Clinical trial NCT03130114: Antibiotics for Children With Severe Diarrhoea
Official title: Antibiotics for Children With Severe Diarrhoea
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diarrhea
Keywords: Mortality
Infant
Antibiotics
Linear Growth
Lead sponsor: World Health Organization
Sponsor class: OTHER
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
name: Center for Public Health Kinetics
name: Kenya Medical Research Institute
name: University of Washington
name: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
name: University of Liverpool
name: Centre pour le developpement des vaccines, Mali
name: University of Maryland, College Park
name: Aga Khan University
name: Muhimbili University of Health and Allied Sciences
name: Boston Children's Hospital
First posted: 2017-04-26
Enrollment: 8268
Sex: ALL
Minimum age (years): 2
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Mortality
timeFrame: 180 days from enrolment
measure: Linear growth
timeFrame: 90 days from enrolment
Secondary outcomes:
measure: Hospitalizations upto Day 90
timeFrame: 90 days
measure: Hospitalization or deaths upto day 90
timeFrame: 90 days
measure: Early hospitalization or death (upto day 10)
timeFrame: 10 days
measure: Change in weight for length Z score
timeFrame: 90 days
measure: Change in weight for age Z score
timeFrame: 90 days
measure: Change in Mid upper arm circumference
timeFrame: 90 days
measure: Antimicrobial resistance in the community
timeFrame: Baseline
measure: Antimicrobial resistance among the study participants (sub-group)
timeFrame: At the end of intervention (90 days) and three months later (180 days)
measure: Antimicrobial resistance among close household child contacts (sub-group)
timeFrame: At the end of intervention (90 days) and three months later (180 days)
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: Icddr,B
city: New Delhi
country: India
facility: Centre for Public Health Kinetics
city: Nairobi
country: Kenya
facility: Kenya Medical Research Institute
city: Blantyre
country: Malawi
facility: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
city: Bamako
country: Mali
facility: Centre pour le Développement des Vaccins (CVD-Mali)
city: Karachi
country: Pakistan
facility: Aga Khan University
city: Dar es Salaam
country: Tanzania
facility: Muhimbili University of Health and Allied Sciences
Study officials:
affiliation: World Health Organization
name: Rajiv Bahl
role: STUDY_DIRECTOR
References:
citation: Antibiotics for Children With Diarrhea (ABCD) Study Group; Ahmed T, Chisti MJ, Rahman MW, Alam T, Ahmed D, Parvin I, Kabir MF, Sazawal S, Dhingra P, Dutta A, Deb S, Chouhan A, Sharma AK, Jaiswal VK, Dhingra U, Walson JL, Singa BO, Pavlinac PB, McGrath CJ, Nyabinda C, Deichsel EL, Anyango M, Kariuki KM, Rwigi D, Tornberg-Belanger SN, Kotloff KL, Sow SO, Tapia MD, Haidara FC, Mehta A, Coulibaly F, Badji H, Permala-Booth J, Tennant SM, Malle D, Bar-Zeev N, Dube Q, Freyne B, Cunliffe N, Ndeketa L, Witte D, Ndamala C, Cornick J, Qamar FN, Yousafzai MT, Qureshi S, Shakoor S, Thobani R, Hotwani A, Kabir F, Mohammed J, Manji K, Duggan CP, Kisenge R, Sudfeld CR, Kibwana U, Somji S, Bakari M, Msemwa C, Samma A, Bahl R, De Costa A, Simon J, Ashorn P. Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2136726. doi: 10.1001/jamanetworkopen.2021.36726.
citation: ABCD study team. A double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the Antibiotics for Children with Diarrhoea (ABCD) trial protocol. Trials. 2020 Jan 13;21(1):71. doi: 10.1186/s13063-019-3829-y.