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

Tracking Information

• First Submitted Date: April 23, 2017
• First Posted Date: April 26, 2017
• Last Update Posted Date: May 19, 2020
• Actual Study Start Date: May 13, 2017
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2019)

• Mortality [ Time Frame: 180 days from enrolment ]
  Proportion of children dying per arm
• 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

Original Primary Outcome Measures (submitted: April 25, 2017)

• Mortality [ Time Frame: 90 days from enrolment ]
  Proportion of children dying per arm
• Linear growth [ Time Frame: 90 days from enrolment ]
  Mean change in length per arm

Current Secondary Outcome Measures (submitted: May 14, 2020)

• Hospitalizations upto Day 90 [ Time Frame: 90 days ]
  Proportion of children with at least one hospitalization upto Day 90 per arm
• 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
• Early hospitalization or death (upto day 10) [ Time Frame: 10 days ]
  Proportion of children with death or any hospitalization per arm (upto day 10)
• 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
• 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
• Change in Mid upper arm circumference [ Time Frame: 90 days ]
  Mean change in MUAC (mm) per arm
• 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
• 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
• 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

Original Secondary Outcome Measures (submitted: April 25, 2017)

Hospitalizations [ Time Frame: 90 days ]

Incidence of hospitalizations per arm

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: April 25, 2017)

• 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
• 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
• Antimicrobial resistance in the community [ Time Frame: Baseline, looking at trends over the 2-3 year study period ]
  Proportion of study participants per arm harbouring antibiotic resistant E. coli bacteria in their stools before any intervention

Descriptive Information

• Brief Title: Antibiotics for Children With Severe Diarrhoea
• Official Title: Antibiotics for Children With Severe Diarrhoea

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3

Study Design

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

• Condition: Diarrhea

Intervention

• 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
• 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

Study Arms

• Placebo Comparator: Control
  Placebo mixture, 0.25 ml / kg / day
  Intervention: Other: Placebo
• Experimental: Azithromycin
  Azithromycin mixture (40 mg / ml), 0.25 ml / kg / day
  Intervention: Drug: Azithromycin

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2020): 8268
• Original Estimated Enrollment (submitted: April 25, 2017): 11500
• Actual Study Completion Date: January 15, 2020
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Months to 23 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bangladesh, India, Kenya, Malawi, Mali, Pakistan, Tanzania

Administrative Information

• NCT Number: NCT03130114
• Other Study ID Numbers: ERC.0002722
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

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.

• Current Responsible Party: Ayesha De Costa, World Health Organization
• Original Responsible Party: Per Ashorn, World Health Organization, Scientist
• Current Study Sponsor: World Health Organization
• Original Study Sponsor: Per Ashorn

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

Investigators

• Study Director: Rajiv Bahl; World Health Organization

• PRS Account: World Health Organization
• Verification Date: May 2020