Azithromycin as Adjunctive Treatment for Uncomplicated Severe Acute Malnutrition
- Conditions
- Severe Acute MalnutritionMalnutrition, Child
- Interventions
- Registration Number
- NCT06010719
- Lead Sponsor
- University of California, San Francisco
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 3000
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Amoxicillin 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). Placebo 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). Azithromycin 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).
- Primary Outcome Measures
Name Time Method Weight Gain 8 weeks This will be measured as weight gain in g/kg/day at 8 weeks from enrollment.
- Secondary Outcome Measures
Name Time Method Number of Transfer to inpatient care 12 weeks Children will be transferred to inpatient care if they develop medical complications, or their condition deteriorates.
Change in Weight-for-height z score (WHZ) 12 months Weight-for-height (WHZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
Change in Weight-for-age Z-score (WAZ) 12 months Weight-for-age (WHZ) Z-scores will be calculated for each study visit. Weight will be measured with a SECA 874 scale to the nearest 0.01kg.
Change in Mid-upper arm circumference (MUAC) 12 months MUAC will be measured at all study visits. Change in MUAC over time will be assessed across study arms using MUAC as a continuous variable. MUAC will be measured with a standard MUAC tape and measurements will be taken in triplicate. The median measurement will be used for analysis.
Height-for-age Z-score (HAZ) 12 months Height-for-age (HAZ) Z-scores will be calculated for each study visit. Height will be measured with a ShorrBoard height/length measuring board with measurements taken in triplicate.
Relapse 12 months Children will be assessed for relapse to moderate acute malnutrition (MAM; MUAC \< 12.5 cm and ≥ 11.5 cm and/or WHZ \< -2 and ≥ -3) or SAM (MUAC \< 11.5 cm and/or WHZ \< -3).
Change in α-diversity Microbiome 8 weeks The primary outcome will be α-diversity using inverse Simpson's diversity index at the 8-week study visit.
Time for Nutritional recovery 12 weeks Nutritional recovery will be defined as per Burkinabé national guidelines: weight-for-height z score (WHZ) ≥ -2 on two consecutive visits and no acute complication or edema for the past 7 days OR mid-upper arm circumference (MUAC)≥ 125mm on two consecutive visits and no acute complication or edema for the past 7 days. The criterion chosen to define recovery is the same as the one used to admit the child to the program.
Mortality 12 months Vital status will be assessed at all scheduled follow-up time points, and the child's vital status (alive, died, defaulted, unknown) will be recorded in the study's mobile application.
Malaria positivity 8 weeks At baseline and 8 weeks, malaria parasitemia by rapid diagnostic test will be measured.
Change in Resistome 12 months Nonhosts read pairs will be aligned to the MEGARes reference antimicrobial database using Burrows-Wheeler alignment with default settings. To decrease false-positive ARD identification, only ARDs with a gene fraction of \>80% will be identified as present in the sample and included in analyses. Each identified ARD will be classified at the class and gene level. The resistome will be evaluated at each time point by arm to evaluate the persistence of alterations to the resistome following oral antibiotics.
Number and type of clinic visits 12 months At each study visit, caregivers will report if they sought medical care for their child for any reason since their last study visit, and if so, how many times they sought care, if the child was hospitalized, and the reason for seeking care (e.g., malaria, pneumonia, etc). different in number and type of clinic visits will be compared by arm and reported at 12 months
Anemia 3 months Hemoglobin will be measured in all children at baseline, 8 weeks, and 3 months using a portable Hemocue 301 system in the field. Anemia will be defined as hemoglobin \<11.0 g/dL.
Trial Locations
- Locations (1)
Centre de recherche en Santé de nouna
🇧🇫Nouna, Kossi, Burkina Faso