Preventing Young Infant Infections Using Azithromycin in Labour (PreYIAL) Trial

Study Overview
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Brief Summary
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A trial to assess cumulative incidence of skin and soft tissue infections (SSTI) in infants (by three months of age) born to mothers receiving a single-dose of 2 grams of oral azithromycin during labour (or immediately prior to delivery in the case of caesarean section), compared to infants whose mothers received placebo.

Detailed Description
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PreYIAL is a Phase III, double-blind, randomised, placebo controlled two arm trial of a single 2g dose of azithromycin or placebo, administered to women who have been admitted for delivery of their baby (either following onset of labour or for caesarean section). The trial includes an estimated 2110 mothers/infant pairs (1055 per arm), with 12 months of follow-up for the mother/infant pair. A swab-study within the main study involves 940 of the mother/infant pairs enrolled and involves follow-up for bacterial carriage outcomes, for 12 months.These swab-study participants will also be included in assessments of the infant and maternal microbiome.

Official Title
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Preventing Young Infant Infections Using Azithromycin in Labour (PreYIAL): a Blinded, Randomised, Placebo-controlled Trial

Conditions
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Bacterial Infections

Intervention / Treatment
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* Drug: Azithromycin 500 mg Oral Tablet x 4
* Drug: Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pregnant women at least 18 years old intending to deliver at Colonial War Memorial Hospital (CWMH) Women who have been admitted to CWMH for delivery at the time of eligibility assessment Women who expect to be available, with their infant, for the duration of the study, and who agree to adhere to all protocol requirements Women who will have a main place of residence within the Greater Suva area for the follow-up period and within a practical distance of the study site to allow compliance with protocol-required visits and follow-up, including attending follow-up at specified clinics Women who have provided written informed consent prior to study-related procedures being performed Exclusion criteria: Women who have a known macrolide allergy Women who have taken antibiotics in the week prior to randomisation A women who is unable or unwilling to provide informed consent for her participation in the trial or the participation of her infant Women who decide prior to randomisation that they are no longer willing to participate or to have their infant participate Women who have ever received, or who are anticipated to receive during the study period, any investigational agent other than the study drug Women who are CWMH, Murdoch Children's Research Institute (MCRI) or study site employees who work directly with study staff, or who are working on the study Women taking warfarin due to the potential for drug interactions with azithromycin Women with any cardiac abnormality Women taking other medications known to prolong the QT interval such as antiarrhythmics; antipsychotic agents; antidepressants; and fluoroquinolones; Women with known electrolyte disturbances: including in cases of hypokalaemia and hypomagnesaemia Women who will undergo general anaesthetic for delivery Women carrying a foetus with intrauterine death confirmed before randomisation Women carrying a foetus with a prognosis unlikely to survive Women with known HIV infection and/or taking nelfinavir Women who have participated in the study during a previous pregnancy Women who have been admitted for management of premature labour who have unruptured membranes (This is a temporary exclusion such that the participant may be assessed for eligibility again in the same or a subsequent admission to CWMH). Women with renal impairment Women with hepatic impairment Women with myasthenia gravis Women who are taking any ergot medications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Blinded, randomized, placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azithromycin<br>A single 2g dose of Azithromycin | Drug: Azithromycin 500 mg Oral Tablet x 4<br>* A single prophylactic dose of antibiotic given during labour<br>|
| Placebo Comparator: Placebo<br>Matching Placebo | Drug: Matching Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of skin and soft tissue infection by 3 months of age in infants | Born to mothers receiving a single dose of 2g Azithromycin during labour. Assessed by history and physical examination at 7 days, 6 weeks and 3 months. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of skin and soft tissue infection, and other infections by 12 months of age in infants | To compare intervention and placebo groups with regard to the cumulative incidence of infant infection (meningitis, sepsis, pneumonia, SSTI, fever, diarrhoea, urinary tract infection) up to 12 months of age; | Birth to 12 Months | 
| Cumulative incidence of maternal infection by 6 weeks and 12 months post-delivery | To compare intervention and placebo groups with regard to the cumulative incidence of maternal infection (mastitis, sepsis, post-operative wound infections, SSTI, fever, meningitis, pneumonia, abdominal or pelvic abscess, endometritis, urinary tract infection, pyelonephritis) by six weeks post-delivery, and similarly up to 12 months post-delivery | Delivery to 12 months | 
| Cumulative incidence of antibiotic usage by 12 months in infants | To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the infant up to 12 months of age; | Birth to 12 months | 
| Cumulative incidence of maternal antibiotic usage by 12 months post-delivery | To compare intervention and placebo groups with regard to the cumulative incidence of the number of courses of antibiotics prescribed to the mother up to 12 months post-delivery | Delivery to 12 months | 
| Number of infant participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 | To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study. | Birth to 12 months | 
| Number of maternal participants with adverse events as assessed by adapted version of CTCAE v5.0 and DAID v2.1 | To compare the number of adverse events including solicited non serious adverse events and all serious adverse events as per study specific definitions throughout the duration of the study. | Delivery to 12 months | 
| Number of infant and maternal participants with Staphylococcus aureus and/or Group A streptococcus as assessed by real-time quantitative PCR (qPCR) from impetigo swabs | The proportion of participants that have Staphylococcus aureus and/or Group A streptoccoccus detected by qPCR from impetigo swabs at key time points throughout the duration of the study, between the two groups | Delivery/birth to 12 months | 
| Number of infant and maternal participants with Staphylococcus aureus and/or Group A streptococcus with azithromycin nonsusceptibility cultured from impetigo swabs. | The proportion of participants that have Staphylococcus aureus and/or Group A streptococcus that is non susceptible to azithromycin cultured from impetigo swabs at key time points throughout the duration of the study, between the two groups | Delivery/birth to 12 months | 
| Swab study outcome - Prevalence of bacterial carriage as assessed by real-time quantitative PCR (qPCR) | Bacterial carriage, the proportion of participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups | Delivery/birth to 12 months | 
| Swab study outcome - Density of bacterial carriage as assessed by real-time quantitative PCR (qPCR) | Density of bacterial carriage, reported as log 10 genome equivalents/ml, of the participants that have at least one of the following bacterial species including GBS, SA, SPN, GAS or E. coli, assessed by qPCR at key time points throughout the duration of the study, between the two groups | Delivery/birth to 12 months | 
| Swab study outcome - Risk of maternal carriage identified through qPCR of common organisms relevant to Sexually Transmitted Infections (STI) | Maternal carriage of common organisms relevant to Sexually Transmitted Infections (STI) (including Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, HSV-1 and HSV-2) as detected by qPCR at key time points throughout the duration of the study, between the two groups. | Delivery/birth to 6 months | 
| Swab study outcome - Risk of antibiotic nonsusceptibility in culture isolates | Antibiotic non susceptibility, based on the proportion of samples from mothers and infants that are non susceptible to antibiotics cultured in the two arms, at key time points throughout the duration of the study | Delivery/birth to 12 months | 
| Swab study outcome - The prevalence of infants with diagnoses that have been associated with microbiome dysbiosis | To compare the infant and maternal microbiome of specified body sites at key time points in the intervention and placebo groups | Delivery/birth to 6 months |