Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00324285 |
| Other study ID # |
2001-007 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
May 10, 2006 |
| Last updated |
November 25, 2017 |
| Start date |
July 2001 |
| Est. completion date |
June 30, 2005 |
Study information
| Verified date |
May 2006 |
| Source |
International Centre for Diarrhoeal Disease Research, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Severe malnutrition is associated with a high rate of mortality, even when using the latest
WHO recommendations. Watery diarrhea as observed in cholera is an additional vital risk to
those children. The fragility of the children together with the complexity of the
pathophysiology and the simplicity of the medical environment where the treatment is
delivered are serious constraints for the development of new therapies. Dehydration is a
special immediate risk in those children who already displayed altered body distribution of
water with potassium, magnesium, zinc and other nutrient deficiency. Dehydration is also
often associated with a decrease in appetite. In addition, the intestinal function is altered
both by the infectious agent and the nutritional status of the child. Recommended therapy for
those children comprises oral rehydration with ReSoMaL (modified ORS for use in severely
malnourished children recommended by WHO), at a relatively low rate, with permanent
monitoring; in addition, breastfeeding should not be interrupted and feeding with F100 (Milk
based formula diet for use in severely malnourished children recommended by WHO) is
recommended. Recently, amylase-resistant starch added to a standard WHO-ORS has been shown to
reduce the duration and severity of adults with cholera. The rationale for using
amylase-resistant starch was that when starch enters the colon it is metabolized by the
bacteria. The short-chain fatty acids thus produced stimulate sodium absorption in the colon,
just like glucose stimulates water absorption in the small intestine. In addition, this
treatment would be of particular interest in malnutrition because short-chain fatty acids are
specific energetic substrate for the colon.In the present project, we propose to test the
hypothesis that addition of amylase-resistant starch to the already recommended treatment of
severely malnourished children with cholera reduces the severity and duration of diarrhea;
this could be achieved through the effect of short-chain fatty acids on colonic sodium
absorption. In addition, a better recovery from malnutrition could be achieved through the
energy provided by short-chain fatty acids to the colon and improved appetite through
improved rehydration. Thus, the aim of the study is to measure the effect of
amylase-resistant starch added to an already accepted treatment (with minimal changes) at the
rehydration and rehabilitation phases of the treatment. A total of 210 children aged 6 mo to
60 mo will be studied in three groups : a) glucose based ORS and amylase-resistant starch; b)
glucose based ORS without amylase resistant starch ; c) rice based ORS . The major outcome
variables on the first phase (diarrhoeal duration and stool output), and second phase (food
intake, weight gain) will be compared between the two treatment groups. The result of the
study if found effective in reducing the duration of diarrhoea, enhance recovery from
diarrhoea and malnutrition in severely malnourished children, will contribute to better case
management of these children.
Description:
STUDY DESIGN This is a randomized controlled clinical trial.
Subjects
Inclusion criteria:
1. History of acute watery diarrhoea of <72 hrs.
2. Either sex.
3. Age - 6m to 60 months
4. Some or severe dehydration.
5. Wt for Ht <70% of NCHS median: with or without edema.
6. Dark field examination positive for Vibrio cholerae.
7. Consent given by the patient or legal guardian.
Exclusion criteria:
1. Bloody diarrhoea.
2. Severe infection (e.g. severe pneumonia, clinical sepsis, meningitis).
3. Those who received antibiotics/antimicrobial for the current illness Sample Size Sample
size is calculated on the basis of duration of diarrhoea of recently completed study
with WHO-ORS vs. ReSoMaL in severely malnourished children with diarrhoea (65±46 vs.
61±45). Expecting 35% reduction of duration of diarrhoea with the proposed new treatment
considering 5% level of significance and 80% power, the sample size in each group is 70.
Considering the stool weight, with reference of (stool wt. 158±95 when treated with WHO
ORS) in severely malnourished children with cholera, the sample size was estimated to be
65 in each group, expecting 30% reduction in stool weight during the first 24 hours with
the new treatment and considering 5% level of significance and 80% power. Finally we
consider to study 70 patients in each treatment group.
Randomization
After enrollment into the study the patients will be randomized to receive one of the
following three solutions:
1. Modified glucose based WHO ORS
2. Modified glucose WHO ORS plus 50 g/L amylase resistant starch.
3. Modified rice based ORS
Since a significant proportion of children might present with ALRI, randomization will be
stratified into two strata:
1. Children with ALRI
2. Children without ALRI Accordingly, two randomization list will be prepared. The
randomization list will be prepared using random table of permuted block of variable
length.
Baseline information
A baseline history and examination will be obtained in order to:
4determine the subject's eligibility for inclusion in the study; 4collect the relevant
data prior to beginning the study.
The baseline history and examination will include:
4identification of the patient; 4a description of the symptoms prior to admission and
their duration; 4detail of any treatment given for the illness before admission;
4results of physical examination including the state of hydration.
Assessment of dehydration This will be done according to the modified WHO guideline used
in ICDDR,B. (Appendix-III).
Laboratory tests After admission blood for Hct, total protein, glucose, and serum
electrolytes will be sent before initiation of the assigned ORS. Serum electrolytes will
be repeated after 24 and 48 hours after initiation of ORS therapy. Stool sample will be
sent for microscopy (including cryptosporidium and giardia) and culture for shigella,
salmonella, Vibrio cholerae and ELISA for rotavirus will be done. Other relevant
investigations like Total WBC count, Differential count and urine microscopy will be
done routinely. Chest X-ray and/or Blood culture will be done, if necessary.
For all blood tests 3 ml of blood will be drawn from a suitable vein in the hand.
Estimation of fecal Starch and SCFAs Feces from 50 patients will be collected in
buckets. The first 24 h collected feces will be weighed and aliquot will be taken and
stored at -20o C until the analysis of SCFAs by HPLC. The second and third stool samples
will be collected from 24-48 h and 48-72 h respectively. The feces will be weighed and
aliquot will be stored at -20oC for the determination of SCFAs.
Fecal starch will be measured enzymatically with a starch-assay kit (Total Starch Assay
Procedure, Megazyme, Warriewood, Australia).
Case Management (Acute Phase) After randomization the children will be treated following
the standardized protocol for management of severely malnourished children used at
ICDDR,B hospital (2,12).
Fluid Therapy (oral) Dehydration assessment will be done according to the WHO guideline
modified for in our last multicentre clinical trial of reduced osmolarity ORS in adult
cholera and children with watery diarrhoea (17). In children with some dehydration, the
fluid deficit will be corrected with the assigned ORS @ 10 ml/kg/hour for the first two
hours, then 5 ml/kg/hour until the deficit will be corrected. In addition, on going
stool losses will be corrected @ 5-10 ml/kg/ after each watery stool. For high purging
patient, the ORS intake will be adjusted according to the on going stool loss. ORS
therapy will be continued until diarrhoea ceased. Randomization of patient, taking
consent and darkfield report collection will not take more than 20 minutes. If delayed
more than 20 minutes the children will be offered glucose based ORS and subsequently
switched over to the assigned ORS. Children with severe dehydration, initial rehydration
will be done with IV fluid (cholera saline; Na 133 mmol/L, Cl 98 mmol/L, K 13 mmol/L and
Acetate equivalent to HCO3 48 mmol/ L) until the patient is out of shock or
disappearance of signs of severe dehydration then the rest of rehydration will be done
as for rehydration in patients with some dehydration as described above.
Infection Control
As a routine practice in ICDDR,B hospital the antibiotic treatments for the study
children are as follows:
Children without apparent extraintestinal infection will receive Inj ampicillin @ 100
mg/kg/24 h in 4 divided doses and Inj. gentamicin @ 5mg/kg/24h in 2 divided doses for 5
days. Patients with lower respiratory tract infection will receive Inj: ceftriaxone 75
mg/kg/24 h I/M or I.V one daily doses and Inj. gentamicin 5 mg/kg/24 h in 2 divided
doses for 5 days. All patients will receive erythromycin 50 mg/kg/24 h in 4 divided
doses for 3 days. Patients with oral thrush will be treated with oral nystacin
suspension 100,000 units (1ml) 6 hourly until cured.
Diet Mother's will be advised to continue breast feeding. Supplementary feeding with
F100 diet will be given @ 10 ml/Kg/ Feed two hourly for day 1 and increased slowly up to
150 Kcal/ Kg/Day over 7 days according to the patient's demand. If the child has a poor
appetite, or is weak, or has painful stomatitis/glossitis, the food will be introduced
through nasogastric tube until the patient will take normal oral feeding. In addition to
F100, semisolid food (Rice, lentil, vegetable etc.) will be given to older children
during convalescent and rehabilitation phase.
Vitamin and Mineral Supplements ( As a routine hospital practice in ICDDRB) Children
without xeropthalmia and above 1yr of age, will be given vit A 200,000 units and 6-12
months age children will be given 100,000unit on admission. Children with xeropthalmia
the same dose will be given on admission, 2nd day and on discharge. Folic acid 1.25 mg
and elemental zinc 2 mg/kg will be given for 15 days. In addition children will be given
multivitamin supplements (1 ml contains it A palmitate 5000 IU, vitamin D 1000 IU,
thiamine hydrochloride 1.6 mg, riboflavin 1 mg, pyridoxine hydrochloride 1 mg,
nicotinamide 10 mg, calcium D-pantothenate 5 mg, ascorbic acid 50 mg). 1 ml twice daily
for 15 days for 1 yr. and above and half the dose will be given to infants less than <1
yr. of age.
Hypoglycemia (blood glucose <3 mmol/L) will be managed with 50 ml 10% glucose orally or
by nasogastric tube. Hyponatraemia (serum sodium, <115mmol/L with or without symptoms
will be managed with Inj. 3% Nacl 12 ml/kg I/V slowly over 4 hrs. Children with serum
sodium between 115 - 125 with symptoms will be treated with 3% NaCl in addition to
adjunct therapy, if needed.
Measurements All intakes ( ORS, water, and food) and outputs (stool, urine and vomit)
will be measured every 6 hours until diarrhoea stops or upto 7 days . Body weight and
vital signs will also be measured 6 hourly.
Study withdrawal
Reasons for withdrawal
1. Any patient developing severe complication such as severe pneumonia, clinical
sepsis, meningitis requiring intensive care.
2. Parents/legal guardian withdraws consent.
3. Patients who will continue diarrhoea more than 7 days
Management of withdrawal cases The withdrawal cases will be transferred to general ward
or ICU and appropriate management will be provided according to routine hospital
practice. Regular follow-up will be done and final outcome of the children will be
recorded.
Data collected up to the time of withdrawal will be included for analysis.
Management after cessation of diarrhoea ( Convalescent / Rehabilitation Phase) All
patients after cessation of diarrhoea and control of other associated infection will be
transferred to nutrition rehabilitation unit(NRU) They will be managed with F100 diet
according to their requirements. Older children will get semisolid food in addition to
F100. During the stay at NRU Vital signs and body weight will be measured once in the
morning daily. Food intake will be measured in every feed until the children stay at
NRU. After seven days the patients will be discharged from the nutrition rehabilitation
unit and will be followed up for next fifteen days at home. They will be supplied with
standard diet according to the protocol. The health workers will visit every alternate
day and will interview the mother about any illness and approximate amount of diet the
child consumed. The health worker will carry a portable electronic balance with a
precision of 1 g and record the body weight of the child.
Definition End of study ( acute phage)- The study end point will be considered when
diarrhoea stops or 7 days of initiation of the ORS whichever comes first.
Cessation of diarrhoea - Diarrhoea will be considered to have stopped when the last
watery stool is passed followed by soft or formed stool and/or no stool for 12 hours.
Hypokalaemia- Hypokalaemia is defined as serum potassium level <3.5 mmol/l. Persistence
of hypokalaemia - If the serum potassium level is <3.5 mmol/l on admission and it
remains at the level even after 48 hours of therapy with ORS, it will be considered as
persistence of hypokalaemia.
Over hydration - As there are no standard criteria for defining over hydration, we have
developed a working definition of over hydration for this protocol based on previous
study reports and our clinical experience. Over hydration will be considered in a child
who has more than a 5% weight gain than expected after correction of dehydration and /
or at least any one of the following signs:
Development of periorbital oedema; Increased heart rate (>160/min); Increased
respiration rate (>60/min); {in the absence of signs suggestive of pneumonia(fever, CXR
abnormalities etc.)} Hypoglycaemia - will be defined as blood glucose £ 3 mmol/l
Hyponatraemia - will be defined as serum sodium < 130 mmol/l
Severe pneumonia:
Patient aged 6 m - 12 m
- respiratory rate > 50/minute with chest in drawing
Patient aged 13 m - 60 m
- respiratory rate > 40/minute with chest indrawing (WHO guideline)
- 'ORS failure' - If after randomization any patient needs I/V rehydration therapy will
be labelled as ORS failure.
Organization of the trial
Study site - The study will be done in the study ward of the Clinical Service Centre of
ICDDR,B.
Study schedule - The study period will be 2 years from starting.
Recruiting and training of study personnel - First one month.
Data collection - 23 months ( Estimated on the basis of bed allotment per protocol and
patient availability)
Data analysis and reporting - 3 months
OUTCOME VARIABLES
Primary Duration of diarrhoeal course and stool output.
Secondary
1. Calorie intake per day
2. Daily weight gain
3. Time to attain 80% weight for height SIGNIFICANCE If the ORS containing amylase
resistant starch is found to reduce the severity diarrhoea and increase the
recovery in patients with acute diarrhoeal illness in severely malnourished
children, it will have a major public health significance as regard to better case
management for malnourished children with diarrhoea.
