Evaluating Impact of Azithromycin Mass Drug Administrations on All-cause Mortality and Antibiotic Resistance: Morbidity Study
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 72,000
- 试验地点
- 6
- 主要终点
- Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 1 Month 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Biannual mass oral azithromycin
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.
干预措施: Azithromycin (Drug)
Biannual mass oral placebo
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
干预措施: Placebo (Drug)
结局指标
主要结局
Presence of malaria parasites on thick blood smear or Rapid Diagnostic Test (RDT) in children 1-60 months
时间窗: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Prevalence of macrolide resistance in the stool as determined by genetic determinants or phenotypic testing
时间窗: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Fraction of conjunctival swabs yielding ocular chlamydia in children 1-60 months
时间窗: 24 months
MORDOR Malawi and Niger. Please note: Each outcome will be analyzed separately for each study site.
Fraction of isolates of pneumococcus exhibiting macrolide resistance by nasopharyngeal swabs in children 1-60 months
时间窗: Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months
MORDOR Malawi, Tanzania and Niger. Please note: Each outcome will be analyzed separately for each study site.
Height over time in children aged 1-60 months
时间窗: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
MORDOR Malawi and Niger Please note: Each outcome will be analyzed separately in each of the two study sites.
Weight for Height over time in children aged 1-60 months
时间窗: Each site will report outcomes at 24 months; Niger will also report outcomes at 48 months
MORDOR Malawi and Niger Please note:Each outcome will be analyzed separately in each of the two study sites.
次要结局
- Genetic determinants of macrolide resistance in the nasopharynx (eg pneumococcal) in individuals 7-12 years of age(24 months)
- Density of asexual stages and gametocytes, in children 1-60 months(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(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(Baseline)
- Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through venous sampling of children 6 months(5 x over 24 weeks after baseline)
- Nasopharyngeal pneumococcal macrolide resistance determinants (eg erythromycin ribosomal methylase B and mefA), serotype, and multilocus sequence type in children 1-60 months(24 months)
- Microbial diversity in the intestinal microbiomes of children aged 1-60 months as measured by using next generation sequencing(24 months)
- Head circumference over time in children aged 1-60 months(24 months)
- Prevalence of helicobacter pylori of children aged 1-60 months(Baseline)
- Antibody response to enteric pathogens and malaria measured with a multiplex bead assay from dried blood spots collected from children 1 - 59 months(Niger will report outcomes at 36, 48 and 60 months)
- Rates of diarrhea among children (1-60 months)(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(6-24 months after baseline; Niger will also report outcomes at 48 months)
- Studies of intestinal permeability and inflammation, microbial translocation, and immune activation assessed through stool (fecal neopterin) of children 6 months(5 x over 24 weeks after baseline)
- 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.(24 months)
- Knee-heel length over time in children aged 1-60 months(24 months)
- 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(24 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.(6-24 months 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(Tanzania will report outcomes at 6-24 months. Each site will report outcomes at 24 months; Niger will also report outcomes at 36 months)
- Resistance (in E.coli phenotypically or genetic determinants) in stool of children aged 1-60 months.(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 1-60 month olds seen in local health clinics for a respiratory complaint(24 months)
- Rates of acute respiratory illness among children 1-60 months.(6-24 months 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(5 x over 24 weeks after baseline)
- Serology for exposure to exotic pathogens of children aged 1-60 months as measured by lateral flow assays or Multiplex bead array(24 months)