Antibiotics for Children With Severe Diarrhoea

NCT ID: NCT03130114

Last Updated: 2020-05-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 8268 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-05-13
• Study Completion Date: 2020-01-15

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.

Conditions

Diarrhea

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Control

Placebo mixture, 0.25 ml / kg / day

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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

Azithromycin

Azithromycin mixture (40 mg / ml), 0.25 ml / kg / day

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

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

Intervention Type: OTHER

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

• Minimum Eligible Age: 2 Months
• Maximum Eligible Age: 23 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

International Centre for Diarrhoeal Disease Research, Bangladesh

OTHER

Sponsor Role: collaborator

Center for Public Health Kinetics

OTHER

Sponsor Role: collaborator

Kenya Medical Research Institute

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: collaborator

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

OTHER

Sponsor Role: collaborator

University of Liverpool

OTHER

Sponsor Role: collaborator

Centre pour le developpement des vaccines, Mali

UNKNOWN

Sponsor Role: collaborator

University of Maryland, College Park

OTHER

Sponsor Role: collaborator

Aga Khan University

OTHER

Sponsor Role: collaborator

Muhimbili University of Health and Allied Sciences

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

World Health Organization

OTHER

Sponsor Role: lead

Responsible Party

Ayesha De Costa

Scientist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Rajiv Bahl

Role: STUDY_DIRECTOR

World Health Organization

Locations

Icddr,B

Dhaka, , Bangladesh

Centre for Public Health Kinetics

New Delhi, , India

Kenya Medical Research Institute

Nairobi, , Kenya

Malawi-Liverpool-Wellcome Trust Clinical Research Programme

Blantyre, , Malawi

Centre pour le Développement des Vaccins (CVD-Mali)

Bamako, , Mali

Aga Khan University

Karachi, , Pakistan

Muhimbili University of Health and Allied Sciences

Dar es Salaam, , Tanzania

Countries

Bangladesh; India; Kenya; Malawi; Mali; Pakistan; Tanzania

References

Somji S, Ashorn P, Manji K, Ahmed T, Chisti M, Dhingra U, Sazawal S, Singa B, Walson JL, Pavlinac P, Bar-Zeev N, Houpt E, Dube Q, Kotloff K, Sow S, Yousafzai MT, Qamar F, Bahl R, De Costa A, Simon J, Sudfeld CR, Duggan CP; ABCD Study Group. Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial. BMJ Paediatr Open. 2024 Apr 11;8(1):e002448. doi: 10.1136/bmjpo-2023-002448.

Reference Type: DERIVED

PMID: 38604769 (View on PubMed)

Pavlinac PB, Platts-Mills JA, Liu J, Atlas HE, Gratz J, Operario D, Rogawski McQuade ET, Ahmed D, Ahmed T, Alam T, Ashorn P, Badji H, Bahl R, Bar-Zeev N, Chisti MJ, Cornick J, Chauhan A, De Costa A, Deb S, Dhingra U, Dube Q, Duggan CP, Freyne B, Gumbi W, Hotwani A, Kabir M, Islam O, Kabir F, Kasumba I, Kibwana U, Kotloff KL, Khan SS, Maiden V, Manji K, Mehta A, Ndeketa L, Praharaj I, Qamar FN, Sazawal S, Simon J, Singa BO, Somji S, Sow SO, Tapia MD, Tigoi C, Toure A, Walson JL, Yousafzai MT, Houpt ER; AntiBiotics for Children with severe Diarrhea (ABCD) Study Group. Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics. J Infect Dis. 2024 Apr 12;229(4):988-998. doi: 10.1093/infdis/jiad252.

Reference Type: DERIVED

PMID: 37405406 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34913980 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31931848 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

ERC.0002722

Identifier Type: -

Identifier Source: org_study_id