Mortality Reduction After Oral Azithromycin: Morbidity Study

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study

Conditions
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Childhood Mortality

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Communities: The community location in target district. The community leader consents to participation in the trial The community's estimated population is between 200-2,000 people. The community is not in an urban area. Individuals (Intervention): - Children-treated arms (all 3 sites): All children aged 1-60 months (up to but not including the 5th birthday), as assessed at the most recent biannual census Individuals (Examination & Sample Collection): All swabs, blood tests, and stool samples: A random sample of children aged 1-60 months (up to but not including the 5th birthday) based on the previous census Anthropometric measurements: All children aged 1-60 months (up to but not including the 5th birthday) will have anthropometric measurements assessed. Nasopharyngeal swabs in untreated children: A random sample of individuals aged 7 - 12 years (7th birthday up to but not including the 12th birthday), as assessed from the previous census Clinic-based nasopharyngeal swabs: All children aged 1-60 months (up to but not including the 5th birthday) who present to a local health clinic in the study area and report symptoms of a respiratory infection Exclusion Criteria: Individuals: Pregnant women All those who are allergic to macrolides or azalides Refusal of village chief (for village inclusion), or refusal of parent or guardian (for individual inclusion)

Ages Eligible for Study
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Minimum Age: 1 Month

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Biannual mass oral azithromycin<br>Comparison of childhood infectious and nutritional morbidity in communities randomized to azithromycin versus communities randomized to placebo. Children aged 1 month to 60 months per community will be offered weight or height-based, directly observed, oral azithromycin suspension every 6 months for 2 years Morbidity monitoring: Collect swabs (nasopharyngeal, nasal, conjunctival), blood samples, (thick/thin blood smears, hemoglobin, dried blood spots), and stool samples from 40 randomly selected children aged 1 month to 60 months per community; collect swabs (nasopharyngeal) from 40 randomly selected children aged 7-12 years per community. Anthropometry for all children aged 1 to 60 months per community. Collect nasopharyngeal swabs from all children aged 1-60 months who are seen at a local health clinic and have a respiratory complaint. | Drug: Azithromycin<br>* Biannual mass oral azithromycin to children<br>* Other names: Zithromax;|
| Placebo Comparator: Biannual mass oral placebo<br>Comparison of childhood infectious and nutritional morbidity in communities randomized to azithromycin versus communities randomized to placebo. Children aged 1 month to 60 months per community will be offered weight or height-based, directly observed, oral placebo every 6 months for 2 years Collect swabs (nasopharyngeal, nasal, conjunctival), blood samples, (thick/thin blood smears, hemoglobin, dried blood spots), and stool samples from 40 randomly selected children aged 1 month to 60 months per community; collect swabs (nasopharyngeal) from 40 randomly selected children aged 7-12 years per community Anthropometry for all children aged 1 to 60 months per community Collect nasopharyngeal swabs from all children aged 1-60 months who are seen at a local health clinic and have a respiratory complaint | Drug: Placebo<br>* Biannual mass oral placebo to children<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 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. | 24 months | 
| Rates of acute respiratory illness among children 1-60 months. | MORDOR Tanzania | 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. | 24 months | 
| Rates of diarrhea among children (1-60 months) | MORDOR Tanzania | 6-24 months after baseline | 
| 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. | 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 | 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 | 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 | 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 | 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. | 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 | 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 | 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 | 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 | 24 months | 
| Head circumference over time in children aged 1-60 months | MORDOR Malawi | 24 months | 
| Knee-heel length over time in children aged 1-60 months | MORDOR Malawi | 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. | 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 | Baseline | 
| Prevalence of helicobacter pylori of children aged 1-60 months | MORDOR Malawi | 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 | Niger will report outcomes at 36, 48 and 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Childhood mortality, Azithromycin, Mass treatment, Infection, Bacterial infections, Trachoma, Chlamydia infections, Diarrhea, Respiratory Infections, Antibiotic resistance, Verbal Autopsy, Microbiome, Malaria