Efficacy of Benefiber-Added, Reduced-Osmolarity WHO-ORS in the Treatment of Cholera in Adults

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Brief Title

Efficacy of Benefiber-Added, Reduced-Osmolarity WHO-ORS in the Treatment of Cholera in Adults

Official Title

Efficacy of Benefiber-Added, Reduced-Osmolarity WHO-ORS in the Treatment of Cholera in Adults

Brief 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.
    

Detailed 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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

total and 24-hourly watery stool output

Secondary Outcome

 ORS intake and duration of diarrhoea, Clinical success (and failure), success (and failure) of oral rehydration therapy, and the proportion of patients requiring "unscheduled intravenous fluid therapy"

Condition

Cholera

Intervention

Benefiber

Study Arms / Comparison Groups

 1
Description:  Benefiber (25 g/L)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

195

Start Date

May 2003

Completion Date

August 2006

Primary Completion Date

February 2005

Eligibility Criteria

        Inclusion Criteria:

          -  Age: 15 - 55 years

          -  Gender: Male (women would be excluded due to difficulties in separation of their urine
             from stools, particularly in those with severely dehydrated and associated mental
             obtundation).

          -  Duration of diarrhoea: 24 hours or less

          -  Clinical signs and symptoms of severe dehydration.

          -  Demonstration of V. cholerae in dark-field microscopy of a fresh stool specimen

          -  Written informed consent for participation in the study (for patients with temporary
             inability to provide consent due to their severe dehydration and mental obtundation,
             initial consent would be obtained from their attendants; however, the consent process
             would be re-applied to the patients when they are fully oriented)

        Exclusion Criteria:

          -  Chronic or iatrogenic diarrhoea

          -  Dysentery (presence of visible blood in stool)

          -  History of receiving antimicrobial or antidiarrhoeal drugs prior to admission

          -  Presence of concomitant infection or underlying disease, which might complicate
             diagnosis and/or assessment of response to study interventions

          -  History of renal or hepatic dysfunction

          -  Failure to obtain informed consent
      

Gender

Male

Ages

18 Years - 55 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Bangladesh

Location Countries

Bangladesh

Administrative Informations


NCT ID

NCT00672308

Organization ID

2002-034



Study Sponsor

International Centre for Diarrhoeal Disease Research, Bangladesh

Collaborators

 University of Basel

Study Sponsor

, , 


Verification Date

December 2004