A Phase 4 interventional study of Azithromycin and Placebo in Childhood Mortality, sponsored by University of California, San Francisco. Completed at 1 site in Burkina Faso. Open to participants aged 8 Days to 27 Days, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-06-27.
Sponsored by University of California, San Francisco · Phase 4, Interventional, and Prevention
Although under-5 mortality rates are declining globally, neonatal mortality remains persistently high in many regions of sub-Saharan Africa. Mass azithromycin distribution to children aged 1-59 months has been shown to reduce childhood mortality in Niger, Tanzania, and Malawi. This study did not evaluate the effect of azithromycin administered during the neonatal period. Observational evidence from high income countries has suggested that macrolides, including erythromycin and azithromycin, may be associated with increased risk of development of infantile hypertrophic pyloric stenosis (IHPS). However, these studies are limited by confounding by indication, as infants only receive antibiotics when they are ill.
The investigators proposed an individually randomized trial of azithromycin versus placebo to establish the efficacy and safety of administration of a dose of azithromycin during the neonatal period. The long-term goal is generate evidence that can be used by neonatal and child survival programs related to the use of azithromycin in the youngest children who have the highest risk of mortality. The investigators hypothesize that a single dose of azithromycin administered in the neonatal period will lead to significantly reduced risk of mortality and that this dose will be safe.
Objectives
This study will be conducted in several regions of Burkina Faso, including peri-urban areas of Ouagadougou and Nouna town, and rural areas that are within 4 hours' drive of a pediatric facility with capacity for performing pyloromyotomy
Child mortality in West Africa is among the highest in the world. Although child health and mortality are improving worldwide, children in the Sahel and sub-Sahel regions of West Africa have the greatest risks of mortality. Burkina Faso's current under-5 mortality rate is estimated 110 per 1,000 live births. Similar to other countries in the region, the major causes of child mortality in Burkina Faso are malaria, respiratory tract infection, and diarrhea. Malnutrition acts as a major underlying contributor to mortality. Neonatal mortality remains persistently high, with approximately 1/5th of neonatal mortality due to pneumonia, meningitis, and sepsis. Interventions that address these underlying causes may be particularly efficacious for reducing mortality.
Younger children at are at a higher risk of mortality. Approximately 2/3rd of under-5 deaths occur during the first year of life. In general, the child mortality rate decreases as age increases. While some improvement has been observed, neonatal mortality is declining at a slower rate than post-neonatal childhood mortality. Many child health interventions are designed specifically for children over 6 months of age, such as vitamin A supplementation, seasonal malaria chemoprevention, and lipid-based nutritional supplementation. Identification of strategies that are safe and effective for the youngest children will be required to address persistently high rates of neonatal and infant mortality.
The MORDOR I study demonstrated a significant reduction in all-cause child mortality following biannual mass azithromycin distribution. Across three diverse geographic locations in sub-Saharan Africa (Malawi, Niger, and Tanzania), biannual mass azithromycin distribution over a two-year period led to a 14% decrease in all-cause child mortality. In Niger, 1 in 5-6 deaths were averted. These results are qualitatively similar to those of a previous study of mass azithromycin distribution for trachoma control in Ethiopia, which found reduced odds of all-cause mortality in children in communities receiving mass azithromycin compared to control communities.
In MORDOR I, the strongest effect of azithromycin was in the youngest cohort of children. Across all three countries, the strongest effect of azithromycin was consistently in children 1-5 months of age, with an approximately 25% reduction in all-cause mortality. However, MORDOR I was not optimized to target the youngest age groups. Although children as young as 1 month were eligible, biannual distributions might not reach some children until 7 months of age. On average, children were first treated at 4 months. Given that there may be a substantial benefit to treating children at younger ages, azithromycin strategies that are designed to target younger age groups may be even more beneficial for reducing child mortality.
Here, the investigators propose a randomized controlled trial designed to evaluate the efficacy of a dose of azithromycin administered during the neonatal period for prevention of mortality within in the first 6 months of life. The investigators propose to randomize births in several geographic regions of Burkina Faso to a single dose of azithromycin or placebo between day 8 and 27 of life. This study is designed to provide evidence of the efficacy of azithromycin treatment for the youngest children.
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Communities
Inclusion Criteria:
Exclusion Criteria:
Individuals:
Inclusion Criteria:
Exclusion Criteria:
a single dose of Azithromycin will be administered to infants between their 8-27th days of life
Drug: Azithromycin
a single dose of placebo will be administered to infants between their 8-27th days of life
Drug: Placebo
a single dose of Azithromycin will be administered to infants between their 8-27th days of life
a single dose of Placebo will be administered to infants between their 8-27th days of life
6 Month Mortality - All Cause
The primary outcome of the study was all-cause mortality rate in infants at 6 months of age.
Time frame: 6 months
12 Month Mortality - All Cause
All-cause Mortality Rate in infants at 12 months of age
Time frame: 12 months
Vital Status
Caregivers will be asked if the child is dead or alive at 365 days of life
Time frame: 12 months
Change in Weight Over Time
Weight gain from baseline to day 180
Time frame: 6 months
Change in Length Over Time
Change in length from baseline to day 180
Time frame: 6 months
Proportion of Infants Developing Infantile Hypertrophic Pyloric Stenosis
Proportion of infants developing infantile hypertrophic pyloric stenosis between 2 to 8 weeks after treatment
Time frame: 8 weeks
Adverse Events
Caregivers will be asked if their child experienced any symptoms for pyloric stenosis since the last visit.
Time frame: 12 months
Neonatal Mortality
Mortality prior to 28 days of life
Time frame: 28 days
| Milestone | Azithromycin | Placebo |
|---|---|---|
| Started | 10898 | 10934 |
| Received allocated treatment | 10898 | 10928 |
| Day 21 | 10069 | 10119 |
| 3 months | 10273 | 10356 |
| Completed | 9606 | 9684 |
| Not completed | 1292 | 1250 |
The primary outcome of the study was all-cause mortality rate in infants at 6 months of age.
| Participants | Azithromycin | Placebo |
|---|---|---|
| 6 Month Mortality - All Cause | 42 | 50 |
All-cause Mortality Rate in infants at 12 months of age
| Participants | Azithromycin | Placebo |
|---|---|---|
| 12 Month Mortality - All Cause | 52 | 64 |
Caregivers will be asked if the child is dead or alive at 365 days of life
| Participants | Azithromycin | Placebo |
|---|---|---|
| Vital Status | 52 | 64 |
Weight gain from baseline to day 180
| g/day | Azithromycin | Placebo |
|---|---|---|
| Change in Weight Over Time | 23.2 ± 5.3 | 23.3 ± 5.4 |
Change in length from baseline to day 180
| mm/day | Azithromycin | Placebo |
|---|---|---|
| Change in Length Over Time | 0.9 ± 0.2 | 0.9 ± 0.2 |
Proportion of infants developing infantile hypertrophic pyloric stenosis between 2 to 8 weeks after treatment
| Participants | Azithromycin | Placebo |
|---|---|---|
| Proportion of Infants Developing Infantile Hypertrophic Pyloric Stenosis | 1 | 0 |
Caregivers will be asked if their child experienced any symptoms for pyloric stenosis since the last visit.
| Participants | Azithromycin | Placebo |
|---|---|---|
| Adverse Events | 0 | 0 |
Mortality prior to 28 days of life
| Participants | Azithromycin | Placebo |
|---|---|---|
| Neonatal Mortality | 9 | 6 |
Collected over 12 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Azithromycin | 52/10,898 (0.5%) | 29/10,898 (0.3%) | 575/10,898 (5.3%) |
| Placebo | 64/10,934 (0.6%) | 15/10,934 (0.1%) | 599/10,934 (5.5%) |
| Event | Azithromycin | Placebo |
|---|---|---|
| Mortality within 28 d of treatmentGeneral disorders | 16/10898 | 8/10934 |
| Hospitalization within 28 d of treatmentGeneral disorders | 14/10898 | 7/10934 |
| Infantile hypertrophic pyloric stenosisGastrointestinal disorders | 1/10898 | 0/10934 |
| Event | Azithromycin | Placebo |
|---|---|---|
| FeverGeneral disorders | 193/10898 | 237/10934 |
| Abdominal painGeneral disorders | 209/10898 | 171/10934 |
| ConstipationGastrointestinal disorders | 82/10898 | 111/10934 |
| RashSkin and subcutaneous tissue disorders | 70/10898 | 86/10934 |
| Vomiting (any)Gastrointestinal disorders | 78/10898 | 49/10934 |
| DiarrheaGastrointestinal disorders | 51/10898 | 61/10934 |
| Vomiting after every feedGastrointestinal disorders | 22/10898 | 9/10934 |
| Projectile vomitingGastrointestinal disorders | 3/10898 | 0/10934 |
| Age, Continuous(days) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Median | 11 (9 to 15) | 11 (9 to 14) | 11 (9 to 14) |
| Sex: Female, Male(Participants) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Female | 5413 | 5431 | 10844 |
| Male | 5485 | 5503 | 10988 |
| Race and Ethnicity Not Collected(Participants) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
| Region of Enrollment(Participants) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Burkina Faso — Center | 919 | 951 | 1870 |
| Burkina Faso — Boucle du Mouhoun | 1299 | 1329 | 2628 |
| Burkina Faso — Cascade | 2009 | 1977 | 3986 |
| Burkina Faso — Center Ouest | 1217 | 1211 | 2428 |
| Burkina Faso — Hauts-Bassins | 5454 | 5465 | 10919 |
| Burkina Faso — Missing | 0 | 1 | 1 |
| Urban dwelling(Participants) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Urban | 8960 | 9055 | 18015 |
| Rural | 1932 | 1869 | 3801 |
| Missing | 6 | 10 | 16 |
| Season of enrollment(Participants) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Rainy (June to October) | 5217 | 5295 | 10512 |
| Dry (November to May) | 5681 | 5639 | 11320 |
| Birthweight(g) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Median | 3000 (2700 to 3250) | 3000 (2700 to 3260) | 3000 (2700 to 3250) |
| Weight at enrollment(g) | Azithromycin | Placebo | Total |
|---|---|---|---|
| Median | 3300 (2980 to 3620) | 3300 (2990 to 3620) | 3300 (2990 to 3620) |
11 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — De-identified data will be available as per the Bill and Melinda Gates open access policy. Individual participant data will be available that underline the reported results (texts, tables, figures, and appendices). The study protocol and statistical analysis plan will also be made available. The data will be available following publication in accordance with the BMGF guidelines.
Supporting information: Study protocol, Statistical analysis plan
Time frame: The data will be available following publication, without any embargo period.
This study is completed, as verified in Jun 2023. You cannot join it, but the record below documents what was studied.
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Studies of the drug tested here: Azithromycin
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