to being 
weighed at each clinical testing visit, body composition will be evaluated via DEXA scans 
at clinical testing visit to assure no changes in either total fat or truncal fat mass 
influence study results.  
Subjects will be provided with daily meal plans that adhere to the composition of the 
treatment arm to which the subject is randomized. Meal plans will be developed by the 
co-Investigator (Silver) using NDS-R software (NDS-R version 2013, Nutrition 
Coordinating Center, Minn, MN) and instructed to subjects by the study dietitian at the 
end of study week 1 (see Schema below). To manipulate the carbohydrate amount (high 
vs low), we will alter the fat content of the diet. There will be no difference among diets in 
protein content. To manipulate type of carbohydrate (complex vs simple), we will provide 
instructions, the written meal plan, and a comprehensive list of which carbohydrate foods 
the subject can/can’t consume.  
To clearly delineate, simple carbohydrates are defined as those carbohydrates classified 
as mono- or di-saccharides, meaning they have one (glucose, galactose, fructose) or 
two (sucrose, lactose, maltose, trehalose) sugar units. Major sources of simple 
carbohydrates (or “sugars”) are: soft drinks, cakes, cookies, pies, fruit punch, sweet tea, 
candy, table sugar, and syrups. Complex carbohydrates are also known as “starches” 
and consist of the oligo- and poly-saccharides, meaning they have 3 or more sugar 
units. Major sources of complex carbohydrates (or “starches”) are: grains, cereals, 
legumes, corn, popcorn, pasta, rice, potatoes and vegetables. We recognize that major 
sources of both simple and complex carbohydrates have components of both and we 
are able to quantify these within a food using the NDS-R software.  
All meal plans will provide 3 meals and 2 snacks per day that meet the macronutrient 
composition and the diet treatment arm:  
 
• 
HTHS Diet: 55% total CHO (½ complex / ½ simple CHO), 30% fat, 15% protein 
• 
HTLS Diet: 55% total CHO (85% complex / 15% simple CHO), 30% fat, 15% protein 
• 
LTHS Diet: 35% total CHO (½ complex / ½ simple CHO), 50% fat, 15% protein 
• 
LTLS Diet: 35% total CHO (85% complex / 15% simple CHO), 50% fat, 15% protein 
 
 
 

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Power Analysis and Sample Size: Our primary outcome is a continuous variable, 
percent time pH < 4.0 in the 24hr period. This is based on the clinical gold standard of 
pH < 4.0 for > 5.5% of the 24hr period. To determine sample size, we used data from 
205 obese patients with chronic GERD from Dr. Vaezi's clinic population. In this sample, 
the SD for percent time < pH was 9.8 and the interclass correlation was 0.39 (  = 
2b / 
(
2b + 
2e)).  We used these values as inputs into a statistical simulation (10,000 
replications) to determine the probability of detecting any treatment group effect using 
the linear mixed effects model. The following table presents the power of an overall (4 
d.f.) test to detect various absolute changes in pH by diet groups (
1, 
2, 
3, 
4).  We 
assume n1=40 subjects per group complete the entire study and n2=5 or n2=3 subjects 
per group complete 80% of the study before returning for pH testing. We use a two-sided 
significance level of 0.05.   
Absolute effect size 
3.7%, 3.7%, 3.7%, 3.7% 
0%, 4.5%, 4.5%, 4.5% 
0%, 4%, 4%, 4% 
0%, 0%, 5%, 5% 
0%, 0%, 0%, 7% 
Power (n1=40, n2=5) 
0.80 
0.89 
0.80 
0.85 
0.87 
Power (n1=40, n2=3) 
0.79 
0.88 
0.79 
0.83 
0.86 
 
Power for different effect size scenarios that give 80%-90% power are presented in the 
table.  If the absolute change in percent time pH < 4 for each of the four diet groups is 
3.7%, we will have 80% power to detect any effect of diet. If 1 diet group is not effective 
and the other groups have a 4.5% effect, we have almost 90% power to detect a diet 
effect. In our pilot data, the 25th/50th/75th percentiles of percent time pH < 4 were 
4.8%/8.5%/12.4%. Thus, a 3.7% decrease is a change from the median to 25th 
percentile, a 4% decrease is a change from the 75th percentile to the median, a 5% 
decrease is a change from the 80th percentile to the median, and a 7.6% decrease is a 
change from the 75th to the 25th percentile. The standard error for any pairwise 
comparison between groups will be 1.9% under all scenarios (n1=40 and n2=3 or n2=5). 
 
2.3  SPECIFIC AIMS:  
Gastro-esophageal reflux disease (GERD) occurs in 25-30% of U.S. adults, including 
veterans,1 and the prevalence of GERD is increasing.2,3 GERD is the most common 
inpatient gastrointestinal (GI) disease discharge diagnosis and the most common 
outpatient diagnosis for GI disorders in the U.S. with > 9 million visits annually.1 The VA 
spends >$177 million yearly on outpatient prescriptions for GERD. Higher body mass 
index (BMI) is associated with increased risk for GERD,4-6 and the increasing prevalence 
of GERD is likely related to the obesity epidemic.2 Indeed, 72% of veterans are 
overweight or obese.7,8 The odds ratio of having GERD is 3-fold greater for obese men 
and 4-fold greater for obese women (compared to normal weight adults). Thus, the 
American 
Gastroenterology 
Association 
guidelines 
advise 
weight 
loss 
for 
overweight/obese people with GERD.9  
It has long been thought that several dietary factors (acidic foods, spicy foods, mint, 
chocolate, caffeine and alcohol) as well as a high fat diet may precipitate GERD 
symptoms. In fact, most studies on dietary factors have targeted total and saturated fat 
intake as risk factors. However, most of the evidence comes from epidemiological data 
or clinical data from hospitalized patients with the most severe forms of GERD 
(esophagitis and adenocarcinoma). When data are adjusted for BMI the relationships 
between total or saturated fat intake and GERD are not significant. Furthermore, weight 
loss trials utilizing low fat diets have not consistently demonstrated improvement in 
GERD symptoms.10 

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We recently conducted a nutrition intervention utilizing a low carbohydrate / high fat diet 
in 144 Caucasian and African American adults age 21-50 years with Class I obesity (BMI 
30.0-39.9). At baseline, 25% of subjects reported experiencing GERD symptoms 
(heartburn, reflux and/or indigestion) at least once a week. Over 1/3 used a proton pump 
inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) at least once a week. At 
baseline, we found that subjects with GERD had significantly higher total sugar intakes 
(101.6 ± 50.3 vs 82.5 ± 40.9 grams/day, p = 0.024), but not higher total fat intakes. 
Notably, total sugar intake was a strong predictor of having GERD symptoms (p = 
0.007). Most unexpectedly, all GERD symptoms and medication use had resolved by 
completion of the 9-week low carbohydrate / high fat diet intervention. Moreover, 
reduced total sugar intake was significantly associated with improved insulin sensitivity 
(HOMA-IR score: r =0.37, p =0.001), independent of weight loss. 
Overarching Hypothesis: Our overarching hypothesis is that the type (not just the 
amount) of dietary carbohydrate intake contributes to GERD symptoms in obese 
persons. 
Specific Hypothesis: Our preliminary findings suggest a physiological mechanism 
between dietary intake and GERD that may be related to type of dietary carbohydrate 
intake (complex vs simple carbohydrate). We hypothesize that modifying the type of 
dietary carbohydrate consumed - by reducing the proportion of simple carbohydrate 
(sugars) consumed - will reduce or resolve GERD symptoms and medication use in 
obese veterans with chronic GERD. We further hypothesize that the mechanistic effects 
of reducing simple carbohydrate intake is related to either: a) improved dietary fiber 
intake and/or glycemic load, and thus, reduced amount and duration of esophageal acid 
exposure; and/or b) improved insulin sensitivity which would positively influence the 
function of key gastrointestinal hormones (ie, gastrin, glucagon, GLP-1, ghrelin11) that 
regulate gastric motility and/or lower esophageal sphincter function.             
Aim 1: To determine effects of dietary carbohydrate consumed (amount and type) on 
percent time with esophageal pH < 4.0, as well as number of reflux episodes, GERD 
symptoms and GERD medication use, in 200 obese veterans who have chronic high 
frequency of GERD symptoms. To meet this aim we will use a randomized controlled 
trial in which we manipulate amount of total and simple dietary carbohydrate intake for 
duration of 9 weeks.  
Aim 2: To assess associations between GERD resolution variables and factors related 
to potential mechanisms by which modifying dietary carbohydrate intake could 
resolve/reduce GERD in obese veterans.  
2a: We will investigate associations related to whether the effect is nutritionally 
mediated by measuring change in dietary fiber load and dietary glycemic load, and 
thus, whether these changes are related to improved gastric acid secretion (% time 
pH < 4), gastric motility, and/or the other parameters that comprise the Johnson-
DeMeester score. 
2b: We will also investigate whether effects are associated with changes in the 
hormonal milieu by measuring hormonal response of gastrin, glucagon, GLP-1, 
ghrelin and insulin, which could potentially influence gastric acid secretion, gastric 
motility and/or lower esophageal sphincter function.    
 
 
 

Protocol Version #: 3.0 3.1 3.3. 
 
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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
3.0 
Animal Studies and Previous Human Studies 
 
PRELIMINARY DATA  
In a recently completed study designed to investigate the effects of a high fat diet on 
cardiometabolic outcomes in 144 obese adults (Silver and Niswender), we found that 36 
of 144 (25%) had a history of GERD symptoms and/or medication use at least once a 
week at baseline.  
Closer assessment of subjects’ dietary intakes revealed that subjects with GERD had 
significantly higher energy intakes, simple carbohydrate intakes (total sugar), sucrose 
intakes, and overall dietary glycemic load – but not higher dietary fat or protein intakes 
(Table 1). In addition, there was no difference in subjects’ intakes of caffeine, as well as 
alcohol, chocolate or other dietary factors commonly associated with GERD (data not 
shown). Notably, in regression modeling, total sugar intake was a strong predictor of 
having GERD symptoms (p = 0.007).     
Table 1. Baseline Demographic and Nutrient Differences  
  
  
  
GERD 
  
No GERD 
  
  
  
(N = 36) 
(N = 108) 
P-Value 
Demographics 
 
 
 
 
  
Age (y) 
39.2 ± 5.9 
 
35.9 ± 6.9 
 
0.011 
Race  
0.039 
        Caucasian 
30 (83%) 
70 (65%) 
  
        African American 
6 (17%) 
38 (35%) 
  
Nutrients (per day) 
  
Amount of Food (g) 
2675.7 ±  610.1 
2778.1 ±  815.9 
0.491 
Energy (kcal) 
2103.1 ± 435.2 
1840.1 ± 435.0 
0.002 
Fat (% kcal) 
37.2 ± 6.0 
38.7 ± 7.8 
0.311 
Protein (% kcal) 
15.6 ± 2.9 
16.9 ± 4.6 
0.095 
Carbohydrate (% kcal) 
46.5 ± 6.1 
 
43.9 ± 9.6 
 
0.135 
Total Fiber (g) 
16.8 ± 6.5 
15.2 ±  5.8 
0.177 
Soluble Fiber (g) 
5.9 ± 2.8 
5.0 ± 2.1 
0.037 
Total Sugar (g) 
101.6 ± 50.3 
82.5 ± 40.9 
0.024 
Sucrose (g) 
52.8 ± 37.8  
36.6 ±  23.5 
0.003 
Fructose (g) 
16.3 ±  12.6 
16.8 ±  12.1 
0.821 
Glycemic Load 
198.9 ±  51.4 
 
166.2 ±  59.1 
 
0.004 
Caffeine (mg) 
160.1 ± 112.6 
133.7 ±  102.6 
0.195 
HOMA-IR (score) 
2.9 ± 2.5 
  
2.5 ± 2.0 
  
0.278 
In the subjects with GERD, all GERD symptoms and medication use had resolved 
by completion of the 9-week low carbohydrate / high fat diet intervention. While 
there was no difference in the average amount of food consumed per day between 
subjects with GERD versus those without, the subjects with GERD did have significantly 
greater reductions in energy intakes, sucrose intakes, and overall dietary glycemic load 
(Table 2).  
 
 

Protocol Version #: 3.0 3.1 3.3. 
 
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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
Table 2. At Week 9 of Low Carbohydrate / High Fat Diet  
  
  
  
GERD 
  
No GERD 
  
  
Baseline GERD Status 
N = 36 
N = 108 
  
GERD Resolved 
36/36 
 
n/a 
 
P-Value 
Amount of Food (grams) 
-141.8 ±  573.7 
-179.2 ±  775.5 
0.821 
Energy (kcal) 
-372.7 ±  400.1 
-144.7 ±  425.4 
0.018 
Fat (% kcal) 
12.9 ±  6.3 
10.9 ±  8.2 
0.239 
Protein (% kcal) 
4.8 ±  3.7 
4.5 ±  4.5 
0.792 
Carbohydrate (% kcal) 
-17.5 ±  6.2 
-15.3 ±  8.9 
0.241 
Total Fiber (g) 
3.3 ± 8.4 
5.2 ± 5.7 
0.211 
Soluble Fiber (g) 
2.5 ± 2.9 
3.6 ± 2.7  
0.114 
Total Sugar (g) 
-62.1 ± 44.0   
-43.4  ±  42.1 
0.057 
Sucrose (g) 
-37.5 ±  28.2 
-22.3 ±  25.4 
0.013 
Fructose (g) 
-9.6 ±  12.8 
-8.6 ±  10.9 
0.711 
Glycemic Load 
82.5 ± 30.1 
 
62.2 ± 39.9 
 
0.018 
Caffeine (mg) 
117.2 ±  92.9 
 
101.9 ±  106.8 
 
0.513 
HOMA-IR Score 
-1.1 ± 1.8 
  
-0.3 ± 1.2 
  
0.018 
 
 
 
4.0 
Inclusion/Exclusion Criteria 
As race, age and gender have not been shown to affect GERD status, we will enroll any 
interested patient who meets the following criteria:  
Inclusion Criteria 
• 
Age: ≥ 21 years 
• 
BMI: 25-45 kg/m2 
• 
GERD diagnosis in the 
medical record which will 
be confirmed by study 
baseline pH testing, if 
baseline pH is not < 4.0 
for ≥ 5.5% of time during 
24hr testing, subject will 
be excluded. 
Exclusion Criteria 
• 
History of type 1 diabetes  
• 
Hernia > 5 cm  
• 
Current or remote history of esophageal 
stricture 
• 
Gastroparesis 
• 
Extra-esophageal GERD 
• 
Barrett’s esophagus or Esophageal 
adenocarcinoma 
• 
History of gastric or bariatric or 
esophageal surgery, radiation or cancer 
• 
History of gastrointestinal 
malabsorption 
• 
Alcohol averaging > 2 drinks per day 
during past 3 months 
• 
Pregnancy / Lactation  
 
 
5.0 
Screening & Enrollment  
 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
All recruitment procedures will be IRB-approved. Study participants will be recruited from 
the VA clinic patient population under the guidance of Dr. Walter Smalley, study co-
investigator and VA gastroenterologist. We anticipate that the majority of patients will be 
recruited from primary care clinics. We will also engage the VA pharmacy service, 
utilizing the robust electronic medical record system, to identify patients currently on 
prescriptions for GERD and who have relevant diagnoses (i.e., ICD-9 codes 530.81 and 
530.11) and are scheduled to come to a given clinic on a specific day. Our study nurse 
will work closely with charge nurses and clinic staff to identify potential subjects. Upon 
review of pharmaco-economic data from TVHS, we have identified that 45% of the total 
TVHS veteran population of 65,000 are obese and that there are currently 19,094 
patients on PPIs. In the course of clinic interactions, clinic staff will determine whether a 
patient has general interest in participating in this study (i.e., provides verbal consent to 
be approached by study nurse for full description of study procedures). From our more 
intensive GI clinical trials, we currently enroll 30-35% of patients approached (personal 
communication W. Smalley).  
Based upon prior published studies in VA facilities, successful recruitment for patients 
with GERD has been documented from the following clinical settings: internal 
medicine/primary care clinics, emergency department, and lastly, general GI clinics. We 
will initially focus our recruiting efforts on the Nashville campus, the Charlotte Avenue 
primary care clinic facility, and at the Murfreesboro Alvin York campus, as a high volume 
of primary and specialty care occurs at these three sites.   
A secondary recruitment strategy will involve the placement of IRB approved posters 
and brochures in the waiting areas of target clinics with basic study information and a 
contact line for potential subjects to register potential interest. We anticipate screening 6-
10 subjects per week for eligibility. We will perform a baseline pH study after consent. 
Based on clinical experience, we expect 15-20% of Vets diagnosed with GERD will be 
screen failures as they will not have pH < 4.0 for > 5.5% of a 24-hour period (personal 
communications W Smalley & M Vaezi). These 15-20% will be excluded from study as 
the underlying hypothesis is that low carbohydrate / low sugar diet will reduce % time 
with pH < 4.0 to < 5.5%.  Thus, we expect to meet our targeted enrollment of 1-2 
subjects per week, which is based on the ability to schedule this number of patients in 
the GI clinic for pH testing. Thus, our recruitment and enrollment goals appear to be 
highly feasible with such a huge patient population at TVHS (currently a total of 65,000 
patients; 29,250 of whom are obese, and 19,100 are currently on PPIs, thus ~65% of 
these obese vets have GERD).  
 
6.0 
Study Procedures 
 
Randomization: 200 subjects (50 per arm) will be randomized to diet treatment arm. we 
have reviewed drop-out rate from clinical trials in gastroenterology in this population (W. 
Smalley and M. Vaezi personal communications), which would predict a 20% drop out 
rate. The number of subjects to enroll reflects a completion rate of 80% (enroll 50 per 
arm = 200 subjects x 0.80 = 160 completers). In considering that drop out could be 
higher, we will now include subjects in our final analyses who notify us they are 
dropping-out between weeks 7–9 by asking them to return for a final visit at the time of 
drop-out (we do this regularly and get agreement from about 66% of subjects to return 
for a final testing session even if they are not continuing to wk 9). Randomization of 
subjects will be carried out using unified reproducible methods (i.e. saved random 
number seed) provided by the Biostatistician (Slaughter). We will use a permuted block 
randomization scheme, stratifying on gender to ensure this covariate is balanced 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
between randomization groups. The block size will be varied randomly. Treatment 
assignments will be contained in sealed, thick envelopes to be opened after informed 
consent is obtained. 
Overall Schema: 
 
Timepoint 
  
Baseline 
Day 1-7 
End Wk 1 
Day 8-57 
Day 57-63 
End Wk 9 
Consent & Enrollment 
X 
Randomization 
X 
Bloodwork 
 
X 
 
X 
 
X 
X 
Diet Intervention 
Off PPIs #1 
Clinical Testing #1 
X 
Off PPIs #2 
Clinical Testing #2 
  
X 
 
Testing Procedures:  
Baseline levels of all measures listed below will be obtained prior to study day 1.  
PPIs will be stopped for 1 week, medications that affect gastric motility for 2 days, H2RAs 
for 2 days, and antacids for 2 days - prior to testing on study days 7 and 63. Additional 
blood work will be drawn on study day 57 for evaluation of levels prior to discontinuation 
of PPIs #2.  
Subjects will be instructed to stop eating and drinking, except water, at 10pm on the 
evening before each clinical testing day. Thus, subjects will arrive at the VA on study 
days 7 and 63 NPO. Subjects will be escorted by study staff from the VA to the 
Vanderbilt Clinical Research Center at 0700. Subjects will be admitted to a private 
outpatient room (has private bed and bathroom). An updated medical history will be 
obtained to ensure absence of recent/current illness. CRC nursing will obtain vital signs 
and perform the blood draw. As part of the blood draw, female subjects will have a 
pregnancy test (via serum βHCG). The study dietitian will perform anthropometric, body 
composition (DEXA), dietary and GERD symptom survey measures as described below. 
The subject will then be escorted by study nurse to the Vanderbilt GI Clinic for 
impedance monitoring and gastric emptying test procedures under the guidance of Dr. 
Michael Vaezi (study co-investigator), as described below. Impedance monitoring will 
continue for a 24-hour period. Subjects will be provided with a meal that is consistent 
with the diet intervention and the treatment arm they are assigned to before being 
discharged home. The study nurse will telephone subjects in the early evening to assure 
no problems from study procedures have developed. Subjects will return to the VA to 
meet briefly with the study nurse on the day after clinical testing to allow data retrieval 
and return of impedance monitoring and gastric emptying equipment.      
For these Testing Visits, at the end of study week 1 and study week 9, participants have 
the choice of staying overnight in a private room at the Vanderbilt Clincial Research 
Center for the 24-hour period of testing, or they can return to the Vanderbilt Digestive 
Disease clinic on the morning after the 24-hours of pH and SmartPill monitoring for the 
removal of the pH catheter and collection of the recording devices. 
 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
 
 
Measures: to be performed in the fasting state at baseline, end study week 1, 
pre/post study week 9 
• 
Bloodwork: 
• 
Glucose: Plasma glucose concentration will be analyzed in triplicate via 
glucose oxidase method using a Beckman glucose analyzer at the VA 
Clinical Laboratory.  
• 
Insulin: Plasma insulin concentration will be shipped to LabCorp and 
analyzed by radioimmunoassay method. 
• 
HOMA-IR: Calculated from glucose and insulin values.   
• 
Hormones: Serum gastrin will be assayed at LabCorp. Glucagon and GLP-1 
by Luminex multiplex assay at the Diabetes Hormone core lab. Serum ghrelin 
(active acylated form) by radioimmunoassay at the Diabetes Hormone core 
lab. While several other hormones are involved in gastric acid secretion and 
motility, we have chosen two key stimulators (gastrin and glucagon) and two 
key inhibitors (GLP-1 and ghrelin), as well as insulin, to investigate in this 
proposal utilizing a dietary intervention in obesity.      
• 
Anthropometrics:  
• 
Height (m) and Weight (kg) measured on calibrated digital equipment will be 
used to calculate BMI.  
• 
Waist Circumference” will be measured using a flexible tape at the level of 
the umbilicus.45 
• 
Body Composition: In addition to total and regional body composition (fat, lean 
and bone mass) obtained from the Lunar iDXA (GE Healthcare), we will use new 
technology recently acquired by VICTR to estimate visceral adipose tissue (VAT) 
– a possible risk factor for GERD.46 This fully automated approach to capture 
VAT has been validated against CT47 and offers several advantages to MRI or 
CT: fast, low cost, exposes one to less radiation, and makes serial 
measurements possible.  
• 
Metabolic Testing: To capture a more objective measure of change in 
energy balance due to the dietary intervention, we will perform indirect 
calorimetry by metabolic cart while subjects are at the CRC on week 1 and 
9. 
• 
24 hour urine collection: To effectively measure how well the body processes 
food intake 
• 
Dietary Intake: will be assessed via averaging three 24-hour diet recalls 
obtained at baseline and again within a 7-day window of each clinical testing visit 
(study weeks 1 and 9). Recalls will be performed by the Vanderbilt Nutrition and 
Diet Assessment Core using the USDA multi-pass methodology,48,49 a 
standardized script, and computer-generated prompts (NDS-R, v. 2013, Nutrition 
Coordinating Center, Minn, MN). We are familiar with underreporting especially in 
people with high BMI and use portion size tools and statistical methods to assure 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
data reliability. The 1st of 3 recalls will be in-person at the CRC, which allows 
training of subjects in the interview methodology. 
• 
Medication Use: will be assessed by two methods: a) we will provide subjects 
with a notebook that includes daily logs for them to record medication type and 
amount; and b) weekly interview by study nurse. In addition, we now have 
bloodwork being drawn pre and post weeks 1 and 9 that will inform medication 
use by measurement of hormone levels, i.e., gastrin.    
• 
24-Hour Impedance Monitoring: will be performed by using a combined MII-pH 
monitoring device (Sandhill Scientific Inc; Highlands Ranch, CO) comprising a 
data recorder (Sleuth System; Sandhill Scientific Inc) and a 2.1 mm diameter 
polyvinyl catheter embedded by one pH and 6 impedance sensors at predefined 
positions. The pH sensors are calibrated before placement using standardized 
buffer solutions at pH 4.0 and 7.0 per manufacturer. The catheter is placed 
intranasally so that the esophageal pH sensor is positioned 5-cm above the 
manometrically defined upper border of the lower esophageal sphincter (LES). 
Intraluminal impedance is measured at 3, 5, 7, 9, 15 and 17cm above the LES. 
Data sampling frequency for both impedance and pH sensors is 50 Hz. Data are 
downloaded from the recorder and analyzed using BioView Analysis software 
(Sandhill Scientific Inc). Reflux episodes are identified by computerized detection 
(Autoscan; Sandhill Scientific Inc.) of proximally directed decreases in 
impedance. Tracings are also manually reviewed by an experienced investigator 
(Vaezi) to confirm accuracy and correct errors. Total, upright and supine reflux 
events are recorded.  Acid reflux events are defined as those with pH ≤ 4 and 
non- or weakly acid reflux events are those occurring at pH > 4. 
• 
Gastric Emptying: Subjects will swallow an activated and calibrated SmartPill 
wireless pH, pressure and temperature capsule. The capsule houses sensors for 
pH, temperature and pressure. Shape and dimensions of the capsule are: 
 cylindrical, 26.8mm long by 11.7mm in diameter. The capsule has a pH range of 
0.5–9 with an accuracy of ± 0.5 pH units. The pressure sensor has a pressure 
range of 0–350 mmHg with an accuracy of 5 mmHg below 100 mmHg and 10% 
at or above 100 mmHg. The temperature sensor has a range of 25–49 C, with an 
accuracy of ± 1 C. Subjects ingest the capsule with 50 cm3 of water and 
afterwards begin eating a standard meal with an additional 120 cm3 of 
water. After activation and ingestion, the capsule signals are transmitted from 
within the GI tract and are captured by a receiving antenna incorporated into the 
receiver. The portable receiver worn by the subject receives and stores data 
which is downloaded to a PC computer. The transfer of data to the PC is 
accomplished via placement of the receiver in a docking station which provides 
an interface for data transmission to a computer as well as connections for 
battery charging. MotiliGI software (SmartPill, Inc.) loaded on the computer 
supports the data transfer, analysis of the recorded date, and displays the test 
results. Capsule gastric emptying time is defined as the duration of time from 
capsule ingestion to an abrupt pH rise (usually >3 pH units) from gastric baseline 
to a pH >4 as the capsule passes from the acidic antrum to the more alkaline 
duodenum. 
• 
GERD Symptoms:  

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
• 
GERD Symptom Assessment Scale (GSAS) will be used to measure the 
frequency, severity and distress for GERD symptoms. Internal consistency is 
>0.80 for symptom severity and distress scales. Validity, stability and 
sensitivity to change in symptom severity over time have been confirmed.17,50   
• 
GERDQ is a 6-item self-administered questionnaire designed for diagnosis 
and management of the GERD patient. It differentiates patients with 
occasional reflux symptoms from those with frequent symptoms. Two items 
measure impact of GERD symptoms on daily life and 4 items are used to 
monitor and evaluate the impact of treatment over time.18  
 
 
7.0 
Risks 
 
• 
Following a special diet and keeping a record of what is eaten and  
medication use may be inconvenient to participant. 
• 
The participant will be required not to eat or drink, except water, after 10 
pm on the night before testing visits at the end of study weeks 1 and 9. 
This may cause the participant to have a headache or a feeling of 
weakness, or the participant may become irritable. 
• 
Blood draw: Blood draws can cause redness, soreness, bleeding or 
bruising at the needle stick site. The CRC nurses will be careful and use 
sterile technique. Sometimes people feel faint. The nurse may put some 
cream (called EMLA) on the skin to numb the area so the participant will 
not feel the needle stick as much. The numbing cream may make the skin 
change color, but this is rare. 
• 
DEXA: Because DEXA is an x-ray, the participants are exposed to some 
radiation.  The amount of radiation from the 2 DEXA scans is equal to the 
amount of radiation in the natural environment if the participants were to 
walk around outside for 17 days.   
• 
Because the participant will not be taking medication for GERD while  are 
participating in this study, it is possible that GERD symptoms may get 
worse. 
• 
24-hour pH Monitoring:   
• 
Lidocaine:  Lidocaine, a numbing drug, has an awful taste and causes 
a strange feeling in the mouth.  There is a rare side effect that this 
drug may cause hoarseness and loss of voice.  There is a very rare 
risk that this drug may cause problems with heart rhythm. 
• 
Possible risks for the participants during 24-hour study include:  nasal 
discomfort, injury to nasal passages such as nose bleedings, allergic 
reaction to lidocaine gel used to numb the nasal passages for 
placement of tube, and rupture of the esophagus by the long tube 
which may require an operation. 
o Smart Pill: You may experience discomfort when swallowing the 
smart pill. In rare cases, the smart pill could get lodged or stuck in 
your esophagus. This may require a procedure to remove the pill. If 
you have an abnormality in how your esophagus works this may 
increase the risk.  

Protocol Version #: 3.0 3.1 3.3. 
 
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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
• 
 
 
 
Risks that are not known: 
There are no known risks with any of the 4 diets. If new information is discovered 
that may affect the risks or benefits of this study, the participant will be told so 
that he/she can decide whether or not to remain in the study. 
 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk  
to Participants or Others 
 
All serious and unanticipated adverse events or problems involving risks to 
subjects that may possibly be or are known to be related to the research activity 
will be reported promptly to the IRB office per Vanderbilt University IRB Policy.  
The PI will ensure proper data and safety monitoring for the materials and data 
used for the purposes of this study. 
 
9.0 
Study Withdrawal/Discontinuation 
 
Subjects may choose not to participate in this research study.  This decision will 
not alter the routine care administered by the physician or the risks associated 
with standard of care procedures.  Additionally, the participant will be removed 
from this study if the investigator does not think it is in best interest for the subject 
to be in this study.  If the participant is removed from the study he/she will be told 
the reason why.   
 
 
10.0 Statistical Considerations 
Data Analysis: To determine if percent time with pH < 4 differs by diet treatment group, 
we will use multivariable linear regression modeling. Models will include baseline percent 
time pH < 4.0 and other variables key to disease severity to improve model precision 
and the diet treatment groups as indicator variables. We will determine if the primary 
outcome (% time pH < 4.0) differs by intervention arm. We will use a linear mixed effects 
regression model to determine if percent time < pH 4 (Yij) differs by diet group. The 
model will incorporate the proportion of time each subject is observed so that subjects 
that drop out 2 or fewer weeks early are included in the analysis and allowed to have a 
smaller response to the diet intervention.  In particular, for subject i at time j, Yij =  + bi 
+ 
1 X1i*tij) + 
2 X2i* tij) + 
3 X3i* tij) + 
4 X4i* tij) + eij where bi ~ N(0, 
2b) is a subject 
specific random intercept used to account for repeated observations on the same 
subject, 
 is the mean at baseline, Xpi are indicator variables for diet group assignment 
with corresponding effects at 9 weeks 
p (p=1,..,4), and independent errors eij ~ N(0, 
2e).  The time the outcome is measured, tij, is included in the model such that ti1 = 0 at 
baseline, ti2 = 1 for subjects who complete the entire study, and ti2 = p for subjects who 
leave after completing a proportion p of the weeks and come back for final pH testing.  
Subjects will be included if p >= 0.8. 
It is understood that some subjects may drop-out, and thus, not return for the final follow-
up visit at week 9, in which case we would have missing values for some response 
variables. Frequently such dropouts are not a random sample of the entire cohort, and 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
analysis of only the complete cases would bias the results. We will now request to 
subjects that inform of us they are dropping out between weeks 7 to 9 that they come in 
for a final visit. We have found that about 2/3 of subjects will agree to come in for a final 
visit even if they are not continuing to the end of study (week 9). This will significantly 
reduce the potential for missing data. We will also attempt to obtain the specific reason 
for dropout on a case by case basis. Indirect information about the nonrandom dropouts 
will be obtained by using binary logistic models to predict the probability of dropping out 
using baseline variables. Thus, the impact of dropout on our results will be compared 
using assumptions that vary from missing completely at random to informative missing.  
 
Sensitivity Analyses: We will use the daily diet data and daily medication checklist (type 
and amount) to conduct secondary analyses and verify the assumptions of our primary 
model. Summary statistics by diet group will be calculated to determine if weight loss, 
PPI use, total CHO, and simple CHO are consistent with the study design.  We will also 
use the linear mixed effects model to determine if total and simple CHO are associated 
with total percent time < pH 4 by replacing the indicator variables in the primary model 
with these continuous covariates and their interaction. A secondary analysis of changes 
in PPI use over time will be considered.  For this analysis, we will use the diary card data 
to create continuous variables of the weekly dose of PPI.  PPI dose will be the outcome 
in a linear mixed effects regression model that includes time modeled flexibly using 
restricted and diet group indicators.  An analogous model using weight as the outcome 
will be estimated. Our study is designed for subjects to maintain weight, but if weight 
loss differs by treatment arm, it may introduce confounding into our study. We will 
include weight loss as a covariate in our regression model to determine if our results are 
altered compared to the main analysis. This additional sensitivity analyses will be 
conducted as needed, for example where weight change is significantly different among 
groups, to assure effects are due to dietary not body weight change.  
Interpretation: Given our expertise in nutrition, metabolism and obesity (Niswender and 
Silver), GERD (Smalley and Vaezi), and GERD biostatistics (Slaughter), our group is 
ideally suited for executing and interpreting this study. We predict that we will uncover 
key diet related factors driving GERD symptoms and esophageal acid exposure in the 
obese Veteran, and we will develop a predictive risk model based on sound science. 
Physiologically, the proposed study will determine whether changes in several plausible 
gut hormones and/or improvement in insulin sensitivity is associated with the 
improvement in GERD with the dietary intervention.   
Our preliminary data suggest that reduction of simple carbohydrate was most robustly 
associated with GERD resolution. The current study design will more rigorously address 
whether it is simple or total carbohydrate that is the driver of GERD symptoms and 
reflux. This has important implications for the development of more broadly disseminated 
dietary recommendations; a moderately high carbohydrate but low simple carbohydrate 
diet may be more tolerable to certain individuals than a low total carbohydrate approach. 
Conversely, if total carbohydrate is determined to be the major factor in the response, 
we will by definition be suggesting fairly high-fat and high-protein dietary intakes. Such 
approaches are increasingly recognized to have efficacy for weight loss as well as 
improvement in cardiometabolic parameters such as lipid profiles. Although dietary fat 
intake has been positively associated with GERD in obese subjects,52 the 4-5 
investigations comparing effects of high fat to low fat diets on esophageal acid exposure 
and GERD symptoms have shown no worse outcomes with high fat diets.20-23 Certainly 
in metabolically at risk populations (such as obese Veterans) we would be conscientious 

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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
regarding the source and composition of dietary fat intake, as well as the protein load of 
the diet.  
The next level of analysis, for example, if lowering simple CHO intake reduces 
symptoms or esophageal acid exposure, will determine whether it is related to total 
dietary fiber intake or glycemic load. This analysis will reveal the extent to which 
“processing” of food ingredients contributes to GERD symptoms. The finding that higher 
dietary fiber and/or lower glycemic load is associated with less GERD would suggest 
that somewhat less of a focus on macronutrient composition (i.e., CHO vs fat) may be 
warranted, with more of a focus on consuming foods closer to their natural state.   
Finally, by profiling several relevant gut hormones and assessing insulin sensitivity, we 
will investigate relationships for factors involved in plausible biological hypotheses for the 
effects of dietary carbohydrate on GERD symptoms. Our observation that reduction in 
simple CHO intake improves insulin sensitivity is consistent with a nutrient excess 
mechanism for insulin resistance. The mechanistic link between insulin sensitivity and 
GERD is most often considered in the context of weight loss, reduced waist 
circumference and improvement in abdominal pressures, and GERD symptoms. Here 
we investigate relationships that may suggest that improving insulin sensitivity 
independent of weight loss improves GERD. This has important implications for clinical 
translation, as induction of significant weight loss, and especially, long term maintenance 
of weight loss is a major clinical challenge. To reap clinical benefits on GERD and GERD 
symptoms without the requirement for weight loss would be a major clinical advantage.  
While gastrin release is not clearly understood to be differentially regulated by different 
macronutrients, GLP-1 and other gut hormones may well be. Thus, we will determine 
whether changes in the levels of any of the proposed gut hormones correlate with 
improvement in GERD. Identification of such an effect will drive specific hypotheses for 
future studies to uncover the mechanisms and clarify a mechanistic role in GERD 
response. 
Thus, analysis of the data from the proposed study will determine which factor(s), fiber 
or glycemic load, total or simple carbohydrate, lower or higher fat in the context of more 
or less simple sugar, or gut hormones, should be targeted in next phase larger scale 
intervention studies. These findings will also drive the development of future experiments 
designed to understand the mechanistic effects of the optimal diet for GERD.  
 
11.0 Privacy/Confidentiality Issues 
 
All efforts, within reason, will be made to keep  personal information in the participant’s 
research record confidential. Careful safeguards are in place, and confidentiality will be 
maintained by coding data and blood samples using only a number to identify the data. 
The number assigned will be specific to this study and will not be related to other 
personal identifiers such as medical record number, telephone number, social security 
number or initials. The identification number will only be known to the study staff. The 
record linking the study number with the participant’s name will be maintained by  
Dr. Niswender, Dr. Silver and the study team.  It will be kept in a locked research office 
and in a locked file cabinet. Computer data will be password-protected.  
 
The Sponsor and/or Vanderbilt may share the participant’s information, without 
identifiers, to others or use it for other research projects not listed in this form.  The 
Sponsor, Vanderbilt, Dr. Niswender, Dr. Silver and the study team will comply with any 

Protocol Version #: 3.0 3.1 3.3. 
 
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Protocol Date: February 4, 2016 March 2, 2016February 13, 2019 
and all laws regarding the privacy of such information.  There are no plans to pay the 
participant for the use or transfer of this de-identified information. 
 
In compliance with the National Institute of Health data sharing initiative, imaging data 
without any personal information attached may be shared with other investigators or 
public data repositories, which provides the research community with open access to 
datasets contributed by labs around the world. Information will be completely 
anonymized with demographics limited to age (accurate to the year up to 90 years old, 
or “90+” for older individuals), gender (male, female), group membership (e.g., 
disease/treatment state) and handedness. Data will be transferred using secure file 
transfer protocols. 
 
12.0 Follow-up and Record Retention 
Follow-Up: Since the study requires that obese subjects maintain their body weight 
during study, they will be provided with a meal plan for caloric restriction and nutrition 
counseling by the study dietitian upon completion. 
 
Record Retention:  The study results will be kept in the participant’s research record for 
at least six years after the study is finished.  At that time, the research data that has not 
been put in the medical records will be kept for an unknown length of time. Any research 
data that has been put into the medical records will be kept for an unknown length of 
time. Unless told otherwise, the participant’s consent to use or share the PHI does not 
expire. If the participant changes his/her mind, he/she will be asked to contact Dr. 
Niswender in writing and let him know that he/she withdraws consent.  Dr. Niswender’s 
mailing address is: 315 Medical Arts Building, 1211 21st Ave South, Nashville, TN 37212. 
At that time, we will stop getting any more data about the participant, but, the health data 
we stored before the participant withdrew consent may still be used for reporting and 
research quality. If the participant decides not to take part in this research study, it will 
not affect treatment, payment or enrollment in any health plans or affect the ability to get 
benefits.  
 
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