Antibiotics for Children With Severe Diarrhoea

Study Overview
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Brief Summary
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Although the current World Health Organization (WHO) recommended management package for acute diarrhoea (ORS, zinc and feeding advice) has contributed to significant reductions in diarrhoea associated mortality, over half a million children continue to die annually as a result of acute diarrhoeal episodes. In addition, rates of mortality in young children in the 90 days following an episode of acute diarrhoea appear at least as high as mortality that occurs during the acute episode. The long-term benefits of antibiotic administration may result from direct antimicrobial effects on pathogens or from other incompletely understood mechanisms including improved nutrition, alterations in immune tolerance or improved enteric function. Optimizing antibiotic treatment of acute diarrhoea episodes in very young children with severe disease may offer the opportunity to significantly reduce diarrhoea associated deaths in the 180 days following presentation for acute diarrhoea and may also improve growth. The investigators propose to evaluate the efficacy of an antibiotic (azithromycin) delivered in a specific, targeted fashion to young children (< 2 years of age) at high risk of diarrhoea associated mortality in a multi-site randomized, double-blind, placebo-controlled trial. The study will evaluate the ability of the intervention to reduce mortality within 180 days of the acute diarrhoeal episode, and improve nutritional status over the first 90 days.

Official Title
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Antibiotics for Children With Severe Diarrhoea

Conditions
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Diarrhea

Intervention / Treatment
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* Drug: Azithromycin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 2 - 23 months, presenting to a designated health care facility at a participating study site with Diarrhoea per caregiver perception and at least 3 loose or watery stools in the previous 24 hours, Diarrhoea for less than 14 days prior to screening and with at least one of the following criteria at presentation: Signs of some or severe dehydration as per WHO Pocket Book 2013 Moderately wasted as defined by a mid-upper arm circumference (MUAC) less than 125 mm (but greater than or equal to 115 mm) or a weight-for-length z-score (WLZ) greater than -3 standard deviations (SD) and less than or equal to -2 SD after rehydration during stabilization period or Severely stunted (length-for-age z-score (LAZ) <-3 SD) and Parent or guardian (caregiver) willing to allow household visits on day 2 and day 3 and willing to return to facility on day 90 and Parent or guardian (caregiver) provides a consent for trial participation on behalf of the child, based on local standards Exclusion Criteria: Dysentery (gross blood in stool reported by caregiver or observed by healthcare worker (HCW)), Suspected Vibrio cholerae infection (determined according to WHO guidelines or clinical suspicion), Previously or currently enrolled in the ABCD study, Concurrently enrolled in another interventional clinical trial, Sibling or other child in the household enrolled in the ABCD study and currently taking study medication, Signs of associated infections (pneumonia, severe febrile illness, meningitis, mastoiditis or acute ear infection) requiring antibiotic treatment, Documented antibiotic use in the 14 days prior to screening (not including standard use of prophylactic antibiotics, i.e. co-trimoxazole use in human immunodeficiency virus (HIV) -exposed children), Documented use of metronidazole within the last 14-days, Known allergy or contraindication to azithromycin antibiotics, Severe acute malnutrition (SAM) defined as weigh-for-length Z-score (WLZ) less than -3 SD, or MUAC less than 115 mm, or edema of both feet, or Living too far from the enrolment health center to ensure adequate Directly Observed Therapy (DOT) on day 2 and day 3

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 23 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Placebo mixture, 0.25 ml / kg / day | Other: Placebo<br>* Participants will receive rehydration, dietary counseling, one 20 mg tablet of zinc per day and 0.25 ml / kg of placebo drug syrup per day, for three days<br>|
| Experimental: Azithromycin<br>Azithromycin mixture (40 mg / ml), 0.25 ml / kg / day | Drug: Azithromycin<br>* Participants will receive rehydration, dietary counseling, one 20 mg tablet of zinc per day and 10 mg (0.35 ml) / kg of azithromycin syrup per day, for three days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Proportion of children dying per arm | 180 days from enrolment | 
| Linear growth | Mean change in length-for-age Z-score per arm. The Z score will be arrived at from the WHO growth charts based on length in cms and age in months | 90 days from enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospitalizations upto Day 90 | Proportion of children with at least one hospitalization upto Day 90 per arm | 90 days | 
| Hospitalization or deaths upto day 90 | Proportion of children with at least one hospitalization or death upto day 90 per arm | 90 days | 
| Early hospitalization or death (upto day 10) | Proportion of children with death or any hospitalization per arm (upto day 10) | 10 days | 
| Change in weight for length Z score | Mean change in weight-for-length Z-score per arm. The Z score will be arrived at from the WHO growth charts based on weight in kg and length in cm for each child | 90 days | 
| Change in weight for age Z score | Mean change in weight-for-age Z-score per arm. The Z score will be arrived at from the WHO growth charts based on weight in kg and age in months for each child | 90 days | 
| Change in Mid upper arm circumference | Mean change in MUAC (mm) per arm | 90 days | 
| Antimicrobial resistance in the community | Proportion of study participants per arm harbouring antibiotic resistant E. coli bacteria in their stools before any intervention | Baseline | 
| Antimicrobial resistance among the study participants (sub-group) | Proportion of study participants per arm harbouring antibiotic resistant S. pneumoniae bacteria in the naso-pharynx or E. coli bacteria in their stools | At the end of intervention (90 days) and three months later (180 days) | 
| Antimicrobial resistance among close household child contacts (sub-group) | Proportion of siblings or other close household contacts (6-59 months old) per arm harbouring antibiotic resistant S. pneumoniae bacteria in the nasopharynx or E. coli bacteria in their stools | At the end of intervention (90 days) and three months later (180 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mortality, Infant, Antibiotics, Linear Growth