Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00672308 |
| Other study ID # |
2002—034 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
May 3, 2008 |
| Last updated |
May 5, 2008 |
| Start date |
May 2003 |
| Est. completion date |
August 2006 |
Study information
| Verified date |
December 2004 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Bangladesh: Ethical Review Committee |
| Study type |
Interventional
|
Clinical Trial Summary
In cholera, the function of small intestine is affected resulting in increased secretion of
electrolytes and water and their reduced absorption leading to profuse watery diarrhoea. The
human colon has the capacity to absorb water and electrolytes. A number of recent studies
have shown that short chain fatty acids (SCFAs) such as acetate, butyrate and propionate
stimulates absorption of sodium in the colon, which is not affected by cyclic AMP. It has
also been shown that SCFAs inhibits c-AMP mediated chloride secretion in the colon.
Benefiber (partially hydrolyzed guar gum) is water soluble fibre, and when added to ORS it
undergoes fermentation in the colon liberating SCFAs. SCFAs not only serves as metabolic
fuel to the enterocytes but they also enhance colonic absorption of salts and water. Thus,
they have potentials to reduce the severity of diarrhoea in patients with cholera. The aim
of this study is to assess the efficacy of Benefiber-added WHO-ORS in the management of
adults with cholera. In this randomized, controlled clinical trial, a total of 174 adult
males with cholera would be studied. Study patients would be selected from those who attend
the Dhaka Hospital of ICDDR,B with a history of diarrhoea of less than 24 hours and signs of
severe dehydration. They would be rehydrated using intravenous fluid (cholera saline) over 4
hrs during which a stool specimen would be subjected for dark-field microscopy for
identification of V. cholerae. Those identified to have cholera would be randomized in equal
numbers to receive either: a) Benefiber (25 g/L) added WHO-ORS, b) Benefiber (50 g/L) added
to the new formulation (Na+ 75, glucose 75, Cl- 65, K+ 20 mmol/L, citrate 10 mmol/L,
osmolarity 245 mosmol/L) of WHO-ORS , or c) the same WHO-ORS but without Benefiber for
maintenance of hydration until resolution of diarrhoea. All patients would be treated with a
single, 300 mg dose of doxycycline capsules and would be provided with the standard hospital
diets. Fluid intake (intravenous fluid, ORS, and plain water) and output (stool, urine, and
vomit) will be measured for each 6-hourly periods of the study. Patients would be
hospitalized until resolution of their diarrhoea. Stool output, intake of intravenous fluid
and ORS, the duration of diarrhoea, and the proportion of patients requiring "unscheduled
intravenous fluid therapy" would be compared between the treatment groups. If Benefiber is
found effective, it would be possible to formulate improved ORS for better case management
of cholera.
Description:
Considerable interest has recently been generated on dietary fibers (DF), and soluble fibers
have emerged both as a subject for research and therapeutic applications. The 'fiber
hypothesis', put forward by Denis Bukitt and Hugh Trowel (1-4), suggests that consumption of
unrefined carbohydrate food protects against many western ailments including colon cancer,
diverticular disease, appendicitis, constipation, haemorrhoids, diabetes, heart disease,
gall stones, and obesity among others. In the line of this hypothesis, many basic laboratory
and clinical works have been done. The term 'dietary fiber' has been used to denote plant
polysaccharides and lignin that are resistant to hydrolysis by human digestive enzymes
(5,6). The detailed chemistry and metabolism of DF have also been studied (7-10). The
classification of fiber is based on their chemical structures (11), and they can be divided
into non-polysaccharides and non-starch polysaccharides. Lignin is the only
non-polysaccharide fiber, which is a polymer of phenolic alcohol that is water insoluble.
The non-starch polysaccharide can be divided into cellulose and non-cellulose fiber.
Cellulose consists of un-branched D-glucose chains in 1,4-ß linkage and is water insoluble.
Non-cellulose polysaccharides include hemicelluloses, mucillages, gums and pectins, and they
consists of various ß linkages of wide variety of hexose and pentose sugars. The
polysaccharide chains are heteroglycans (chains with more than one type of monosaccharide).
The hemicellulosic materials are polymers of xylose, mannose and glucose with side chains of
galactose and arabinose. The pectic substances are polymers of galacturonic acids. Likewise,
the gums and mucillages are branched carbohydrate polymers (e.g. gum, which is a linear
mannan with galactose side chains). Non-cellulose polysaccharides vary in degree of their
water solubilities (7,9,10).
In man, fiber is mainly degraded in the large intestine by the bacterial flora. Many of the
effects of fiber on stool output arise from this degradation. The main products of fiber
fermentation are short chain fatty acids (SCFAs) including acetate, propionate and butyrate,
which are the major anions in the colon. Bacteria utilize SCFAs and proliferate, absorbing
water from the colonic epithelium in the course of their metabolism, and thus decrease the
free water content in the lumen (11). The SCFAs that are not utilized by the bacteria are
largely absorbed by the colon (12). Their transepithelial transport is associated with
stimulation of sodium transport from the colon in several species including human (13-15).
This effect may be particularly important in acute diarrhoeal diseases where purging, and
associated reduced food intake might deplete the colon of SCFAs leading to colonic
dysfunction (16, 17). Thus, luminal SCFAs levels in the colon might influence the clinical
course of acute diarrhoeal diseases. SCFAs have also been shown to be clinically important
in one diarrhoeal disease in animal -transmissible gastroenteritis of swine (18). Animals
infected with the virus develop acute enteritis with marked fluid loss from the small
intestine. Young animals develop severe diarrhoea as their colonic mucosa is incapable of
absorbing fluid, whereas older infected animals has been shown to have increased colonic
absorption by about six-folds over the controls. This compensatory response prevents severe
diarrhoea and is related to the development of colonic fermentation with the production of
SCFAs.
Cholera is a disease of humans affecting the small intestine where fluid and electrolyte
secretion is increased while their absorptions are decreased leading to profuse watery
diarrhoea. As the human colon has the capacity to absorb water and electrolyte (19), some
compensation is expected reducing the diarrhoeal loss. In recent studies (20, 21) SCFAs have
been shown to stimulate sodium absorption in the colon, an effect that is not influenced by
c-AMP, and additionally they have been found to inhibit cyclic AMP-mediated chloride
secretion in the colon.
The SCFA-enhanced colonic absorption of water and electrolytes might be exploited in the
treatment of acute diarrhoeal diseases. Oral rehydration therapy has dramatically changed
the management of acute diarrhoeal disease. Yet, oral rehydration therapy is in the process
of being improved. Cereal-based oral rehydration solutions (ORS) have been shown to reduce
the stool volume by about 30% to 40% compared to the WHO-ORS (22, 23). It is possible that,
at least a part of their effect on stool volume reduction might be attributed to SCFAs
produced by unabsorbed carbohydrate including dietary fiber in the colon. Diversion colitis
is an inflammatory process affecting the bypassed colon and rectum following surgical
diversion of faecal stream (24). The inflammation disappears after surgical re-anastomosis,
where topical steroids are usually ineffective (25). Rectal instillation of SCFAs has
resulted in the disappearance of symptoms and endoscopic change over a period of 4-6 weeks;
remission has been maintained for over a year by regular rectal SCFAs treatment (26). These
findings suggest that SCFAs also play a role in mucosal healing in colitis
The colonic epithelial cells utilize SCFAs as source of energy for their various metabolic
activities (27, 28). Human colonocytes use butyrate in preference to glucose, glutamine or
ketone bodies as fuel source (27). Thus, in contrast to small intestinal cells, colonic
epithelial cells derive the major part of their energy supply from the lumen rather than
from the blood. Depriving luminal nutrition of the mucosa has been found to induce fluid
secretion (29). The lack of luminal SCFAs in the colon may be involved in special diarrhoeal
states such as diversion colitis and antibiotic associated diarrhoea. Diarrhoea is not
uncommon after abdominal operations, particularly after closure of a temporary colostomy
(30). Although there is no proof, this postoperative diarrhoea might be attributed to lack
SCFAs in the colon, which might perhaps be reversed by the intake of fermentable fiber (31).
Lengthy preoperative bowel preparation by antibiotic and lavage, and diminished oral
nutrition probably contributes to postoperative diarrhoea. Lack of luminal SCFAs can
similarly explain the diarrhoea often seen in the terminal stages of malnutrition and
starvation. In these conditions, intestinal infections might not always be implicated and it
seems likely that diarrhoea is a manifestation of organ-specific malnutrition of the colon
(32). Diarrhoea is often associated with the use of broad-spectrum antibiotics, and
colonization by toxin producing clostridium difficile accounts for only a third of these
cases (33). The use of antibiotics suppresses the formation of SCFAs from fermentable
carbohydrate (34), a feature that might also be responsible for diarrhoea. Although there
are lots of data suggesting antidiarrhoeal effect of fermentable fibers, their therapeutic
application in diarrhoeal disease is yet to be examined. Some recent clinical studies have
demonstrated the beneficial effect of dietary fiber in treatment of adult cholera (35) and
in the treatment of children with acute diarrhoea (36). In children with acute diarrhoea,
Benefiber-added ORS has been observed to reduce the mean duration of diarrhoea by 16 hours,
(74 vs. 90 h; p <0.05). Further studies are required to evaluate the effect of Benefiber in
reducing severity and duration of cholera, a form of severe dehydrating diarrhoea.
Guar gum: a soluble fiber
Guar gum is a dietary fiber obtained from the endosperm of the seeds of the Indian cluster
bean (Cyanopsis tetragonolobus) of the family Leguminosae. The guar plant is a pod bearing,
nitrogen-fixing legume, which has been grown for centuries in India and Pakistan, where it
is one of the principal crops and is used as food for both humans and animals. It is now
being grown in America for use in various industries (food, cosmetic and paper industries)
(37).
Chemically, guar gum is a non-starch polysaccharide, a galactomannan, which on contact with
water form a highly viscous gel. In the colon, guar gum is fermented to form SCFAs.
Initially, guar gum was used as thickener and emulsion stabilizer in food processing on the
basis of its gelling property (37). Our present interest about guar gum is its therapeutic
use as a dietary fiber.
"Benefiber" (partially hydrolyzed guar gum)
Guar gum forms gel with water, is rather viscous, and thus unsuitable for therapeutic uses
(e.g. in liquid enteral nutrition). Benefiber is a partially-hydrolized (in vitro by the
enzyme endo-B-mannase) guar gum, which is a soluble fiber. It is expected that Benefiber
will be readily utilized by colonic microflora with the production of the same products of
fermentation as the guar gum. The partial hydrolysis of the guar gum (e.g. Benefiber)
results in significant reduction in the viscosity of the solution. It is also expected that
it will not cause any delay in gastric emptying and also will not interfere with normal
absorption of macronutrients (carbohydrate, protein and fat). In one study (38), the
addition of Benefiber to a liquid formulation of diet significantly delayed the colonic
transit time without affecting the oro-caecal transit time. The result of another recent
study (39) in Liestal, Switzerland observed that the Benefiber did not affect the absorption
of glucose, amino acid and fat.
Benefiber was chosen for this study for several reasons. First, it is partially-hydrolyzed
guar gum (PHGG), and it completely dissolves in water making a clear solution. Second, other
fibers are usually viscous, and thus not suitable for use in ORS; the amylase-resistant
starch is not soluble and it only makes a suspension. Third, in in vitro studies of
fermentation, using fresh faecal inoculate, SCFAs production was observed to be highest with
PHGG in comparison with the other commercial fiber substitutes (40). Fourth, in our study in
non-cholera diarrhoea in children, we observed PHGG to be clinically useful (36). In this
study (36), we used PHGG in a dose of 20g/L. This dose was selected arbitrarily on the basis
of standard dose used in the preparation of liquid formulation diets. In the proposed study,
we would like to test two different doses (25 g/L and 50 g/L) to determine if there is an
additional benefit of increasing the dose.
Based on the findings of our previous study as well as studies done elsewhere, we are very
hopeful that the addition of Benefiber to WHO-ORS would lead to its fermentation in the
colon resulting in the production of SCFAs, which would improve colonic function including
colonic absorption of salt and water and thus reduce the stool output as well as shorten the
duration of diarrhoea in adults with cholera.
Safety issue of Benefiber
Benefiber is a food material obtained from vegetable source has been used in cereals,
juices, shakes, yogurt, soups, backed goods, and as a fiber source in enteral nutrition
products. It has undergone extensive toxicity testing and found to be safe (41). In human
volunteer studies (38, 39), enteral nutrition products supplemented with Benefiber 20 g/L
found to be safe. Two clinical trials (36, Alam et al., unpublished data) in children have
been performed in ICDDR,B recently - in one study ORS was supplemented with Brenefiber 20
g/L and in other study comminuted chicken-based diet was supplemented with Benefiber 20 g/L.
No adverse effects have been noted in these studies. In the proposed study, Benefiber will
be supplemented with ORS either 25 g/L or 50 g/L for the treatment of adult cholera. As the
cholera patients have profuse watery stools with short transit time, 50% of fibers are
expected to excrete through stool unchanged. As the treatment of cholera is for a short
duration (2-3 days), so we do not anticipate any adverse effects.
