Azithromycin as Adjunctive Treatment for Uncomplicated Severe Acute Malnutrition

NCT ID: NCT06010719

Last Updated: 2025-10-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 3000 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-10-23
• Study Completion Date: 2028-12-29

Brief Summary

Amoxicillin is recommended by the World Health Organization (WHO) as adjunctive therapy for the treatment of uncomplicated severe acute malnutrition (SAM). Because children with uncomplicated SAM may have asymptomatic infection due to immune suppression, presumptive treatment with a broad-spectrum antibiotic may be beneficial by clearing any existing infection and improving outcomes. Two randomized placebo-controlled randomized trials have evaluated amoxicillin for uncomplicated SAM and have found conflicting results. These results may indicate either that antibiotics are not helpful for the management of uncomplicated SAM, or that a better antibiotic is needed. Recently, the investigators demonstrated that biannual mass azithromycin distribution as a single oral dose reduces all-cause child mortality in sub-Saharan Africa. Children with uncomplicated SAM, who have an elevated risk of mortality relative to their well-nourished peers, may particularly benefit from presumptive azithromycin treatment. Our pilot data demonstrated feasibility in rapid enrollment of children with uncomplicated SAM in our study area, and showed no significant difference between azithromycin and amoxicillin, demonstrating equipoise for a full-scale trial. Here, the investigators propose an individually randomized trial in which children will be randomized to a) azithromycin, b) amoxicillin, or c) placebo, and evaluated for differences in weight gain, nutritional recovery, and the gut microbiome. The results of this study will strengthen the evidence base for policy related to the use of antibiotics as part of the management of uncomplicated SAM, including additional evidence of amoxicillin versus placebo as well as evaluation of an antibiotic class that has not been considered for uncomplicated SAM, which may lead to changes in guidelines for treatment.

Detailed Description

General study design. The investigators propose a 1:1:1 individually randomized placebo-controlled trial in which children aged 6-59 months with SAM (based on weight-for-height Z-scores (WHZ) and/or mid-upper arm circumference (MUAC), defined in Eligibility) are randomized to one of three study arms: 1) a single oral 20 mg/kg dose of azithromycin followed by 13 doses of placebo; 2) a 7-day twice-daily course of oral amoxicillin (14 total doses); or 3) 7 days of twice-daily placebo (14 total doses). Children will be followed weekly until nutritional recovery, and then at 8 weeks (primary outcome), and 3, 6, 9, and 12 months to assess relapse and vital status. The primary outcome will be weight gain in g/kg/day at 8 weeks from enrollment. Children in all groups will receive ready-to-use therapeutic food per standard of care guidelines (described below).

Study area and study team. This study will be conducted in Boromo District, Burkina Faso in West Africa. Boromo is in central Burkina Faso and experiences a large burden of SAM annually. As in much of the Sahel, food insecurity and malnutrition are highly seasonal, with the malnutrition season aligning with the rainy season from approximately July through October, prior to the annual harvest in November to December. The central Sahel, which includes Burkina Faso, is a particularly vulnerable region for childhood malnutrition due to seasonal food insecurity, ongoing political instability, and climate change which may alter or shorten growing seasons. The COVID-19 pandemic has increased risk of poor nutritional outcomes among children, particularly in already vulnerable settings. The Sahel, and Burkina Faso in particular, is a critical region for nutritional interventions due to the continued high prevalence of underweight and high mortality rates, and lack of progress in reducing underweight in children. Previous evidence has suggested that the etiology of SAM varies across sub-Saharan Africa, and that SAM in the Sahel may be more likely due to calorie insufficiency (marasmus) compared to other regions that have a higher prevalence of protein malnutrition (kwashiorkor). Amoxicillin has been hypothesized to have greater efficacy in children with kwashiorkor vs marasmus, which may partially explain discrepant results in amoxicillin trials from Malawi and Niger. Given the large burden of malnutrition in the Sahel, evidence tailored specifically to this setting is critical to inform policy. The trial will be conducted jointly by the University of California, San Francisco (PI: Dr. Catherine Oldenburg) and the Centre de Recherche en Santé de Nouna (PI: Dr. Ali Sié). Our team has collaborated on multiple randomized controlled trials for child health since 2016. In addition to expertise in design, conduct, and analysis of antibiotic trials, our team has extensive expertise in pediatric microbiome and resistome outcomes in antibiotic trials (led by Dr. Thuy Doan).

Enrollment facilities. Our pilot study was conducted in 6 health facilities in Boromo over a single malnutrition season. For the full trial, the investigators propose to expand to 18 primary healthcare facilities and enroll over a 3-year period (covering 3 malnutrition seasons). These facilities represent the first tier of the country's government-run healthcare system and provide basic preventative and curative care and are often nurse-led.

Healthcare for children under 5 years of age attending public facilities is free of charge. Primary care facilities typically provide outpatient treatment of common childhood illnesses, vaccination clinics, and antenatal and maternity care. Each facility hosts a nutrition clinic 1-2 days/week during which children are screened and receive care for uncomplicated SAM on an outpatient basis. Children with a clinical complication requiring inpatient treatment will be referred to the local district hospital for treatment and will not be enrolled in the trial. Children in the outpatient nutritional program receive weekly follow-up care, although rates of default outside of trial settings are high. These facilities are typically under-resourced and experience frequent stock-outs of key components of the outpatient SAM treatment package (e.g., RUTF). All enrolled children will receive all components of outpatient SAM package through the trial.

The investigators propose a 1:1:1 randomized double masked placebo-controlled trial to determine whether a single oral dose of azithromycin is superior to 1) amoxicillin or 2) placebo for weight gain in children with SAM. Children aged 6-59 months with SAM per Burkinabé national guidelines will be randomized to one of three study arms and followed for 12 months, with the primary outcome being weight gain (g/kg/day) at 8 weeks after enrollment in the study. Children will be followed weekly until recovery, at 8 weeks, and then every 3 months to assess for relapse and mortality.

Conditions

Malnutrition, Child; Severe Acute Malnutrition

Study Design

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

Study Groups

Azithromycin

Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the azithromycin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the standard amoxicillin treatment will be changed to azithromycin. Children will receive a directly observed dose of azithromycin (20 mg/kg, single directly observed dose, oral suspension), followed by a 7-day course of placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).

Group Type: EXPERIMENTAL

Azithromycin

Intervention Type: DRUG

oral azithromycin (20 mg/kg, single directly observed dose, oral suspension),

Amoxicillin

Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the amoxicillin arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, including a 7-day course of amoxicillin (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).

Group Type: ACTIVE_COMPARATOR

Amoxicillin

Intervention Type: DRUG

Standard of Care. A 7-day, twice-daily course of amoxicillin will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).

Placebo

Children enrolled in the trial will be randomized to either the azithromycin, amoxicillin, or placebo arm. Children randomized to the placebo arm will receive all standard severe acute malnutrition (SAM) outpatient treatment per Burkinabe national guidelines, except that the the standard amoxicillin treatment will be changed to placebo (administered at 80 mg/kg, split into 2 daily doses for 7 days, oral suspension).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

A 7-day, twice-daily course of placebo will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).

Interventions

Azithromycin

oral azithromycin (20 mg/kg, single directly observed dose, oral suspension),

Intervention Type: DRUG

Amoxicillin

Standard of Care. A 7-day, twice-daily course of amoxicillin will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).

Intervention Type: DRUG

Placebo

A 7-day, twice-daily course of placebo will be offered as a syrup to children (80 mg/kg divided into twice-daily doses, estimated with weight-based dosing).

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age 6-59 months
• WHZ<-3 SD or MUAC<115 mm
• Primary residence within a catchment area of an enrollment site
• Available for full 8-week study (primary endpoint)
• Not admitted to a nutritional program for SAM treatment in the previous 2 weeks
• No edema
• No antibiotic use in the past 7 days
• No clinical complications requiring antibiotic or inpatient treatment**
• No congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of SAM treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc)
• No known allergies to macrolides/azalides or amoxicillin/penicillin
• Sufficient appetite according to a feeding test with RUTF
• Written informed consent from at least one parent or guardian

Exclusion Criteria

• Age less than 6 month or more than 59 months
• WHZ>-3 SD or MUAC>115 mm
• Primary residence is not within a catchment area of an enrollment site
• Not Available for full 8-week study (primary endpoint)
• Admitted to a nutritional program for SAM treatment in the previous 2 weeks
• Edema
• Antibiotic use in the past 7 days
• Clinical complications requiring antibiotic or inpatient treatment**
• Congenital abnormality or chronic debilitating illness that would lead to predictable growth faltering or reduce likelihood of SAM treatment benefit (such as cerebral palsy, Down syndrome, congenital heart disease, cleft lip/palate, etc)
• Known allergies to macrolides/azalides or amoxicillin/penicillin
• No Sufficient appetite according to a feeding test with RUTF
• No Written informed consent from at least one parent or guardian

• Per Burkinabé guidelines, children any of the following conditions will not be eligible for the trial and will be referred to an inpatient facility: MUAC <115 mm with complications; MUAC <115 mm plus edema; bipedal pitting edema; anorexia or no appetite for RUTF; diarrhea and dehydration; unable to ingest anything without vomiting; severe pneumonia; open cutaneous lesions; hypothermia (35*C); fever (38.5*C); paleness suggesting severe anemia; hypoglycemia; very weak, lethargic, or unconscious; convulsions; signs of vitamin A deficiency; or a condition requiring IV infusion or an NG tube.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 59 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre de Recherche en Sante de Nouna, Burkina Faso

OTHER_GOV

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Catherine Oldenburg, ScD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

Centre de recherche en Santé de nouna

Nouna, Kossi, Burkina Faso

Site Status: RECRUITING

Countries

Burkina Faso

Central Contacts

Catherine Oldenburg, ScD

Role: CONTACT

catherine.oldenburg@ucsf.edu

4154761442

Elodie Lebas, RN

Role: CONTACT

elodie.lebas@ucsf.edu

4154761442

Facility Contacts

Ali Sie, MD PDH

Role: primary

sieali@yahoo.fr

+22670252957

Bountogo Mamadou, MD

Role: backup

drbountogo@yahoo.fr

+22670398944

References

Oldenburg CE, Sie A, Coulibaly B, Ouermi L, Dah C, Tapsoba C, Barnighausen T, Ray KJ, Zhong L, Cummings S, Lebas E, Lietman TM, Keenan JD, Doan T. Effect of Commonly Used Pediatric Antibiotics on Gut Microbial Diversity in Preschool Children in Burkina Faso: A Randomized Clinical Trial. Open Forum Infect Dis. 2018 Nov 2;5(11):ofy289. doi: 10.1093/ofid/ofy289. eCollection 2018 Nov.

Reference Type: BACKGROUND

PMID: 30515431 (View on PubMed)

Bountogo M, Zakane A, Ouedraogo TA, Ouermi L, Compaore G, Compaore A, Coulibaly B, Koueta F, Burroughs HR, Fetterman I, La Mons JL, Lebas E, Doan T, Hsiang M, O'Brien KS, Arnold B, Sie A, Oldenburg CE. Azithromycin as adjunctive treatment for uncomplicated severe acute malnutrition (AMOUR): study protocol for a double-masked randomised controlled trial. BMJ Open. 2025 Jul 1;15(7):e104591. doi: 10.1136/bmjopen-2025-104591.

Reference Type: DERIVED

PMID: 40592757 (View on PubMed)

Other Identifiers

5R01HD111532

Identifier Type: NIH

Identifier Source: secondary_id

View Link

23-39411

Identifier Type: -

Identifier Source: org_study_id