Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis & Death (PregnAnZI-2)
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|ClinicalTrials.gov Identifier: NCT03199547|
Recruitment Status : Recruiting
First Posted : June 27, 2017
Last Update Posted : November 7, 2018
|First Submitted Date ICMJE||June 23, 2017|
|First Posted Date ICMJE||June 27, 2017|
|Last Update Posted Date||November 7, 2018|
|Actual Study Start Date ICMJE||October 21, 2017|
|Estimated Primary Completion Date||October 2020 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||neonatal mortality [ Time Frame: from Birth to Day 28 ]
All deaths excluding Severe Birth Asphyxia (SBA), severe congenital malformation (SCM) and very low birth weight (VLBW)
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT03199547 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis & Death|
|Official Title ICMJE||Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis and Death: a Phase III Double-blind Randomized Clinical Trial|
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 (12,500 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.
other data elements, such as eligibility criteria or outcome measures. (Limit: 32,000 characters) Project title: Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase III double-blind randomized clinical trial Acronym: PregnAnZI-2
LIST OF INVESTIGATORS
Dr Anna Roca, PhD MRC Unit The Gambia PO Box 273 Banjul The Gambia, West Africa firstname.lastname@example.org
Prof Umberto D'Alessandro Director - MRC Unit The Gambia PO Box 273 Banjul The Gambia, West Africa email@example.com
Dr Christian Bottomley PhD Trial Statistician London School of Hygiene and Tropical Medicine London Christian.firstname.lastname@example.org
Dr Halidou Tinto PhD Site PI Burkina Faso Clinical Research Unit of Nanoro Burkina Faso email@example.com
Clinical Trial Coordinators:
Dr Bully Camara MD MRC Unit The Gambia PO Box 273 Banjul The Gambia, West Africa +2204495917
Dr Marc Tahita Clinical Research Unit of Nanoro Burkina Faso BACKGROUND AND RATIONALE Neonatal and maternal sepsis are major contributors to the high burden of mortality in sub-Saharan Africa (SSA). Bacterial infections are leading causes of neonatal deaths, representing 1 out of 3 deaths in this age group (1).
Neonatal sepsis is the consequence of bacterial infection during early life. Newborns may be infected during labour (through the birth canal) or during the first days/weeks of life, when they may become infected because of the close physical contact with the mother, if the latter carries bacteria (i.e. in the nasopharyngeal tract), a common occurrence in resource-limited settings, particularly in SSA. Streptococcus pneumoniae and group A Streptococcus are important in the late neonatal period (from the second week of life), while group B Streptococcus (GBS), Staphylococcus aureus and Escherichia coli occur often in both the early and late neonatal periods (2).
AZI is a semi-synthetic azalide macrolide that is structurally related to erythromycin but has a broader spectrum of antibacterial activity, improved tissue penetration and a more favourable pharmacokinetic profile (3). Azithromycin is a cheap, wide spectrum, oral antibiotic that is safe to use in mothers and newborns, does not require special storage conditions, and can be delivered at the most peripheral level of care.
Between 2013 and 2015, we conducted as first proof-of-concept, a double-blind randomized trial on the effect of 2g of AZI administered to Gambian women in labour on maternal and neonatal bacterial carriage (4). The primary endpoint was bacterial carriage at day 6 in the newborn (i.e. S.aureus, GBS or S.pneumoniae). The rationale for the study was that this intervention would decrease bacterial carriage of the study bacteria both, in the mother and the newborn and consequently the risk of invasive bacterial disease or sepsis. We found that the intervention substantially reduced the prevalence of carriage of each of these three bacteria, both in the newborn and the mother, during the entire neonatal/puerperal period (4).
Figure 1. Prevalence of nasopharyngeal bacterial carriage during the neonatal period.
Our study also showed that women in the AZI group had a lower prevalence of the study bacteria in the breast milk during the entire neonatal period (day 6: 9.6% vs 21.9%, RR=0.44, p<0.001) and in the vaginal tract (8-10 days: 13.2% vs 24.2% RR=0.55 - p<0.001).
Although the study was not designed to evaluate clinical endpoints, prevalence of these endpoints decreased significantly in the AZI group (5). The use of antibiotics, and the occurrence of fever, mastitis and puerperal infections were significantly lower in the AZI group (Table 1). Newborns in the intervention group had fewer infections (skin infections, umbilical infections, ear infections, conjunctivitis or mild sepsis) during the neonatal period (Table 2). There were also fewer neonatal deaths due to severe infections in the AZI group (0.4% versus 1.4% excluding neonates with severe congenital malformations).
Table 1. Clinical endpoints and antibiotic use of study women during the puerperal period.
MATERNAL Azithromycin (N=414) Placebo (N=415) RR(95%CI) p-value Maternal infections n(%) n(%) Mastitis 6(1.4) 21(5.1) 0.29(0.12,0.70) 0.005 Puerperal sepsis 4(1.0) 5(1.2) 0.80(0.22,2.97) 1 Related infections 3(0.7) 9(2.2) 0.33(0.09,1.23) 0.143 Others 2(0.5) 5(1.2) 0.40(0.08,2.06) 0.451 Any of above 17(4.1) 38(9.2) 0.45(0.26,0.78) 0.005 Fever 8(1.9) 24(5.8) 0.33(0.15,0.74) 0.006 Use of antibiotic (for clinical care) 25(6.0) 42 (10.1) 0.58(0.36,0.94) 0.031 Table 2. Clinical endpoints and antibiotic use of study children during the neonatal period.
NEONATES Azithromycin (N=419) Placebo (N=424) RR(95%C) p-value Neonatal infections n(%) n(%) Skin infection 13(3.1) 27(6.4) 0.49(0.25,0.93) 0.034 Umbilical infection 1(0.2) 4(0.9) 0.25(0.03,2.25) 0.374 Conjunctivitis 37(8.8) 45(10.6) 0.83(0.55,1.26) 0.417 Otitis 3(0.7) 5(1.2) 0.61(0.15,2.52) 0.725 Oral infection 12(2.9) 13(3.1) 0.93(0.43,2.02) 1 Sepsis 18(4.3) 15(3.5) 1.21(0.62,2.38) 0.598 Meningitis 0(0.0) 1(0.2) NA 1 Pneumonia 3(0.7) 4(0.9) 0.76(0.17,3.37) 1 Any of above 76(18.1) 101(23.8) 0.76(0.58,0.99) 0.052 Fever 54(12.9) 43(10.1) 1.27(0.87,1.85) 0.235 Use of any antibiotic (for clinical care) 43(10.1) 42(10.0) 0.99(0.66,1.5) 1 The time point when the endpoints occurred during the follow-up period are summarized in Figure 2 below.
Figure 2. Proportion of mothers and newborns infected at different points during the follow up.
p-values from the log-rank test (mothers p=0.001, newborns p=0.04) AZI was safe for both the mothers and the newborns. Hypertrophic pyloric stenosis (HPS) was not observed in any of the study children during the 2-month follow up period (4).
Azithromycin is a cheap, wide spectrum, oral antibiotic that is safe to use in mothers and newborns, does not require special storage conditions, and can be delivered at the most peripheral level of care.
In the trial presented here, we want to assess the impact of using AZI during labour on neonatal mortality as well as maternal and neonatal sepsis and infant growth. If successful, this simple intervention could be easily implemented through the health system at the most peripheral level of care. It has the potential to achieve wide coverage in SSA where low-cost interventions aiming at reducing neonatal mortality are urgently needed. In addition, the intervention should concomitantly protect women and newborns. Azithromycin resistance will also be monitored as the former trial showed high rates of AZI resistance for S. aureus. However, AZI is not widely used in SSA for clinical treatment and therefore any short-term resistance arising from the intervention would have little impact on clinical care.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
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)Masking: Triple (Participant, Investigator, Outcomes Assessor)
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 numberPrimary Purpose: Prevention
|Condition ICMJE||Neonatal SEPSIS|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||June 2021|
|Estimated Primary Completion Date||October 2020 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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
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
|Ages ICMJE||16 Years and older (Child, Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Listed Location Countries ICMJE||Burkina Faso, Gambia|
|Removed Location Countries|
|NCT Number ICMJE||NCT03199547|
|Other Study ID Numbers ICMJE||SCC 1532|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||London School of Hygiene and Tropical Medicine|
|Study Sponsor ICMJE||London School of Hygiene and Tropical Medicine|
|Collaborators ICMJE||Not Provided|
|PRS Account||London School of Hygiene and Tropical Medicine|
|Verification Date||November 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP