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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
Sponsor:
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

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 (12,500 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.


Condition or disease Intervention/treatment Phase
Neonatal SEPSIS Drug: Azithromycin Drug: Placebo Oral Tablet Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12500 participants
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)
Masking Description: 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
Primary Purpose: Prevention
Official Title: Pre-delivery Administration of Azithromycin to Prevent Neonatal Sepsis and Death: a Phase III Double-blind Randomized Clinical Trial
Actual Study Start Date : October 21, 2017
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Experimental: AZITHROMYCIN
A single dose of 2G Azithromycin or Placebo will be administered orally to women in labour
Drug: Azithromycin
The women will be randomized to receive a single dose of Azithromycin or Placebo

Placebo Comparator: Placebo oral tablet
A single dose of 2G Azithromycin or Placebo will be administered orally to women in labour
Drug: Placebo Oral Tablet
The women will be randomized to receive a single dose of Azithromycin or Placebo




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. Neonatal sepsis-Early-onset of Culture confirmed sepsis [ Time Frame: Day 1- Day 3 ]
    isolation of a miro-organism that is not a common contaminant from a normally sterile body site (i.e. blood or CSF)

  2. Early-onset clinical sepsis [ Time Frame: Day 1- Day 3 ]
    neonate hospitalised within 3 days of life and who in the absence of another recognisable congenital infection had at least one laboratory criteria and either: respiratory distress (one criterion required) or at least two clinical criteria

  3. Late-onset culture confirmed sepsis [ Time Frame: Day 3 - Day 28 ]
    isolation of a micro-organism that is not a common contaminant from a normally sterile body (i.e. blood or CSF) site if a microorganism has been observed in the gram stain (i.e. CSF)

  4. Late-onset clinical sepsis [ Time Frame: Day 3- Day 28 ]
    neonate hospitalised with at least one laboratory criteria and either: respiratory distress (twocriteria required), OR one feature of respiratory distress and one other clinical criterion OR at least two other clinical criteria

  5. All-caused hospitalisation during the follow up period [ Time Frame: 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 ]
    Hospitalisation will be defined as admission to an inpatient ward or at least a 12 hour stay. We will exclude from this endpoint all hospitalizations due to injuries

  6. Infant mortality [ Time Frame: Birth to 12 Months ]
    All-cause mortality excluding injuries (only for those included in the anthropometrical sub-study).

  7. Malnutrition and Severe malnutrition [ Time Frame: At 6, 9 and 12 months of age ]
    through anthropometrical measurements and using WHO child-growth standards to calculate Z-scores for height-for-age (HAZ), weight-for-age (WAZ), weight-for-height (WHZ), head circumference-for-age, and MUAC for age [WHO Anthro version 3.2.2, January 2011]. Children with z-scores <-2SD and <-3SD will be classified as malnourished and severely-malnourished, respectively

  8. Post-partum sepsis- Women [ Time Frame: Day 1 to Day 28 ]

    this will be defined as admission of the mother for endometritis (defined below) or culture-confirmed infection of sterile site (i.e. blood of CSF; or bacteria detected in the gram stain) or wound infection (see definition below) [23].

    • Endeometritis: at least two of the following signs of uterine tenderness, fever (>38.0 oC), foul-smelling or purulent lochia, or vaginal discharge diagnosed by clinicians and/or nurses.
    • Wound infection is defined as perineal wound infection among vaginal parturients or cesarian wound infection among ceasarean section parturients

  9. All-cause maternal hospitalisation [ Time Frame: Day 1 to day 28 ]
    Hospitalisation will be defined as admission to an inpatient department or a visit to an emergency department that results in at least a 12-hour stay excluding hospitalizations due to injuries



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pregnant women attending study health facilities for delivery will be enrolled
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03199547


Contacts
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Contact: Anna Roca, PhD +220-4405442-6 ext 2305 aroca@mrc.gm

Locations
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Burkina Faso
Clinical Research Unit of Nanora Recruiting
Nanora, Burkina Faso
Contact: Halidou Tinto, PhD         
Contact       tintohalidou@yaoo.fr   
Gambia
Medical Research Council Unit The Gambia Recruiting
Banjul, Gambia
Contact: Bully Camara, MD    +220-4495442-6 ext 3027    bucamara@mrc.gm   
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
Investigators
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Principal Investigator: Anna Roca, PhD MRC Unit The Gambia

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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT03199547     History of Changes
Other Study ID Numbers: SCC 1532
First Posted: June 27, 2017    Key Record Dates
Last Update Posted: November 7, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sepsis
Toxemia
Neonatal Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Infant, Newborn, Diseases