Neonates and Azithromycin, an Innovation in the Treatment of Children in Burkina Faso (NAITRE)

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

1. Establish the efficacy of a single dose of azithromycin administered during the neonatal period compared to placebo in infants 8 to 27 days of life for reduction in all-cause mortality.
2. Establish the safety of a single dose of azithromycin administered during the neonatal period.

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

Study Overview

• Status: Completed
• Conditions: Childhood Mortality
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21832
• Phase: Phase 4

Contacts and Locations

Study Locations

• Burkina Faso
  • Nouna, Burkina Faso, BP 02
    • Centre de recherche en Santé de nouna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 week to 3 weeks (Child)
• Accepts Healthy Volunteers: Yes

Description

Communities

Inclusion Criteria:

• Within 4 hours of a facility that can provide services for pyloromyotomy (Ouagadougou or Bobo Dioulasso)
• Accessible during the rainy season
• Ultrasound machine available OR a facility in which an ultrasound machine could be placed is within 1 hour

Exclusion Criteria:

• Refusal of village chief

Individuals:

Inclusion Criteria:

• Weight over 2500 g
• Able to feed orally
• Family intends to stay in study area for at least 6 months
• Appropriate consent from at least one caregiver
• No known allergy to azalides
• Not living within one of the communities included in the community study(CHAT/CHATON)
• No hepatic failure manifested by neonatal jaundice

Exclusion Criteria:

• Weight <2500 g
• Unable to feed orally
• Family planning to move
• Mother/caregiver not willing to participate
• Allergic to azalides
• Living in one of the communities included in the community study (CHAT/CHATON)
• Hepatic failure manifested by neonatal jaundice

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithromycin; a single dose of Azithromycin will be administered to infants between their 8-27th days of life	Drug: Azithromycin; a single dose of Azithromycin will be administered to infants between their 8-27th days of life
Placebo Comparator: Placebo; a single dose of placebo will be administered to infants between their 8-27th days of life	Drug: Placebo; a single dose of Placebo will be administered to infants between their 8-27th days of life

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
6 Month Mortality - All Cause	The primary outcome of the study was all-cause mortality rate in infants at 6 months of age.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital Status	Caregivers will be asked if the child is dead or alive at 365 days of life	12 months
Neonatal Mortality	Mortality prior to 28 days of life	28 days
12 Month Mortality - All Cause	All-cause Mortality Rate in infants at 12 months of age	12 months
Change in Weight Over Time	Weight gain from baseline to day 180	6 months
Change in Length Over Time	Change in length from baseline to day 180	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	8 weeks
Adverse Events	Caregivers will be asked if their child experienced any symptoms for pyloric stenosis since the last visit.	12 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Bill and Melinda Gates Foundation; Centre de Recherche en Sante de Nouna, Burkina Faso
• Investigators: Principal Investigator: Catherine E Oldenburg, PhD, University of California, San Francisco; Principal Investigator: Tom M Lietman, MD, University of California, San Francisco; Principal Investigator: Ali Sie, MD, PhD, Centre de Recherche en Sante de Nouna, Burkina Faso

Publications and helpful links

General Publications

• Oldenburg CE, Sie A, Bountogo M, Zakane A, Compaore G, Ouedraogo T, Koueta F, Lebas E, Brogdon J, Nyatigo F, Doan T, Porco TC, Arnold BF, Lietman TM; NAITRE Study Team. Neonatal azithromycin administration for prevention of infant mortality. NEJM Evid. 2022 Apr;1(4):EVIDoa2100054. doi: 10.1056/EVIDoa2100054. Epub 2022 Mar 17.
• Bountogo M, Sie A, Zakane A, Compaore G, Ouedraogo T, Lebas E, Brogdon J, Nyatigo F, Arnold BF, Lietman TM, Oldenburg CE. Antenatal care attendance and risk of low birthweight in Burkina Faso: a cross-sectional study. BMC Pregnancy Childbirth. 2021 Dec 13;21(1):825. doi: 10.1186/s12884-021-04310-6.
• Sie A, Bountogo M, Nebie E, Ouattara M, Coulibaly B, Bagagnan C, Zabre P, Lebas E, Brogdon J, Godwin WW, Lin Y, Porco T, Doan T, Lietman TM, Oldenburg CE; NAITRE Study Group. Neonatal azithromycin administration to prevent infant mortality: study protocol for a randomised controlled trial. BMJ Open. 2019 Sep 4;9(9):e031162. doi: 10.1136/bmjopen-2019-031162.

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2019
• Primary Completion (Actual): May 1, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: September 19, 2018
• First Submitted That Met QC Criteria: September 21, 2018
• First Posted (Actual): September 24, 2018

Study Record Updates

• Last Update Posted (Actual): June 27, 2023
• Last Update Submitted That Met QC Criteria: June 9, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: neonates; azithromycin; mass drug administration; childhood mortality
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: OPP1187628-B

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: The data will be available following publication, without any embargo period.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes