LAKANA , a Cluster-randomized, Double-blinded, Parallel Group, Controlled Trial, Testing the Effects of Mass Drug Administration of Azithromycin on Mortality and Other Outcomes Among 1-11 Month Old Infants in Rural Mali.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 149,201
- 试验地点
- 1
- 主要终点
- Mortality
研究概览
简要总结
The LAKANA trial will assess the impact on mortality and other health outcomes of quarterly and biannual azithromycin mass drug administration (MDA) when delivered to 1-11-month (29-364 days) old infants in a high-mortality setting where malaria is holoendemic but there is also a functioning seasonal malaria chemoprevention (SMC) program in place. The long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood mortality, and to determine the most effective treatment regimen. The main study hypotheses in terms of mortality effect are: i) Biannual azithromycin MDA to 1-11 month old infants reduces their mortality, ii) Quarterly azithromycin MDA to 1-11 month old infants reduces their mortality, iii) Quarterly azithromycin MDA has a bigger mortality effect than biannual MDA.
详细描述
Mass drug administration (MDA) of azithromycin has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. Because of the observed heterogeneity and possible effect modification by SMC or other co-interventions, further trials in new settings are needed in order to make evidence-based public health recommendations about the use of this treatment. The objectives of the LAKANA trial are:
- To evaluate the impact of two azithromycin MDA regimens on infant mortality and other health outcomes, when provided in a rural West-African high-mortality context with an ongoing seasonal malaria chemoprevention program.
- To evaluate the effect of alternative MDA frequencies on antimicrobial resistance (AMR) and host microbiota composition.
- To test hypotheses that azithromycin MDA eliminates malaria parasitaemia and reduces systemic and intestinal inflammation in asymptomatic children and to collect and store biological samples for assessing other possible mechanisms of azithromycin effect.
- To investigate the feasibility of alternative azithromycin MDA strategies, including economic analysis.
The LAKANA trial will be conducted in 1151 villages from 7-10 health districts in the Kayes, Kita and Koulikoro regions of Mali. LAKANA is a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial, with adaptive design. Participating villages will be randomly allocated to three different intervention groups in a ratio of 3 : 2 : 4 (control : azithromycin quarterly : azithromycin biannually). Within each participating village, consenting households will be visited quarterly (at 3-month intervals), nine times. At the first eight of these visits, 1-11-month-old eligible infants (age 29-364 days), for whom there is a consent for study drug provision, will be given a single dose of study drug (azithromycin mixture or respective placebo mixture).
Mortality and serious adverse events (SAEs) data will be collected, and mortality-related questions answered using data from all the included 1151 villages. Mixed-effect Poisson regression model will be used to estimate the intervention effects on mortality, with random intercepts for the clusters. The investigators will explore effect modification by testing for interaction between the MDA intervention and the following variables:
- Age at the time of the MDA
- Sex of the child
- Weight-for-age
- Seasonality: rainy season vs non-rainy season at the time of the MDA
- SMC given to the child within 3 months before an MDA
- Order of MDA in the village
- District of residence
- Distance from the nearest health facility (in km)
- Household asset index
- Water, Sanitation, and Hygiene (WASH) index
- National outreach strategy category (standard/advanced)
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)
盲法说明
The investigators will utilize a matching placebo to mask study arm allocation. All children aged 1-11 months in all study communities will be offered biannual or quarterly azithromycin or placebo distribution in an identical fashion. Placebo will be identical to azithromycin in appearance, taste, odor, and packaging. The interventions will be coded only with a letter code.
入排标准
- 年龄范围
- 29 Days 至 364 Days（Child）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •On a cluster (village) level:
- •Location within Kayes, Kita, or Koulikoro region of Mali
- •Considered accessible and safe by the local health authorities and research team
- •Considered non-urban by the local health authorities and research team
- •Permission from community leadership
- •On a household level (for trial enrollment):
- •Location within a cluster that is included in the study
- •Verbal consent from a head of household or an adult authorized by her / him
- •On a child level (for receiving study medication):
- •Residence in a household enrolled in the trial
- •Age between 29 and 364 days
- •Verbal consent from at least one caregiver
排除标准
- •On child level (for not receiving study medication):
- •Weight below 3.0 kg
- •Known allergy to macrolides, as judged by a caregiver report of the infant experiencing an adverse reaction after oral ingestion of medication, which was deemed likely to be a macrolide by the interviewing data collector.
研究组 & 干预措施
Control
Placebo mixture will be administered as a single dose in oral suspension form for children 1-11 months of age:
- Single-dose of 0.5 ml / kg child weight
- Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of placebo mixture.
干预措施: Placebo (Drug)
Azithromycin-biannually (Azi-biannual)
Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age:
- Single-dose of 0.5 ml / kg child weight
- Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of study drug.
- Azithromycin will be given at quarterly visits between January and June, and Placebo mixture will be given at quarterly visits between July and December. Azithromycin dose will be 20 mg / kg.
干预措施: Placebo (Drug)
Azithromycin-biannually (Azi-biannual)
Azithromycin or placebo will be administered as a single dose in oral suspension form for children 1-11 months of age:
- Single-dose of 0.5 ml / kg child weight
- Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of study drug.
- Azithromycin will be given at quarterly visits between January and June, and Placebo mixture will be given at quarterly visits between July and December. Azithromycin dose will be 20 mg / kg.
干预措施: Azithromycin (Drug)
Azithromycin-quarterly
Azithromycin will be administered as a single dose in oral suspension form for children 1-11 months of age:
- Single-dose of 0.5 ml (20 mg) / kg child weight.
- Participating households within villages allocated to this group will be visited quarterly (at 3-month intervals), for nine times. At the first eight of these visits, 1-11 month old eligible infants, for whom there is a consent for study drug provision, will be weighed and given a single dose of azithromycin.
干预措施: Azithromycin (Drug)
结局指标
主要结局
Mortality
时间窗: 3-month time interval (total of 8 intervals per cluster)
Mortality rate (deaths per 1,000 years at risk) among children 1-11 months of age.
次要结局
- Morbidity(3-month time interval (total of 8 intervals per cluster))
- Length-for-age Z-score(3-month time interval (total of 3 intervals per cluster))
- Length(3-month time interval (total of 3 intervals per cluster))
- Weight(3-month time interval (total of 3 intervals per cluster))
- Weight-for age Z-score(3-month time interval (total of 3 intervals per cluster))
- Weight-for-length Z-score(3-month time interval (total of 3 intervals per cluster))
- Mid-upper arm circumference(3-month time interval (total of 3 intervals per cluster))
- Percentage of moderate or severe stunting(3-month time interval (total of 3 intervals per cluster))
- Percentage of moderate or severe wasting(3-month time interval (total of 3 intervals per cluster))
- Percentage of moderate or severe Underweight(3-month time interval (total of 3 intervals per cluster))
- Prevalence of phenotypic and genotypic macrolide resistance(12-month time interval (total of 3 intervals per cluster))
- Prevalence of phenotypic and genotypic AMR resistance to other "ACCESS" group antibiotics(12-month time interval (total of 3 intervals per cluster))
- Blood C-reactive protein concentration(Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.)
- Blood malaria parasitemia and hemoglobin concentration(Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.)
- Fecal neopterin, myeloperoxidase, and alpha-1-antitrypsin concentrations(Biological samples taken before and 14 days after the fourth MDA round, 9 months after village enrollment.)
- Incidence of Adverse events(3-month time interval)
- Incidence of Serious Adverse events(within 14 days after MDA round.)
- Mortality in children aged 12-59 month(3-month time interval (total of 8 intervals per cluster))
- Percentage of guardians and health care workers reporting MDA acceptable(24 months after enrollment)
- Percentage of the study population reached with MDA(24 months after enrollment)
- Cost and Cost-effectiveness of the intervention(24 months after enrollment)
研究者
Per Ashorn
MD, PhD, Professor of Pediatrics
Tampere University