Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis & Death

NCT03199547 | Completed Phase 3 DMC

• 1 other identifier: SCC 1532
• Study Type: interventional
• Target: 11,985
• Locations: 2 countries
• Sites: 2

Brief Summary

Though maternal and neonatal health are high priority areas for international development, maternal and neonatal mortality remain unacceptably high. Worldwide there are 1 million maternal and 4 million neonatal deaths every year and half of them occur in sub-Saharan Africa. Post-partum and neonatal severe bacterial infections, namely sepsis, are leading causes of maternal and neonatal deaths in sub-Saharan Africa. Newborns can be infected during labour - when passing through the birth canal - and also during the first days/weeks of life, as a consequence of the close physical contact with the mother, when the latter carriers bacteria. As the mother is an important source of bacterial transmission to the newborn, treating mothers with antibiotics during labour should decrease their bacterial carriage and therefore lower transmission to the newborn. As carriage is a necessary step towards severe disease, this intervention should in turn result in the lower occurrence of severe bacterial disease and mortality during the neonatal period. In many high-income countries, pregnant women are screened during pregnancy for vaginal carriage of Group B Streptococcus, the bacteria responsible for the vast majority of neonatal sepsis in the developed world. If women are carriers, they are treated with intravenous antibiotics during labour to decrease the risk of severe disease to their off-spring. Although this intervention has been successful in developed countries, infrastructure and resource limitations in regions like sub-Saharan Africa prevent both screening and use of intravenous antibiotics. Also, in Africa several bacterial pathogens are responsible for neonatal sepsis and the antibiotics needed in the continent should cover a wider number of bacteria; and ideally cover also bacteria responsible for severe post-partum disease in the mother. We will conduct a large trial in West Africa, The Gambia and Burkina Faso, with the main objective of determining if a single dose of an oral antibiotic given to women during labour decreases newborn mortality. The trial will also assess the effect of the antibiotic on lowering newborns and maternal hospitalization during the first week's post-partum. We have selected an antibiotic (azithromycin) that in sub-Saharan Africa has already been used for elimination of other prevalent diseases such as trachoma. This antibiotic is safe, requires a single oral administration, has no special storage requirements and has the potential to eliminate most of the bacteria commonly causing severe disease in newborns and post-partum women in the continent. Very important this antibiotic is not widely used in clinical care in the continent, and therefore, any temporal increase of resistance induced by the intervention should not have implications on current treatment guidelines. Before going to the large trial proposed here (12,000 women to be recruited), we have generated robust preliminary data on the effect of the intervention in a proof-of-concept trial conducted in The Gambia (829 women and their offspring recruited). We found that in fact, babies born from mothers who had taken this antibiotic during labour were less likely to carry bacteria that can potentially cause severe disease. These babies were also three times less likely to have bacterial skin infections or umbilical infections, both highly common among African newborns. Besides, fever or mastitis (again both very common in the region) during the post-partum period were four times lower among mothers who had taken the antibiotic during labour. Such trial confirmed our hypothesis of impact on bacterial transmission but it was too small to assess the effect of the antibiotic on mortality and hospitalizations. The preliminary trial also showed that women from the azithromycin group were less likely to need antibiotics for treatment infections during the puerperal period, decreasing then the pressure on the scarcity of antibiotics available in the continent. The advantages of our approach are its simplicity, low cost and the possibility of protecting both mothers and babies with the same intervention.

Conditions

Neonatal SEPSIS

Outcome Measures

Primary Outcomes (1)

• neonatal sepsis and mortality

  The primary endpoint of the study is a composite endpoint of prevalence of neonatal sepsis and mortality rate (from birth to 28 days) (deaths from severe birth asphyxias, major congenital malformations and VLBW are excluded from the primary endpoint).

  from Birth to Day 28

Secondary Outcomes (9)

• Neonatal sepsis-Early-onset of Culture confirmed sepsis

  Day 1- Day 3

• Early-onset clinical sepsis

  Day 1- Day 3

• Late-onset culture confirmed sepsis

  Day 3 - Day 28

• Late-onset clinical sepsis

  Day 3- Day 28

• All-caused hospitalisation during the follow up period

  28 days forAll study participants will be followed for 28 days except those participating in the sub-studies; 4 months for children in carriage sub-study; 12 months for children participating in the anthropometrical sub-stud

Study Arms (2)

AZITHROMYCIN

EXPERIMENTAL

A single dose of 2G Azithromycin or Placebo will be administered orally to women in labour

Drug: Azithromycin

Placebo oral tablet

PLACEBO COMPARATOR

A single dose of 2G Azithromycin or Placebo will be administered orally to women in labour

Drug: Placebo Oral Tablet

Interventions

Azithromycin DRUG

The women will be randomized to receive a single dose of Azithromycin or Placebo

AZITHROMYCIN

Placebo Oral Tablet DRUG

The women will be randomized to receive a single dose of Azithromycin or Placebo

Placebo oral tablet

Eligibility Criteria

• Age: 16 Years+
• Gender Eligibility Details: Pregnant women attending study health facilities for delivery will be enrolled
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Pregnant women in labour (aged 16 years or more) attending the study health facilities for delivery who have previously given consent and willing to continue participation

You may not qualify if:

• Known HIV infection. Any chronic or acute conditions of the women that might interfere with the study as judged by the research clinician.
• Planned travelling out of the catchment area during the following 28 days Planned caesarean section or known required referral Known severe congenital malformation Intrauterine death confirmed before randomisation Known allergy to macrolides Already participating in another trial

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead

Study Sites (2)

Clinical Research Unit of Nanoro

Nanoro, Burkina Faso

Location

Medical Research Council Unit The Gambia

Banjul, The Gambia

Location

Related Publications (3)

• Bojang A, Chung M, Camara B, Jagne I, Guerillot R, Ndure E, Howden BP, Roca A, Ghedin E. Genomic approach to determine sources of neonatal Staphylococcus aureus infection from carriage in the Gambia. BMC Infect Dis. 2024 Sep 9;24(1):941. doi: 10.1186/s12879-024-09837-5.

  PMID: 39252007 DERIVED

• Getanda P, Jagne I, Bognini JD, Camara B, Sanyang B, Darboe S, Sambou E, Barry M, Kassibo K, Cham A, Mendy H, Singateh BKJ, Ndure E, Rouamba T, Bojang A, Bottomley C, Howden BP, D'Alessandro U, Tinto H, Roca A; PregnAnZI-2 Carriage Study Group. Impact of Intrapartum Azithromycin on the Carriage and Antibiotic Resistance of Escherichia coli and Klebsiella pneumoniae in Mothers and Their Newborns: A Substudy of a Randomized, Double-Blind Trial Conducted in The Gambia and Burkina Faso. Clin Infect Dis. 2024 Dec 17;79(6):1338-1345. doi: 10.1093/cid/ciae280.

  PMID: 38752311 DERIVED

• Roca A, Camara B, Bognini JD, Nakakana UN, Some AM, Beloum N, Rouamba T, Sillah F, Danso M, Jones JC, Graves S, Jagne I, Getanda P, Darboe S, Tahita MC, Ndure E, Franck HS, Edmond SY, Dondeh BL, Nassa WGJ, Garba Z, Bojang A, Njie Y, Bottomley C, Tinto H, D'Alessandro U; PregnAnZI-2 Working Group. Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial. JAMA. 2023 Mar 7;329(9):716-724. doi: 10.1001/jama.2022.24388.

  PMID: 36881034 DERIVED

MeSH Terms

Conditions

Neonatal Sepsis

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Study Officials

• Anna Roca, PhD

  MRC Unit The Gambia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The active study drug and placebo will look identical and will not be identifiable. The study drugs will be allocated to the participants according to the randomisation number
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a Phase III, double-blind, placebo controlled randomized clinical trial. Women attending the study health facilities in labour will be randomized to receive either a single dose of oral AZI (2g) or placebo (1:1)

Study Record Dates

• First Submitted: June 23, 2017
• First Posted: June 27, 2017
• Study Start: October 21, 2017
• Primary Completion: May 31, 2021
• Study Completion: May 31, 2021
• Last Updated: March 31, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

BU (1); TH (1)