Tolerability of an Amino Acid-based Oral Rehydration Solution in Children With Short Bowel Syndrome
Phase: NA
Conditions: Short Bowel Syndrome
Sponsor: Boston Children's Hospital

Enterade® Protocol  
 
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Project Title:  Tolerability of an Amino Acid-based Oral Rehydration Solution in Children with 
Short Bowel Syndrome 
 
Principal Investigator: Christopher Duggan, MD, MPH 
 
Study Site: Boston Children’s Hospital (BCH) 
 
Protocol Date: July2017 
 
1. Background 
Intestinal failure (IF) is defined as a critical reduction of the gut mass/function below the 
minimum needed to absorb nutrients and fluids required for adequate homeostasis, growth and 
development. It is a condition in which severe malabsorption results in the need for lifesaving 
parenteral nutrition (PN) or enteral nutrition (EN) (1). In neonates, the most common cause of IF 
is surgical short bowel syndrome (SBS), which is defined as the need for prolonged parenteral 
nutrition following surgery for congenital or acquired gastrointestinal disorders. SBS is 
characterized by a compromised bowel absorptive capacity because of a reduced mucosal 
surface, which if left untreated can result in diarrhea, fluid and electrolyte imbalance, and 
malnutrition. Limiting the duration of PN by promoting enteral autonomy has been shown to 
decrease complications and improve survival for pediatric patients with IF (2).  
 
When possible, the gastrointestinal tract is preferred for feeding because it is the most 
physiological and safest way to provide nutrition. Enteral feeding tolerance in SBS is evaluated 
by measuring stool or ostomy output, by the observation of clinical signs of intolerance, as well 
as serum electrolyte concentrations (3). Standard oral rehydration solutions are commonly used 
in the management of excessive intestinal fluid loss, as adjunctive therapy to enteral nutrition. 
 
In children with intact intestinal tracts presenting with 
diarrhea, oral rehydration solution (ORS) is a simple cost-
effective solution containing glucose and electrolytes that 
can be used to prevent and treat dehydration due to diarrhea 
of any cause across all ages (4). Standard ORS takes 
advantage 
of 
a 
glucose-coupled 
sodium 
transport 
mechanism with absorption of molecules across the luminal 
membrane being facilitated by the protein sodium glucose 
co-transporter 1 (SGLT1) (figure 1). To take advantage of 
this Na-glucose co-transport, WHO and UNICEF currently 
recommend a glucose-based ORS with a total osmolarity of 
245 mmol/L for the management of childhood diarrhea (5).  
In the past few decades, different formulations and 
substrates  including sucrose (6), glycine (7), alanine and glutamine (8), of the standard WHO-
ORS have been attempted.  
 
There is limited data regarding the use of oral rehydration solutions in the setting of SBS with 
bowel resections involving the different parts of the small and/or large bowel. Studies in adults 
confirm that ostomy output is highly correlated with ostomy sodium concentration (9), and 
treatment guidelines generally recommend replenishment of ostomy losses with oral glucose 
electrolyte solutions (10).  . In infants and young children, there is only a single case series that 
evaluated ORS use in infants who had undergone diverting ostomy. Five infants (3 with 
intestinal atresias, one with colonic aganglionosis and one with midgut volvulus) were treated 
with Orosal 65 (an ORS containing Na 65 mmol/L, glucose 20 g/L and osmolality 281 mOsm/kg) 

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in a volume that replaced ostomy losses (range 45-105 ml/kg/day) (11). Although improvements 
were claimed, no detailed data were presented on serial electrolytes, ostomy output or clinical 
outcomes.  
 
Thus there is very little published data on ORS in children with SBS, and a need to measure 
and document outcomes. This preliminary study will evaluate tolerability and palatability of 
enterade® among pediatric patients with SBS and help inform a future single-center, cross-over 
randomized control trial between enterade® and a glucose-based ORS (ie. Pedialyte/Gatorade).  
 
Specific Aim 
1. To monitor tolerability of enterade® compared to current ORS (as measured by stool 
output, consistency, frequency). 
2. To measure palatability of enterade® compared to current ORS. 
 
Hypothesis 
1. Enterade® will be better tolerated compared to current ORS with less frequency of 
abdominal distension, stool and emesis frequency. 
2. Enterade® ORS will be comparable to current ORS with similar taste ratings.  
 
2. Methods 
We propose an open label single center pilot study to evaluate the tolerability and palatability of 
an amino acid-based ORS, enterade® (advanced oncology formula), among patients with SBS.  
 
Enterade® (advance oncology formula) contains no 
glucose, but does contain five amino acids (AA) that 
can function as sodium co-transporters (Table 1). The 
amino acids in enterade® were selected based on the 
optimization of the following functions: 1) Amino acids 
that showed significant coupled sodium absorption; 2) 
Amino acids that decreased paracellular permeability; 
3) Amino acids that did not stimulate electrogenic 
chloride secretion; 4) Amino acids that increased crypt 
number, proliferation, and increase in villous height or 
surface area of absorption (12). Enterade® (advance 
oncology formula) is commercially available.  
 
 
3. Preliminary data  
Enterade® (advanced oncology formula)has been demonstrated to reduced gastrointestinal 
symptoms in patients with gastrointestinal toxicity in the setting of chemotherapy.  
 
 
In a preliminary study, enterade®  ( advanced oncology 
formulation) was provided to 139 cancer patients experiencing 
gastrointestinal chemotherapy and radiotherapy induced 
toxicity such as diarrhea, nausea, vomiting, dehydration, 
weight loss, and malaise. After a 2-week observation, 118 
subjects completed toxicity forms and were therefore eligible 
for evaluation; 60 patients used enterade® >7 days, 43 
patients used enterade® for <7 days, and the remaining 15 
patients did not use enterade®.The severity of initial 
Table 1: Composition Enterade® ORS 
(Advanced Oncology) 
Aspartic Acid (g/L) 
1.06 
Threonine (g/L) 
.95 
Tyrosine (g/L) 
.21 
Valine (g/L) 
1.17 
Serine (g/L) 
1.05 
Sodium (mEq/L) 
42.25 
Potassium (mEq/L) 
10 
Citrate (mEq/L) 
3.35 
Magnesium (mEq/L) 
1.2 
Calcium Chloride  (mEq/L) 
1.2 
Osmolarity (mOsm/L) 
162.2 

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symptoms and age ranges were similar in all groups. As shown on Figure 3, statistical 
difference (p=<0.001) was appreciated in reduction of gastrointestinal symptoms (diarrhea and 
nausea) in patients who consumed enterade® product for greater than 7 days.  Weight loss, a 
difficult clinical problem, was assessed as an individual endpoint and reached statistical 
significance. Patients who used the product for >7 days had a 69% improvement, compared to 
13% in <7 days, and 0% improvement on those who did not use enterade® (p=0.024). 
Dehydration improvement was significance among patients who used enterade >7 days, 
compared to patients consuming enterade® <7 days. 
 
 
A recent published study among mice with 
irradiation induced gastrointestinal toxicity 
evaluated the mechanism of enterade® ( 
advanced oncology formula) and altered 
gastrointestinal function demonstrating an 
increase in crypt progenitors compared to 
saline (12).  Mice treated with enterade® 
(advanced oncology formula) were also 
appreciated to have a significant difference in 
villous length and crypt count compared to 
saline treated mice (Figure 3).  
 
4. Experimental Design  
 
Study Design: This is a single center, open label pilot study among short bowel syndrome (SBS) 
patients at a major national pediatric intestinal rehabilitation referral center. Patients with SBS 
will participate in a 14-day trial measuring the tolerability and palatability of an AA-ORS, 
enterade® (advanced oncology formula), in addition to their regular diet. Eligible intestinal 
rehabilitation patients will be identified through the Center for Advanced Intestinal Rehabilitation 
(CAIR) CAIR clinic at Boston Children’s Hospital. 
 
The CAIR program was one of the first multidisciplinary programs for intestinal failure 
established in the United States in 1999. The Center cares for more than 300 patients with IF 
and has pioneered novel surgical and nutritional therapies for this condition (1, 3, 13-18). In 
addition, the PI has led numerous trials that evaluate the safety and efficacy of ORS (4, 19-22). 
 
Inclusion criteria:  
 
Male and female patients with a diagnosis of short bowel syndrome (as defined by surgical 
therapy for congenital or acquired gastrointestinal disease) between the ages of 1-17 
 
Patients who are in intestinal continuity or with diverting ileostomy, jejunostomy 
 
Patients must be on a stable enteral nutrition regimen with oral rehydration fluids that are 
taken orally.  
 
Stable GI medication regimen (e.g., loperamide, cholestyramine, SBBO regimen) 
 
Exclusion criteria:  
 
Patients receiving IV antibiotics within the previous 72h. 
 
Patients with a primary diagnosis of a motility disorder (e.g., chronic intestinal pseudo-
obstruction) or epithelial cell disorder (e.g., microvillus inclusion disease) 
 
Malnourished (as defined by WHZ <-2)  
 
Figure 3. AA-ORS (enterade® oncology formula) 
increased crypt count and villus length following 
irradiation. *Indicates statistically significant difference (P 

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Sample Size: We propose a pilot study using a sample of 5 patients with short bowel syndrome 
who are currently outpatient. 
 
Methods and materials  
The design of the trial is influenced by several pertinent clinical features of patients with short 
bowel syndrome. Each patient with SBS has unique anatomic and demographic factors that 
affect absorptive function (e.g., age, residual bowel length, underlying diagnosis of SBS). Oral 
rehydration solution frequency and quantity will be tailored to each individual participant based 
on current ORS volume tolerability. It will be administered orally in addition to their regular diet. 
Enterade® will be distributed in 8 ounce sealed bottles by the research team, free of cost, to 
participating patients.  
 
Eligible participants will document daily fluid intake, stool output and other subjective intestinal 
parameters of tolerability on a daily dairy (Refer to Appendix A, B, D).  
(1) Stool output:  For patients with ostomies, we will obtain total daily ostomy output 
(mL) during each 14-day ORS study period.  Patients in intestinal continuity will 
measure frequency and consistency of stool (see Appendix C). 
(2) Measures of feeding intolerance will be monitored by frequency of emesis or 
abdominal distension. 
(3) Patients will rate the palatability of their current ORS on day 1, and Enterade® on 
day 14 utilizing the facial hedonic method (23). 
 
We will obtain and record the following patient information: demographic information, medical 
and surgical history, residual bowel length, anthropometrics (length, weight), specifics of 
parenteral nutrition support, and type and feeding rate of enteral nutrition at time of enrollment 
(Table 1). Palatability facial hedonic measurements and symptom log sheets will be mailed back 
on pre-labeled enveloped supplied during enrollement. 
  
 
 
5. Analytical approach  
The primary outcome will be tolerance of enterade®, as measured by frequency of abdominal 
distension, emesis as well as changes in stool frequency and consistency from baseline.  
Exposure viable is the change in ORS to enterade®. 
 
The secondary outcome will be each participants rating of enterade® taste as measured on a 
100-mm visual analog scale (worst (0mm), best taste (100mm)).   
 
 
6. Risks & Benefits 
 
Recruitment
Day 0
Day 7
Day 8-14
Day 15
Weight ( Kg)
x
Pre-solution data collection
x
Enterade solution
x
x
Phone call 
x
x
Symptom Diary
x
x
Palatability   scale
x
x
Week 2
x
x
Week 1
Table 1: Schedule of Events
Day 1-6

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Risks: 
The risks associated with enterade® are anticipated to be minimal. Enterade® (advanced 
oncology formula) is an oral rehydration solution that is commercially available 
(https://enterade.com/) and generally regarded as safe.  
 
Questionnaires are brief and will not have personal identifiers. Confidentiality of subjects will be 
preserved at all costs. All patient identifiers will be removed from the study record and secured. 
 
Benefits: 
Our cumulative discoveries from five patients have the potential to aid in our understanding of 
outcomes while on an amino acid based oral rehydrating solution in children with SBS.  During 
our pilot trial, tolerance and palatability data will be documented. Collected data will be 
instrumental in the design of a more definitive study using a randomized controlled crossover 
trial that compares enterade® to pedialyte among patients with SBS.  
 
7. Statistical approach  
We will compare continuous outcomes (average stool frequency, consistency and ostomy 
output) between current ORS and enterade® with t-tests (for normally distributed data) or 
Wilcoxon tests (for non-normally distributed data). Taste score differences among solutions will 
compare mean distance in visual analog scale between solutions 
 
Univariate descriptive statistics for our population will include: 1) baseline SBS disease 
information (age, sex, underlying diagnosis, length of residual bowel); and 2) mean daily stool 
output prior to and after enterade® exposure. Categorical variables will be compared with chi 
square analysis (or Fisher exact test if cell size is less than 3), and continuous variables will be 
compared with t-test (or non-parametric testing if they are not normally distributed). 
 
8. Confidentiality 
For those patients meeting inclusion criteria, the study purpose, procedures, costs, risks, 
benefits and alternatives to participation will be thoroughly explained and presented to the 
patient and their family. Once patients and families have had enough time to consider 
participation and have expressed a willingness to participate, informed consent will be obtained 
from the parents or legal guardian and child assent when appropriate based on age and IRB 
requirements. Enrolled patients in this study will be given a code (or number) that is not derived 
from or related to information about the individual and is not otherwise capable of being 
translated to identify an individual. The link between this code and any information that identifies 
the patient will be kept in a password protected electronic file accessible only by the study 
researcher. In addition, any data that we obtain from the patient’s medical record will have any 
and all personally identifiable information removed.  
 
9. Clinical Significance  
SBS is a devastating disease with a significant associated morbidity stemming from poor enteral 
function. Understanding outcomes relating to alternative regimens, such as enterade®, could 
potentially help reduce dehydration secondary to diarrhea by enhancing fluid absorption with 
ultimately a reduced need for PN and decreased duration of in-patient admissions leading to 
improved morbidity and cost-effective care.  
 
10. Financial Relationship 
Manufacturers of enterade® (Entrinsic Health Solutions) will only be providing participants with 
free samples of enterade®, and will not be covering the cost of the trial or involved with 
participants in study. 

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