Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT06179589 |
Other study ID # |
PR-17028 |
Secondary ID |
|
Status |
Completed |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
December 1, 2020 |
Est. completion date |
April 30, 2023 |
Study information
Verified date |
April 2023 |
Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Background (brief):
1. Burden: Diarrhea is the second deadliest disease for under-five children globally and
the situation is more serious in developing countries. It was responsible for 688
million illnesses and 499,000 deaths worldwide in children less than 5 years of age in
2015 (Kotloff, 2017). Majority of the deaths from diarrhea occur before the second
birthday of the children and it contributes to more than 20% of overall death in infants
and young children.
2. Knowledge gap: Oral rehydration solution (ORS) is being used as a standard treatment for
acute watery diarrhea for long time and which is one of the best inventions in the
history of medicine. The ORS currently recommended by the WHO/UNICEF contains glucose,
sodium chloride, potassium chloride, and tri-sodium citrate dehydrate, which is optimal
for rehydration of patients of all ages with dehydration from acute diarrhea of any
aetiology. However, oral rehydration therapy (ORT) with the present ORS formulation has
certain limitations - it does not reduce the volume, frequency or the duration of
diarrhea. Additionally, the failure of present standard ORS to reduce dramatically stool
output likely contributes to the relatively limited use of ORS by mothers as they do not
feel that ORS is helping their child from the episode of diarrhea. Thus, it warrants the
development of newer and improved formulation of ORS to become more effective against
diarrhea.
3. Relevance: It has been reported that the glucose contained in standard ORS may fail to
absorb fluid and electrolytes adequately from gut and worsen diarrhea in different
patho-physiological ways as the present WHO ORS is hypo-osmolar. Whereas, certain
neutral amino acids (e.g. glycine, L-alanine, L-glutamine) are able to enhance the
absorption of sodium ions and water from gut. By using this concept, the University of
Florida (UF), developed a sugar-free, shelf-stable amino acid-based hydration medicinal
food named 'VS002A' that effectively rehydrates, and improves barrier function of the
bowel following infections targeting the gastrointestinal tract. So, the investigators
ought to know whether VS002A will be superior or not to WHO-ORS in the treatment of
acute non-cholera watery diarrhea in infants and young children.
Hypothesis (if any): The amino acid-based ORS "VS002A" will reduce duration of non-cholera
watery diarrhea in infants and young children when compared to treatment with standard
WHO-ORS.
Objectives: To compare the efficacy of amino acid-based ORS "VS002A" compared to standard
Glucose-based WHO ORS in infants and young children suffering from acute non-cholera watery
diarrhea.
Methods:
- It will be a randomized, double-blind, two cell clinical trial at Dhaka Hospital of
icddr,b. Total 312 (156 in each arm) male children aged 6-36 months old with acute
(onset <48 hours) non-bloody watery diarrhea will be included in this study. However,
patients with severe malnutrition, any systemic illness, cholera, unwilling to comply
with study protocol, remain significantly dehydrated 4 hours after intravenous fluid
infusion (if required at start), has documentation of taking antibiotics or
antidiarrheal 48 hours before admission will be excluded.
- Intervention arm participants will get amino acid ORS (VS002A) and control arm will get
standard glucose based WHO-ORS. Other aspects of clinical managements for diarrhea as
per hospital guideline will be similar in both cases and controls
Description:
Hypothesis to be tested:
The amino acid-based ORS "VS002A" will reduce the duration of non-cholera, watery diarrhea in
infants and young children when compared to treatment with standard WHO-ORS.
Specific Objectives:
1. To evaluate and compare clinical responses (duration of diarrhea, stool output, ORS
intake, and clinical success) in infants and young children suffering from acute
non-cholera watery diarrhea treated with standard Glucose-based WHO ORS and amino
acid-based ORS "VS002A".
2. To evaluate and compare electrolyte imbalance as possible complications in infants and
young children suffering from acute non-cholera watery diarrhea treated with standard
Glucose-based WHO ORS and amino acid-based ORS "VS002A".
Background of the Project including Preliminary Observations:
Diarrheal disorders constitute a leading cause of morbidity and mortality globally, and
continue to be a major concern particularly for developing countries (Platts-Mills, 2015;
WHO/UNICEF, 2013;Bern, 1992). Estimates show that in the year 2010, globally there were 1.7
billion episodes of diarrhea and 7.6 million deaths in children less than 5 years of age,
mostly in the developing world; 72% of the deaths occurred in the first 2 years of life (Liu,
2012, 2015; Walker, 2013). In the Southeast Asian region, diarrhea is responsible for more
than 20% of the total deaths among infants and young children (Liu, 2012, 2015).
Acute infectious diarrheal diseases are caused by a number of microbial pathogens. The
bacterial pathogens include Vibrio cholerae, enterotoxigenic Escherichia coli, Shigella,
Salmonella, and Campylobacter. Rotavirus is the most prominent viral diarrheagenic pathogen
and also the leading cause of infantile diarrhea, whereas Entamoeba histolytica, Giardia
lamblia and Cryptosporidia are the important parasites causing diarrhea. Based upon the
pathogenetic mechanisms, these organisms may be broadly divided into two groups - secretory
and invasive. V. cholerae is the prototype pathogen causing secretory diarrhea through
liberation of an enterotoxin which stimulates intestinal secretion via intracellular
accumulation of cyclic AMP (Fasano, 2002). There is insignificant inflammation or structural
change in the intestinal mucosa and the diarrhea is watery in nature. Sufficient loss of
fluids and electrolytes leads to dehydration, and thus the mainstay of treatment of patients
with acute infectious secretory diarrhea is fluid replacement. On the other hand, Shigella
(the prototype invasive pathogen) invades the gut mucosa and induces an inflammatory
reaction, producing a dysenteric illness (Levine, 1982). The amount of fluid loss is minimal,
and antibiotics are generally required in their management. In the developing countries,
recent studies show that the commonest attributable microbial causes of moderate-to-severe
diarrheal illnesses in infants and young children are: rotavirus, Cryptosporidium,
enterotoxigenic E. coli producing heat-stable toxin (ST-ETEC, with or without co-expression
of heat-labile enetrotoxin), and Shigella (Kotloff, 2013; Liu, 2016).
The standard clinical intervention in acute watery diarrhea is the use of oral rehydration
solution (ORS), continued feeding, and oral zinc supplementation (WHO/UNICEF, 2013; WHO,
1995). The development of ORS for the treatment of dehydration due to diarrhea is one of the
most significant therapeutic advances in the history of medicine. It is based upon the
observations that even in a secreting small intestine it is possible to achieve a positive
gut balance of fluid and electrolytes by adding glucose to the salt solution (Pierce, 1968;
Fordtran, 1975). ORT is now recognized as a major scientific advance of utmost practical
importance. The ORT solution currently recommended by the WHO/UNICEF contains glucose, sodium
chloride, potassium chloride, and trisodium citrate dehydrate, which is optimal for
rehydration of patients of all ages with dehydration from acute diarrhea of any etiology. It
is estimated that ORS alone can successfully rehydrate 90% of patients with dehydration from
acute diarrhea who previously would have required intravenous therapy therapy (Hirschorn,
1991).
However, ORT with the present ORS formulation has certain limitations - it does not reduce
the volume, frequency or the duration of diarrhea (Mahalanabis, 1996). This is a constraint
on the acceptance of ORT as a treatment of diarrhea, since the mothers and the health-care
providers expect earlier recovery and a reduced severity of the disease, which is partly
responsible for the widespread use of ineffective (and often harmful) antibiotics and other
anti-diarrheal agents. These limitations prompted the development of the concept of improved
ORS (initially termed 'super ORS') (Mahalanabis, 1986). Conceptually, an improved ORS should
be able to reduce stool volume (by enhancing better reabsorption of fluid secreted into the
small intestine), shorten duration of diarrhea (by reducing ileal effluent flow and
stimulating colonic salvage), and reduce failure rate of ORT in patients with high purging
rate. Several strategies were used to develop and test improved ORS - including the use of
amino acids in addition to glucose, replacing glucose with glucose-polymers, using cereals
instead of glucose, adding non-absorbable fermentable products to the ORS, and making the ORS
hypo-osmolar by reducing both glucose and sodium concentrations. The recently recommended
hypo-osmolar ORS is the result of intense search for such an improved ORS. Though the new
hypo-osmolar ORS is more efficacious than the previously standard ORS, the duration of
diarrhea is still not shortened, and there are failures with ORT (Alam, 1999). Thus, there is
scope for further improvements of ORT.
The ORS takes advantage of the glucose-coupled intestinal sodium transport mechanism across
the luminal membrane by the protein sodium glucose co-transporter 1 (SGLT1). Although
nutrient independent sodium absorption across the intestinal epithelial brush border membrane
is impaired in diarrhea, co-transport of sodium and glucose is preserved. This allows
absorption of sodium and thus water as provided by oral rehydration solutions (Figure 1). Key
in the success of use of ORS for rehydration is the fact that these physiological processes
stay intact, even in the setting of severe diarrhea.
However, although ORS substantially enhances glucose-stimulated sodium absorption and
correction of dehydration, it does not significantly decrease stool output, which is one of
the main reasons for underutilization of ORS (Greenough, 1993; Wagner, 2015). Although an
adequate explanation for this has not been established, it could be explained if glucose also
stimulated anion secretion. In fact, based upon in vitro studies on the effect of glucose on
active chloride and fluid secretion in mouse small intestinal cells and human colorectal
adenocarcinoma (Caco-2) cells, glucose not only enhanced sodium absorption via SGLT1, a
well-established phenomenon, but also stimulated active electrogenic chloride secretion via
an increase in intracellular Ca2+ (Yin, 2014, AJP Cell). In clinical or experimental
conditions, glucose-stimulated chloride secretion is most likely to occur in the villous cell
region. These observations raise the possibility that in those clinical conditions in which
there is villous damage and impaired glucose-stimulated sodium absorption, glucose may have
deleterious effects on overall fluid and electrolyte movement by virtue of its stimulation of
active chloride secretion.
In young children with acute non-cholera watery diarrhea, the rate of treatment failure due
to clinically evident glucose intolerance is generally expected to be around 2% (Santosham M,
1982). However, 30% of young Peruvian children with acute diarrhea had detectable glucose
malabsorption leading to treatment failure in 7% of the patients (Salazar-Lindo E, 1986).
Thus, it may be hypothesized that simple dietary modifications and/or changes in the ORS
formulation, such that glucose is replaced with compounds that do not stimulate chloride
secretion, could significantly alter the outcome of the disease process.
Since certain neutral amino acids (e.g. glycine, L-alanine, L-glutamine) are also able to
enhance the absorption of sodium ions and water, one approach to developing an improved ORS
formulation was based on adding neutral amino acids or their dipeptides to WHO-ORS
(Mahalanabis, 1983). The first studies of glycine-containing ORS were inconclusive; a
meta-analysis of seven clinical trials conducted later showed that the ORS formulations
containing glucose (or maltodextrin) and glycine (or glycyl-glycine) were not clinically
superior to the standard WHO-ORS (International Study Group on Improved ORS, 1991). A summary
of the eight clinical trials comparing L-alanine containing ORS with the WHO-ORS also showed
variable results; in general, the differences in children with non-cholera diarrhea were not
statistically significant (Bhan, 1994). Three clinical trials comparing glutamine-containing
ORS with the WHO-ORS showed that it does not have any clinical advantage in children with
non-cholera diarrhea (Bhan, 1994). One common thing among all the trials is that all the
experimental amino acid-containing ORSs also contained glucose in variable amounts (9 g/L to
20 g/L); also most of these solutions had relatively high osmolarity (320 - 400 mosmol/L).
One study which compared glucose-free glutamine-containing ORS with the WHO-ORS showed
similar efficacy in children with acute non-cholera diarrhea (Gutierrez, 2007); it is to be
noted that glutamine behaves like glucose in stimulating anion secretion (Yin, 2014). In a
study comparing L-isoleucine supplemented glucose-containing ORS with WHO-ORS in young
children with acute diarrhea, the differences were not statistically significant (Alam,
2011). However, in adult patients suffering from severe cholera, L-histidine-supplemented ORS
was found superior to a histidine-free ORS; both the experimental and control solutions were
rice-based and glucose-free (Rabbani GH, 2005). In another study, a glucose-free
peptilose-based ORS was found more advantageous and acceptable than the WHO-ORS for treatment
of mostly acute watery diarrhea among children (Simakachorn, 1993).
Previous studies on VS002:
Entrinsic Bioscience, a small business formed from intellectual property from the University
of Florida (UF), developed a sugar-free, shelf-stable amino acid-based hydration medicinal
food that effectively rehydrates, and improves barrier function of the bowel following
infections targeting the gastrointestinal tract (GI). VS002's proprietary formulation of
select amino acids contains no glucose. Studies in humans and animals demonstrate that
sugar-free VS002 is an effective rehydration solution in a variety of circumstances.
Irradiation increases paracellular permeability in the gut with associated nutrient
malabsorption, fluid imbalance, and bacterial translocation. In addition, irradiation induces
active chloride ion secretion and fluid loss, and reduces transport of many carbohydrates,
proteins and electrolytes. In a series of studies with radiation-induced enteritis with
associated villus atrophy, an optimal composition of a novel ORS was defined based upon the
observations that the inclusion of specific amino acids caused tightening of the mucosal
barrier and reversal of symptoms of radiation-induced enteric dysfunction (Yin, 2014). VS002
thus consists of only the amino acids that improve electrolyte and water absorption and
correct the increased gut permeability noted following irradiation and infectious disease.
It has been observed that certain amino acid-based pathways for sodium transport become the
dominant pathway to compensate during times of stress. These pathways can be utilized to
rehydrate the intestinal epithelial cells and restore normal bowel function. Eight specific
amino acids retained their absorptive capacity from the gut lumen following radiation and at
the same time decreased paracellular permeability: Lysine, Aspartic acid, Glycine,
Isoleucine, Threonine, Tyrosine, Valine, and Serine.
Studies with VS002 have shown that VS002 administration i) rapidly rehydrates to increase
fluid and electrolyte absorption, ii) tightens the mucosal barrier, thus decreasing local and
systemic inflammation, and iii) increases crypt count and villus height, leading to an
increase in the surface area of absorption. There is no toxicity associated with VS002
administration and the results of studies in animals and humans suggest that VS002 can serve
as a highly safe and effective supportive care in place of standard ORS (Yin, 2014;
Cheuvront, 2018; Clarke, 2018; Sollanek, 2018).
Results of In Vivo Studies Irradiated mice: Irradiated mice were treated either with saline
or with VS002 for 14 days. Treatment with VS002 reduced mortality, preserved body weight,
decreased pica (indication of nausea), and improved electrolyte and nutrient absorption (Yin,
2014; 2017) Mice with Rotavirus enterotoxin: Mice were exposed to rotavirus enterotoxin
(NSP4) and sections of gut were tested for transport in vitro, and glucose-coupled sodium
transport was found significantly impaired along with increased chloride secretion in the
presence of NSP4. Glucose in the presence of NSP4 further increased the chloride secretion
(Yin, 2017) Healthy Humans: Trials in healthy humans demonstrated i) VS002 safety; and ii)
rehydration efficacy compared to a variety of commercial, glucose-containing beverages
(sports drink, ORS). These studies included adults with diarrhea, healthy soldiers, young
college students, and older adults (> 60 years old). Thus, administration of VS002 using
eight amino acids to increase intestinal water and electrolyte absorption was associated with
safe rehydration. See below for further study details.
VS002 was provided to > 250 adults treated for diarrhea in Indonesia and the Philippines. The
consumption of VS002 was well tolerated by all subjects, with no adverse events (Olveda,
2016; Abdulah, 2018).
A study in healthy U.S. Soldiers and civilians (n = 26, males and females) examined the
effect of rehydration via a common sports drink or VS002 after a bout of hypertonic or
isotonic dehydration (3-4% body mass). Rehydration via VS002 resulted in improved rehydration
of the extracellular space compared to the common sports drink, as well as greater fluid
retention in the VS002 group (p < 0.05). The consumption of VS002 was well tolerated by all
subjects, with no adverse events (Cheuvront, 2018).
Another study evaluated the ability of VS002 to optimize hydration compared to water in
healthy adults (n = 40, males and females). Consumption of VS002 resulted in improved
retention compared to water (p < 0.05). The consumption of VS002 was well tolerated by all
subjects, with no adverse events (Sollanek, 2018).
The ability of VS002 to optimize hydration was also compared in younger and older adults (n =
24, males and females). Consumption of VS002 resulted in improved retention compared to water
(p < 0.05). The consumption of VS002 was well tolerated by all subjects, with no adverse
events (Clarke, 2019).
In a randomized, double-blind study to evaluate the efficacy of VS002, 587 adult patients
received either WHO-ORS or VS002 to treat diarrhea. Safety results revealed that no patient
consuming VS002 experienced any serious adverse events, whereas a small number of patients
taking WHO-ORS did. Efficacy data for clinical cure rates were not clinically or
statistically significant between treatment groups.
Therefore, it is hypothesized that VS002 will also be superior to WHO-ORS in the treatment of
acute watery non-cholera diarrhea in infants and young children.
Advanced Amino acid-based ORS: VS002A Traditional oral rehydration solutions (ORS) contain
sugars which stimulate intestinal sodium and water absorption through a variety of
mechanisms. However, it has been under-appreciated that traditional ORS possess no
anti-diarrheal functions and may exacerbate infectious diarrheal secretions (Yin et al.,
2017).
Safety data of Advanced amino acid based ORS: VS002A
The food additive amino acids may be safely used as nutrients added to foods as individual
amino acids in the free, hydrated, or anhydrous form, or as the hydrochloride, sodium, or
potassium salts:
(1) L-Alanine; (2) L-Arginine; (3) L-Asparagine; (4) L-Aspartic acid; (5) L-Cysteine; (6)
L-Cystine; (7) L-Glutamic acid; (8) L-Glutamine; (9) Aminoacetic acid (glycine); (10)
L-Histidine; (11) LIsoleucine; (12) L-Leucine; (13) L-Lysine; (14) DL-Methionine (not for
infant foods); (15) LMethionine; (16) L-Phenylalanine; (17) L-Proline; (18) L-Serine; (19)
L-Threonine; (20) LTryptophan; (21) L-Tyrosine; (22) L-Valine.
EBS amino acid formulas are fully compliant with FDA 21 CFR requirements.
Gut health biomarkers Although oral rehydration therapy has greatly reduced
diarrhoea-associated mortality, burden of diarrheal disease still persists in children below
5 years who are living under unsanitary condition and limited public health resources. This
contributes to 43% of stunted growth and impaired cognitive development, affecting one-fifth
of children worldwide and one-third of children in low- and middle-income countries (LMICs)
(Guerrant, 2013; Kosek, 2013). Vicious cycle of enteric infection and malnutrition often
leads to enteropathy for extended periods of time in young children when adequate water and
sanitation are lacking (Guerrant, 2013; Owino, 2016). This type of enteropathy is known as
Environmental Enteric Dysfunction (EED).
EED, previously known as tropical enteropathy or environmental enteropathy, is a sub-acute
inflammatory condition of the small intestinal mucosa of unknown etiology (Ramakrishna,
2006). It is characterized by structural changes in the small intestine including villous
atrophy and crypt hyperplasia compromising nutrient absorption and pathogenic barrier
(increased permeability and inflammatory cell), impaired gut immune function, malabsorption,
growth faltering, and generally asymptomatic, as distinct from diarrheal disease (Owino,
2016; Sullivan, 1991).
Data are limited from LMICs including Bangladesh on inflammatory and pathological changes in
the gut wall like EED among children with diarrhea. In this study we will study plasma
Citrulline (CIT) concentration as potential marker of functional enterocyte mass and
absorptive functions of intestine, and Tryptophan-Kyanurenine (KT) ratio as a marker of gut
inflammation.
CIT is an amino acid produced by intestinal epithelial cells and found lower in patients with
enteropathy. One animal study reported lower plasma CIT level in the neonatal calves with
diarrhea compared to healthy control (Gultekin, 2019). Tryptophan (TRP), a plant-derived
essential amino acid (EAA) is needed to support growth and health in humans. In response to
infection, TRP is mostly catabolized by an enzyme indoleamine 2,3-dioxygenase (IDO) to a
toxic metabolite kynurenine (KYN). Low plasma TRP, high KYN and elevated KT ratio are found
to be associated with infections (e.g. patients with inflammatory bowel disease suffer from
diarrhoea) and chronic immune activation (Kosek, 2016).