Antibiotics for Children With Severe Diarrhoea (ABCD)

• ClinicalTrials.gov Identifier: NCT03130114
• Recruitment Status: Completed
• First Posted: April 26, 2017
• Last Update Posted: May 19, 2020
• Sponsor: World Health Organization
• Collaborators: International Centre for Diarrhoeal Disease Research, Bangladesh; Center for Public Health Kinetics; Kenya Medical Research Institute; University of Washington; Malawi-Liverpool-Wellcome Trust Clinical Research Programme; University of Liverpool; Centre pour le developpement des vaccines, Mali; University of Maryland, College Park; Aga Khan University; Muhimbili University of Health and Allied Sciences; Boston Children's Hospital
• Information provided by (Responsible Party): Ayesha De Costa, World Health Organization

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diarrhea	Drug: Azithromycin; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8268 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Active drug (azithromycin) will be delivered as dry powder, in opaque glass bottles. Control children with receive placebo powder that will appear, smell, and taste similar to the active drug. All drug bottles will be coded with participant numbers only, so that no-one will know the contents of the bottle.
• Primary Purpose: Treatment
• Official Title: Antibiotics for Children With Severe Diarrhoea
• Actual Study Start Date: May 13, 2017
• Actual Primary Completion Date: January 15, 2020
• Actual Study Completion Date: January 15, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Mortality [ Time Frame: 180 days from enrolment ]
   Proportion of children dying per arm
2. Linear growth [ Time Frame: 90 days from enrolment ]
   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

Secondary Outcome Measures :

1. Hospitalizations upto Day 90 [ Time Frame: 90 days ]
   Proportion of children with at least one hospitalization upto Day 90 per arm
2. Hospitalization or deaths upto day 90 [ Time Frame: 90 days ]
   Proportion of children with at least one hospitalization or death upto day 90 per arm
3. Early hospitalization or death (upto day 10) [ Time Frame: 10 days ]
   Proportion of children with death or any hospitalization per arm (upto day 10)
4. Change in weight for length Z score [ Time Frame: 90 days ]
   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
5. Change in weight for age Z score [ Time Frame: 90 days ]
   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
6. Change in Mid upper arm circumference [ Time Frame: 90 days ]
   Mean change in MUAC (mm) per arm
7. Antimicrobial resistance in the community [ Time Frame: Baseline ]
   Proportion of study participants per arm harbouring antibiotic resistant E. coli bacteria in their stools before any intervention
8. Antimicrobial resistance among the study participants (sub-group) [ Time Frame: At the end of intervention (90 days) and three months later (180 days) ]
   Proportion of study participants per arm harbouring antibiotic resistant S. pneumoniae bacteria in the naso-pharynx or E. coli bacteria in their stools
9. Antimicrobial resistance among close household child contacts (sub-group) [ Time Frame: At the end of intervention (90 days) and three months later (180 days) ]
   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

Eligibility Criteria

• Ages Eligible for Study: 2 Months to 23 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Bangladesh

Icddr,B

Dhaka, Bangladesh

India

Centre for Public Health Kinetics

New Delhi, India

Kenya

Kenya Medical Research Institute

Nairobi, Kenya

Malawi

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Blantyre, Malawi

Mali

Centre pour le Développement des Vaccins (CVD-Mali)

Bamako, Mali

Pakistan

Aga Khan University

Karachi, Pakistan

Tanzania

Muhimbili University of Health and Allied Sciences

Dar es Salaam, Tanzania

Sponsors and Collaborators

World Health Organization

International Centre for Diarrhoeal Disease Research, Bangladesh

Center for Public Health Kinetics

Kenya Medical Research Institute

University of Washington

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

University of Liverpool

Centre pour le developpement des vaccines, Mali

University of Maryland, College Park

Aga Khan University

Muhimbili University of Health and Allied Sciences

Boston Children's Hospital

Investigators

• Study Director: Rajiv Bahl; World Health Organization

  Study Documents (Full-Text)

Documents provided by Ayesha De Costa, World Health Organization:

Statistical Analysis Plan  [PDF] May 14, 2020

Study Protocol  [PDF] December 21, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ayesha De Costa, Scientist, World Health Organization
• ClinicalTrials.gov Identifier: NCT03130114
• Other Study ID Numbers: ERC.0002722
• First Posted: April 26, 2017
• Last Update Posted: May 19, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• 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.

• 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

Keywords provided by Ayesha De Costa, World Health Organization:

Mortality; Infant; Antibiotics; Linear Growth

Additional relevant MeSH terms:

Diarrhea; Signs and Symptoms, Digestive; Azithromycin; Anti-Bacterial Agents; Anti-Infective Agents