Antibiotics for Children With Severe Diarrhoea (ABCD)

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.

Study Overview

• Status: Completed
• Conditions: Diarrhea
• Intervention / Treatment: Other: Placebo; Drug: Azithromycin

• Study Type: Interventional
• Enrollment (Actual): 8268
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh
    • Icddr,b
• India
  • New Delhi, India
    • Centre for Public Health Kinetics
• Kenya
  • Nairobi, Kenya
    • Kenya Medical Research Institute
• Malawi
  • Blantyre, Malawi
    • Malawi-Liverpool-Wellcome Trust Clinical Research Programme
• Mali
  • Bamako, Mali
    • Centre pour le Développement des Vaccins (CVD-Mali)
• Pakistan
  • Karachi, Pakistan
    • Aga Khan University
• Tanzania
  • Dar es Salaam, Tanzania
    • Muhimbili University of Health and Allied Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Placebo mixture, 0.25 ml / kg / day	Other: Placebo; 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
Experimental: Azithromycin; Azithromycin mixture (40 mg / ml), 0.25 ml / kg / day	Drug: Azithromycin; 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: World Health Organization
• Collaborators: Boston Children's Hospital; University of Washington; Aga Khan University; International Centre for Diarrhoeal Disease Research, Bangladesh; University of Liverpool; Kenya Medical Research Institute; University of Maryland, College Park; Malawi-Liverpool-Wellcome Trust Clinical Research Programme; Muhimbili University of Health and Allied Sciences; Center for Public Health Kinetics; Centre pour le developpement des vaccines, Mali
• Investigators: Study Director: Rajiv Bahl, World Health Organization

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2017
• Primary Completion (Actual): January 15, 2020
• Study Completion (Actual): January 15, 2020

Study Registration Dates

• First Submitted: April 23, 2017
• First Submitted That Met QC Criteria: April 25, 2017
• First Posted (Actual): April 26, 2017

Study Record Updates

• Last Update Posted (Actual): May 19, 2020
• Last Update Submitted That Met QC Criteria: May 14, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Antibiotics; Infant; Mortality; Linear Growth
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: ERC.0002722

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The Principal investigators are currently discussing this between themselves and their research organizations. The plan is to make the data available as soon as possible.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No