NCT03682653: NAITRE

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

Completed Phase 4 Results posted Last updated 27 June 2023

What this trial tests

Phase 4 trial testing Azithromycin in Childhood Mortality in 21,832 participants. Completed in 31 December 2022.

Timeline

11 April 2019

Primary endpoint
1 May 2022

31 December 2022

Quick facts

Lead sponsor	University of California, San Francisco
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	prevention
Enrollment	21,832
Start date	11 April 2019
Primary completion	1 May 2022
Estimated completion	31 December 2022
Sites	1 location across Burkina Faso

Drugs / interventions tested

• Azithromycin (azithromycin) — full drug profile →
• Placebo

Conditions studied

• Childhood Mortality — all drugs for Childhood Mortality →

Sponsor

University of California, San Francisco

Who can join

Adults 8 Days to 27 Days, any sex, with Childhood Mortality. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

6 Month Mortality - All Cause Primary · 6 months

The primary outcome of the study was all-cause mortality rate in infants at 6 months of age.

Group	Value	95% CI
Azithromycin	42
Placebo	50

12 Month Mortality - All Cause Secondary · 12 months

All-cause Mortality Rate in infants at 12 months of age

Group	Value	95% CI
Azithromycin	52
Placebo	64

Vital Status Secondary · 12 months

Caregivers will be asked if the child is dead or alive at 365 days of life

Group	Value	95% CI
Azithromycin	52
Placebo	64

Change in Weight Over Time Secondary · 6 months

Weight gain from baseline to day 180

Group	Value	95% CI
Azithromycin	23.2	± 5.3
Placebo	23.3	± 5.4

Change in Length Over Time Secondary · 6 months

Change in length from baseline to day 180

Group	Value	95% CI
Azithromycin	0.9	± 0.2
Placebo	0.9	± 0.2

Proportion of Infants Developing Infantile Hypertrophic Pyloric Stenosis Secondary · 8 weeks

Proportion of infants developing infantile hypertrophic pyloric stenosis between 2 to 8 weeks after treatment

Group	Value	95% CI
Azithromycin	1
Placebo	0

Adverse Events Secondary · 12 months

Caregivers will be asked if their child experienced any symptoms for pyloric stenosis since the last visit.

Group	Value	95% CI
Azithromycin	0
Placebo	0

Neonatal Mortality Secondary · 28 days

Mortality prior to 28 days of life

Group	Value	95% CI
Azithromycin	9
Placebo	6

Adverse events — posted to ClinicalTrials.gov

Time frame: 12 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Azithromycin

Serious: 29/10898 (0%)

Deaths: 52/10898

Placebo

Serious: 15/10934 (0%)

Deaths: 64/10934

Serious adverse events (3 terms)

Reaction	System	Azithromycin	Placebo
Mortality within 28 d of treatment	General disorders	—	—
Hospitalization within 28 d of treatment	General disorders	—	—
Infantile hypertrophic pyloric stenosis	Gastrointestinal disorders	—	—

Other adverse events (8 terms — click to expand)

Reaction	System	Azithromycin	Placebo
Fever	General disorders	—	—
Abdominal pain	General disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Vomiting (any)	Gastrointestinal disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Vomiting after every feed	Gastrointestinal disorders	—	—
Projectile vomiting	Gastrointestinal disorders	—	—

Most-reported serious reactions: Mortality within 28 d of treatment, Hospitalization within 28 d of treatment, Infantile hypertrophic pyloric stenosis.

Data from ClinicalTrials.gov NCT03682653 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Antimicrobial Resistance Following Azithromycin Mass Drug Administration: Potential Surveillance Strategies to Assess Public Health Impact.
   Mack I, Sharland M, Berkley JA, Klein N, et al · · 2020 · cited 31× · PMID 31633161 · DOI 10.1093/cid/ciz893
2. Neonatal azithromycin administration for prevention of infant mortality.
   Oldenburg CE, Sié A, Bountogo M, Zakane A, et al · · 2022 · cited 27× · PMID 35692260 · DOI 10.1056/evidoa2100054
3. Neonatal azithromycin administration to prevent infant mortality: study protocol for a randomised controlled trial.
   Sie A, Bountogo M, Nebie E, Ouattara M, et al · · 2019 · cited 16× · PMID 31488494 · DOI 10.1136/bmjopen-2019-031162
4. Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali (LAKANA): study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial.
   Adubra L, Alber D, Ashorn P, Ashorn U, et al · · 2023 · cited 12× · PMID 36597115 · DOI 10.1186/s13063-022-06966-7
5. Antenatal care attendance and risk of low birthweight in Burkina Faso: a cross-sectional study.
   Bountogo M, Sié A, Zakané A, Compaoré G, et al · · 2021 · cited 11× · PMID 34903190 · DOI 10.1186/s12884-021-04310-6
6. Neonatal Azithromycin Administration and Growth during Infancy: A Randomized Controlled Trial.
   Sie A, Bountogo M, Zakane A, Compaoré G, et al · · 2023 · cited 9× · PMID 36972694 · DOI 10.4269/ajtmh.22-0763
7. Infant mortality and growth failure after oral azithromycin among low birthweight and underweight neonates: A subgroup analysis of a randomized controlled trial.
   Bountogo M, Sié A, Zakane A, Compaoré G, et al · · 2023 · cited 5× · PMID 37186577 · DOI 10.1371/journal.pgph.0001009
8. Neonatal Azithromycin Exposure and Childhood Growth: Long-Term Follow-Up of a Randomized Controlled Trial.
   Bountogo M, Ouermi L, Dah C, Sié A, et al · · 2024 · cited 1× · PMID 39013367 · DOI 10.4269/ajtmh.24-0016