Childhood Mortality
Conditions
Keywords
Childhood mortality, Azithromycin, Mass treatment, Infection, Verbal Autopsy
Brief summary
Our long-term goal is to more precisely define the role of mass azithromycin treatments as an intervention for reducing childhood mortality. We propose a single multi-site (multi-country), cluster-randomized trial comparing communities randomized to oral azithromycin with those randomized to placebo. We hypothesize that mass azithromycin treatments will reduce childhood mortality.
Detailed description
We will assess childhood mortality over three years, comparing communities where children aged 1-60 months receive biannual oral azithromycin (Azithromycin arm) for two years, to communities where the children receive biannual oral placebo (Control arm) for two years. During the third year at the Niger site only, everyone will receive azithromycin. This is a cluster-randomized trial; at each site, communities within a contiguous area of 300,000 to 600,000 individuals will be randomized to azithromycin or placebo using simple random sampling. Niger contingency study: In the event that mass distributions of oral azithromycin are proven to reduce mortality in 1-60 month-old children, then we will treat all communities in Niger with mass azithromycin distributions to test whether the intervention continues to reduce childhood mortality after the initial 2 years of mass treatments.
Interventions
DRUGAzithromycin
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. In Niger during year 3, all communities will be offered azithroymcin.
DRUGPlacebo
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. In Niger during year 3, all communities will be offered azithroymcin.
Sponsors
Bill and Melinda Gates Foundation
Johns Hopkins University
London School of Hygiene and Tropical Medicine
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to 60 Months
Healthy volunteers
Yes
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 - All children aged 1-60 months (up to but not including the 5th birthday), as assessed via biannual census.
Exclusion criteria
Individuals \- Refusal of village chief (for village inclusion), or refusal of parent or guardian (for individual inclusion)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality Rate in Children Aged 1-60 Months | 24 Months | This is a single multi-site trial, with each country as a secondary analysis. Also, an interim analysis of efficacy and futility will be conducted according to a pre-specified plan in the Statistical Analysis Plan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | 24 Months | Deaths were assessed via biannual population census. A pre-specified outcome was cause of death, assessed by verbal autopsy. |
| Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death | 24 months | Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death during the 24 month phase |
| All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children | 24 months | We recorded clinic visits one year prior the study and during the first year of the study and collected outcomes of these visit. |
| Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | 24 Months | At 6-monthly intervals a census of the communities was conducted, and for child deaths a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. Mortality due to pneumonia or diarrhea by age group and arm are shown in the outcome measure data table below. |
| Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | 24 Months | Cause-specific mortality by intention-to-treat for the four main inferred causes of death in the study area. |
Countries
Malawi, Niger, Tanzania, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Biannual Mass Oral Azithromycin Comparison of childhood mortality 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.
In Niger during year 3, all communities will be offered azithroymcin.
Azithromycin: 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. In Niger during year 3, all communities will be offered azithroymcin. | 97,047 |
| Biannual Mass Oral Placebo Comparison of childhood mortality 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
In Niger during year 3, all communities will be offered azithroymcin.
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. In Niger during year 3, all communities will be offered azithroymcin. | 93,191 |
| Total | 190,238 |
Baseline characteristics
| Characteristic | Total | Biannual Mass Oral Placebo | Biannual Mass Oral Azithromycin |
|---|---|---|---|
| Age, Customized Age group 12-23 months | 36443 Participants | 17886 Participants | 18557 Participants |
| Age, Customized Age group 1-5 months | 14005 Participants | 6870 Participants | 7135 Participants |
| Age, Customized Age group 24-59 months | 114695 Participants | 56117 Participants | 58578 Participants |
| Age, Customized Age group 6-11 months | 25095 Participants | 12318 Participants | 12777 Participants |
| Number of communities | 1512 communities | 750 communities | 762 communities |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 190238 Participants | 93191 Participants | 97047 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Malawi | 78920 participants | 39534 participants | 39386 participants |
| Region of Enrollment Niger | 76092 participants | 35747 participants | 40345 participants |
| Region of Enrollment Tanzania | 35226 participants | 17910 participants | 17316 participants |
| Sex: Female, Male Female | 93920 Participants | 46019 Participants | 47901 Participants |
| Sex: Female, Male Male | 96318 Participants | 47172 Participants | 49146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3,262 / 97,047 | 3,392 / 93,191 |
| other Total, other adverse events | 0 / 97,047 | 0 / 93,191 |
| serious Total, serious adverse events | 3,273 / 97,047 | 3,400 / 93,191 |
Outcome results
Primary
All-cause Mortality Rate in Children Aged 1-60 Months
This is a single multi-site trial, with each country as a secondary analysis. Also, an interim analysis of efficacy and futility will be conducted according to a pre-specified plan in the Statistical Analysis Plan.
Time frame: 24 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biannual Mass Oral Azithromycin | All-cause Mortality Rate in Children Aged 1-60 Months | 14.6 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | All-cause Mortality Rate in Children Aged 1-60 Months | 16.5 deaths per 1000 person-years |
Primary
All-cause Mortality Rate in Children Aged 1-60 Months
This was a pre-specified contingency study in Niger only in which all communities were treated with mass azithromycin during the third year of the study following the primary 24-month endpoint.
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biannual Mass Oral Azithromycin | All-cause Mortality Rate in Children Aged 1-60 Months | 23.3 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | All-cause Mortality Rate in Children Aged 1-60 Months | 24.0 deaths per 1000 person-years |
Secondary
All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children
We recorded clinic visits one year prior the study and during the first year of the study and collected outcomes of these visit.
Time frame: 24 months
Population: Number of children visiting health centers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Biannual Mass Oral Azithromycin | All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children | 5229 post-treatment clinical visits |
| Biannual Mass Oral Placebo | All-cause and Cause-specific Health Clinic Visits in 1-60 Month-old Children | 7647 post-treatment clinical visits |
Secondary
Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only)
Cause-specific mortality by intention-to-treat for the four main inferred causes of death in the study area.
Time frame: 24 Months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Pneumonia | 1.15 deaths per 1000 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Malaria | 3.68 deaths per 1000 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | HIV/AIDS | 1.06 deaths per 1000 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Diarrhoea | 0.67 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Diarrhoea | 0.72 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Pneumonia | 1.40 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | HIV/AIDS | 1.54 deaths per 1000 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Malawi Only) | Malaria | 3.84 deaths per 1000 person-years |
Secondary
Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only)
Deaths were assessed via biannual population census. A pre-specified outcome was cause of death, assessed by verbal autopsy.
Time frame: 24 Months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Injury | 0.22 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Malnutrition | 0.39 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | AIDS | 0.12 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Measles | 0.30 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Meningitis | 0.82 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Dysentery | 0.74 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Diarrhea | 3.01 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Pertussis | 0.04 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Pneumonia | 3.27 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Malaria | 5.60 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Hemorrhagic fever | 0.08 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Other infection | 4.24 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Unspecified | 1.43 Deaths per 1000 person years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Total | 22.3 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Hemorrhagic fever | 0.06 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Injury | 0.23 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Pertussis | 0.04 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Malnutrition | 0.42 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Unspecified | 1.81 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | AIDS | 0.12 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Pneumonia | 3.96 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Measles | 0.28 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Other infection | 5.06 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Meningitis | 1.22 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Malaria | 7.22 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Dysentery | 1.14 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Total | 27.3 Deaths per 1000 person years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Niger Only) | Diarrhea | 3.60 Deaths per 1000 person years |
Secondary
Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only)
At 6-monthly intervals a census of the communities was conducted, and for child deaths a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. Mortality due to pneumonia or diarrhea by age group and arm are shown in the outcome measure data table below.
Time frame: 24 Months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 1- 5 months | 0.46 deaths per 100 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 6- 11 months | 0.47 deaths per 100 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 12 - 23 months | 0.29 deaths per 100 person-years |
| Biannual Mass Oral Azithromycin | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 24 - 59 months | 0.15 deaths per 100 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 24 - 59 months | 0.10 deaths per 100 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 1- 5 months | 0.90 deaths per 100 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 12 - 23 months | 0.29 deaths per 100 person-years |
| Biannual Mass Oral Placebo | Cause-specific Mortality Rate in Children Aged 1-60 Months, as Assessed From Verbal Autopsy (Tanzania Only) | Age group Mortality: 6- 11 months | 0.56 deaths per 100 person-years |
Secondary
Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death
Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death during the 24 month phase
Time frame: 24 months
Population: all children 1-59 months treated
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Biannual Mass Oral Azithromycin | Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death | 853 usd per death averted |
| Biannual Mass Oral Placebo | Cost-effectiveness of Mass Azithromycin Administration, Per Averted Childhood Death | 0 usd per death averted |