The long-term goal of this study is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood morbidity and increasing growth, and for the potential selection of antibiotic resistance. The investigators propose a set of 3 cluster-randomized trials in Malawi, Niger, and Tanzania comparing communities randomized to oral azithromycin with those randomized to placebo. To assess the generalizability of the intervention, investigators will monitor for antibiotic resistance, which could potentially limit adoption of mass antibiotic treatments. The investigators will also assess several measures of infectious diseases. The investigators hypothesize that mass azithromycin treatments will reduce childhood morbidity and will be accompanied by an acceptable level of antibiotic resistance.
The investigators will assess childhood infectious disease morbidity and macrolide resistance over two years, comparing communities where children aged 1-60 months receive biannual oral azithromycin to communities where the children receive biannual oral placebo. Randomization of Treatment Allocation. In each site, 30 communities within a contiguous area of 300,000 to 600,000 individuals will be randomized into the azithromycin or placebo arm. The investigators will use a simple random sample separately for each study site, but without stratification or block randomization within the site. These communities are being randomized from the same pool of communities eligible for a sister trial (Mortality Reduction After Oral Azithromycin (MORDOR) - Morbidity Study). Specific Aims Specific Aim 1: To assess whether macrolide resistance is greater in a population-based community sample of pre-school children, or in a clinic-based sample of ill pre-school children Specific Aim 2: To assess whether biannual mass azithromycin treatments of pre-school children can eliminate ocular chlamydia in a hypoendemic area Specific Aim 3: To assess the diversity of the microbiome of the nasopharynx, nares, conjunctiva, and gastrointestinal tract
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
72,000
Biannual mass oral azithromycin to children
Biannual mass oral placebo to children
UCSF Proctor Foundation
San Francisco, California, United States
Johns Hopkins University
Baltimore, Maryland, United States
College of Medicine at the University of Malawi, Blantyre
Blantyre, Malawi
The Carter Center, Niger
Niamey, Niger
Kongwa Trachoma Project
Kongwa, Tanzania
London School of Hygiene & Tropical Medicine
London, United Kingdom
Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months
MORDOR Malawi and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: 24 months
Height over time in children aged 1-60 months
MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Weight for Height over time in children aged 1-60 months
MORDOR Malawi and Niger Please note:Each outcome will be analyzed separately in each of the two study sites.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Density of asexual stages and gametocytes, in children 1-60 months
MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Hemoglobin concentration and presence of anemia (hemoglobin <11 g/dL) in children 1-60 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age
MORDOR Niger
Time frame: 24 months
Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 1-60 month olds seen in local health clinics for a respiratory complaint
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: 24 months
Rates of acute respiratory illness among children 1-60 months.
MORDOR Tanzania
Time frame: 6-24 months after baseline
Presence of the trachoma grades "follicular trachoma" (TF) and "intense inflammatory trachoma" (TI), as defined by the World Health Organization (WHO) simplified grading system, in children 1-60 months
MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately for each study site.
Time frame: 24 months
Rates of diarrhea among children (1-60 months)
MORDOR Tanzania
Time frame: 6-24 months after baseline
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Proportion of rectal/stool isolates with evidence of resistance (in for example E.coli) to macrolides and other antibiotics commonly used to treat pediatric infections among children 1-60 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: 6-24 months after baseline; Niger will also report outcomes at 48 months
Proportions of E. coli isolates resistant to macrolides and to antibiotics commonly used to treat pediatric infections among children 1-60 months hospitalized for pneumonia and diarrhea.
MORDOR Tanzania
Time frame: 6-24 months after baseline
Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months
MORDOR Malawi
Time frame: 5 x over 24 weeks after baseline
Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through urine samples for L:M ratios of children 6 months
MORDOR Malawi
Time frame: 5 x over 24 weeks after baseline
Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months
MORDOR Malawi
Time frame: 5 x over 24 weeks after baseline
Nasopharyngeal pneumococcal evidence of beta lactam and macrolide resistance in in children 1-60 months as measured by RNA-sequencing of the resistome
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
Nasopharyngeal pneumococcal macrolide resistance determinants (eg erythromycin ribosomal methylase B and mefA), serotype, and multilocus sequence type in children 1-60 months
MORDOR Niger
Time frame: 24 months
Microbiome in the stool, nasopharynx, nares, and conjunctiva in children aged 1-59 months, as measured using next generation sequencing. Arms will be compared using Euclidean distance and diversity compared using Simpson's index.
Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments. MORDOR Niger
Time frame: 24 months
Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing
Investigators will examine the effects of mass azithromycin (pre-treatment and post-treatment) on the human microbiome of African children by performing metagenomic experiments. MORDOR Malawi
Time frame: 24 months
Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array
MORDOR Malawi
Time frame: 24 months
Head circumference over time in children aged 1-60 months
MORDOR Malawi
Time frame: 24 months
Knee-heel length over time in children aged 1-60 months
MORDOR Malawi
Time frame: 24 months
Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Time frame: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
Prevalence of carriage of a panel of gastrointestinal parasites (Ancylostoma duodenale, Necator americanus, Ascaris lumbricoides, Trichuris trichiura, Giardia lamblia, Cryptosporidium hominis) of children aged 1-60 months
MORDOR Malawi
Time frame: Baseline
Prevalence of helicobacter pylori of children aged 1-60 months
MORDOR Malawi
Time frame: Baseline
Antibody response to enteric pathogens and malaria measured with a multiplex bead assay from dried blood spots collected from children 1 - 59 months
MORDOR Niger
Time frame: Niger will report outcomes at 36, 48 and 60 months