Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase III double-blind randomized clinical trial

Lead Research Organisation: MRC Unit, The Gambia

Abstract

In a recently completed proof-of-concept trial, we found that 2g of azithromycin given to women in labour decreased the prevalence of neonatal nasopharyngeal bacterial carriage by more than 50%. Although the study was not designed or powered for clinical endpoints, in an adhoc analysis we found a significant decrease of clinical episodes of bacterial infections in both the mother (puerperal period) and the newborn (neonatal period) in the intervention arm. Azithromycin was safe for both the mothers and the newborns.
As a follow-up to the former trial, we are conducting a multi-country phase III, double-blind, placebo-controlled, randomised trial in which 12,500 women in labour will be randomised to receive either a single dose of 2g of oral azithromycin or placebo (ratio 1:1) to assess the effect of the intervention on neonatal mortality and maternal and neonatal sepsis. Recruitment will take place in two countries, The Gambia and Burkina Faso.
Ancillary studies evaluating the impact on the intervention on antibiotic resistance are in progress.

Technical Summary

The primary objective of the study is assess the effect of one oral dose of azithromycin (2g) given to women in labour on neonatal mortality (from birth to day 28). Exclusion criteria include: stillbirths; severe birth asphyxias (Apgar score 1-3); severe congenital malformations and; very low birth weight (<1.5Kg).

In addition the trial will also evaluate the effect of the intervention on other clinical endpoints in both neonates and mothers, and on microbiological endpoints (prevalence of carriage and resistance):

Secondary endpoints:

(i) Neonates (from birth to 28 days of life) – to evaluate the effect of the intervention in the
a. Prevalence of neonates with clinical sepsis
b. Prevalence of neonates with culture-confirmed sepsis
c. Prevalence of neonates hospitalised
d. Prevalence of neonatal mortality among VLBW
e. Prevalence of neonates with skin infection
f. Prevalence of neonates with bacterial conjunctivitis
g. Prevalence of neonates with umbilical infections
h. Prevalence of neonates with malaria
i. Prevalence of neonates taking antibiotics

(ii) Infants (1,000 babies per country followed up to 1 year) – to evaluate the effect of the intervention in the
a. Prevalence of all cause-mortality
b. Prevalence of <-2SD Z-scores for height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), body mass index-for-age, head circumference-for-age, and MUAC for age (at 28 days, 6, 9 and 12 months).

(iii) Mothers (post-partum period – up to 28 days after delivery) – to evaluate the effect of the intervention in the
a. Prevalence of women with post-partum sepsis
b. Prevalence of women with post-partum mastitis
c. Prevalence of women with post-partum malaria
d. Prevalence of women with post-partum fever
e. Prevalence of women taking antibiotics during the post-partum period
f. Prevalence of all cause-hospitalisation during the post-partum period
g. Prevalence of all cause-mortality during the post-partum period )

(iv) Microbiological objectives (for all hospitalised newborns) – to evaluate the effect of the intervention in the
a. Prevalence of S. pneumoniae and Klebsiella spp in the nasopharynx.
b. Prevalence of E.Coli and Pseudomonas spp in the rectal tract.
c. Prevalence of S. aureus, GBS, GAS in the oropharynx.

(v) Microbiological objectives (random selection of 250 participant pairs in each country) – to evaluate the effect of the intervention in the
a. Prevalence of S. pneumoniae and Klebsiella spp from nasopharyngeal swabs (NPS) collected at birth (day 0), day 6, day 28 and 4 months of age.
b. Prevalence of E.Coli and Pseudomonas spp from RS collected at birth (day 0), day 6, day 28 and 4 months of age
c. Prevalence of S. aureus, GBS and GAS from oropharyngeal swabs (OPS) collected at birth (day 0), day 6, day 28 and 4 months of age.
d. Prevalence of S. aureus, GBS, GAS, E. Coli, Pseudomonas spp and Klebsiella spp in the breast milk samples collected at day 6, day 28 and 4 months.

(vi) Qualitative research:
a. Perceptions and acceptability of taking antibiotic during labour among pregnant women and the study communities.

(vii) Health economics
a. Costs of delivering azithromycin during labour in a health facility
b. Cost of a newborn death.
c. Hospitalisation treatment costs.
d. Disability Adjusted Life Years prevented by the intervention.

Planned Impact

Our study will evaluate a novel approach for preventing an important proportion of maternal and neonatal deaths in sub-Saharan Africa (SSA). The proposal has been developed in response to the current Sustainable Development Goal number 3 in which Maternal and Neonatal Health are global health priorities. The beneficiaries of the proposed intervention are women in labour attending health facilities for delivery and their offspring in SSA; they represents approximately two thirds of all deliveries occurring in The Gambia and in other SSA countries. The intervention is easy to implement (one dose of azithromycin given when the woman arrives at the health facility in labour) and low cost.

Azithromycin has been used in several randomized trials and interventions with different purposes, showing the high potential of this drug to decrease morbidity and mortality. However, we believe that azithromycin given to women in labour can have an impact on neonatal outcomes. Such new concept has been explored by the proof-of-concept study we carried out in The Gambia, in which 829 women and their offspring were included. The proof-of-concept study was designed to assess the effect of the intervention on bacterial colonization in both the women and their babies. Besides the strong impact of colonization, the study showed also a decrease on clinical outcomes in mothers and babies in the intervention arm. However, the study was too small to determine the impact of the intervention on neonatal mortality and severe morbidity. Therefore, we are proposing an adequately powered trial that will specifically evaluate the effect of the intervention on clinical outcomes, including severe morbidity and mortality.

Beyond the potential impact on public health, this trial has the opportunity to expand academic knowledge on maternal and neonatal health. We will generate a large amount of data on risk factors for maternal and neonatal morbidity and mortality, and on the aetiology of sepsis that can be prevented using innovative interventions. We will also learn if preventing infections during early life results into a better growth in infancy (another common cause of mortality) in SSA.

Building on the encouraging results of our proof-of-concept trial, the current trial includes social science, health systems research and a cost-effectiveness analysis. If the trial proves that neonatal sepsis and episodes of maternal or neonatal hospitalization and death can be prevented by a single administration of azithromycin to women in labour, we will evaluate the cost per episode prevented, the overall cost-effectiveness of the intervention and the feasibility of implementing this new intervention into the current health system in SSA.

As the proposed study will be conducted in a poor-resource setting, capacity building will be an important component. This study will offer the opportunity for African medical doctors and laboratory-based staff to have hands-on training in research methods of infectious diseases and global health. All study staff will receive continuous training on clinical research, such as Good Clinical Practices, Good Laboratory Practices and Ethics. In addition, we will include specific training sessions for the field staff; laboratory technicians will be working to the highest microbiological and scientific standards (the MRCG microbiology laboratory is the WHO reference for the West African region).

Translation of research findings into practice would be facilitated by the inclusion of representatives of the Burkina and Gambian Ministries of Health. If the trial is successful, their support will be key for the involvement of international policy-makers and public health organizations to accelerate the intervention's scale up.

Publications

10 25 50
 
Description BMGF: Investment Scheme
Amount $1,400,000 (USD)
Funding ID GRANT AGREEMENT Investment ID OPP1196513 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2018 
End 07/2022
 
Description International Symposium on Streptoccocus agalacatiae Disease
Amount £4,000 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2018 
End 02/2018
 
Description Workshop grant
Amount $48,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 03/2019 
End 06/2019
 
Description Bill and Melinda Gates Foundation Intra-partum Azithromycin Workshop 
Organisation Bill and Melinda Gates Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution This workshop will provide an opportunity for researchers working on studies investigating intra-partum azithromycin interventions to improve neonatal and maternal health to harmonize definitions across different on-going and planned studies, as well as share technical knowledge about the potential for azithromycin as an intervention to improve neonatal and maternal health.
Collaborator Contribution The BMGF provided funding for the workshop, as well as managed some logistical details. MRCG at LSHTM provided administrative assistance for organizing workshop location and activities. All participating groups will generate presentations and input for the workshop sessions.
Impact On-going: the workshop is scheduled for June 26 to June 28th 2019
Start Year 2019
 
Description Preventing Young Infant Infections using Azithromycin in Labour (PreYIAL): a blinded, randomised, placebo-controlled trial in Fiji 
Organisation National Health and Medical Research Council
Country Australia 
Sector Public 
PI Contribution Collaborating author: harmonizing endpoints and definitions for improved analysis opportunities in the future and increased possibility of policy implementation.
Collaborator Contribution Harmonized endpoints and definitions for broad analysis after the trials and improved possibilities of policy implementation.
Impact Both trials are on-going, and outcomes are yet to be determined.
Start Year 2017
 
Description Illustrating Antenatal Care project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact we met with health facility staff members at the health Centre we work in The Gambia. Posters were designed and adopted. After the final poster designs were chosen, they were printed and displayed throughout the health center. The posters would benefit preganant women attending the antenal clinic with visual material (posters)that illustrate key concepts they will be covering during their antenatal care talks. Effective illustrations and imagery is particularly important for use in health talks in this population, where literacy is low. Government Ministry of Health were very impressed with the public engagement, they wanted the posters we created to be displayed in other government health facilities.
Year(s) Of Engagement Activity 2019
 
Description WellCome Trust Meeting: Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation describing the results from PregnAnZI 1 and the on-going work with PregnAnZI-2.
Year(s) Of Engagement Activity 2019
 
Description Women In Science - Medical Research Council the Gambia Unit at LSHTM 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Five schools were invited to join an Open Day held at MRCG where female scientists and professionals discussed their work and career paths with groups of high school students. Additionally, a round table event was held for all MRCG staff members to discuss the obstacles for women in science.
Year(s) Of Engagement Activity 2018