Azithromycin-Prevention in Labor Use Study (A-PLUS)

Neonatal SEPSIS Clinical Trial

Official title:

Prevention of Maternal and Neonatal Death/Infections With a Single Oral Dose of Azithromycin in Women in Labor (in Low- and Middle-income Countries): a Randomized Controlled Trial

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03871491
• Other study ID #: CP Azithromycin
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 1, 2020
• Est. completion date: September 30, 2024

Study information

• Verified date: May 2023
• Source: NICHD Global Network for Women's and Children's Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Maternal and neonatal infections are among the most frequent causes of maternal and neonatal deaths, and current antibiotic strategies have not been effective in preventing many of these deaths. Recently, a randomized clinical trial conducted in a single site in The Gambia showed that treatment with oral dose of 2 g azithromycin vs. placebo for all women in labor reduced selected maternal and neonatal infections. However, it is unknown if this therapy reduces maternal and neonatal sepsis and mortality. The A-PLUS trial includes two primary hypotheses, a maternal hypothesis and a neonatal hypothesis. First, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce maternal death or sepsis. Second, a single, prophylactic intrapartum oral dose of 2 g azithromycin given to women in labor will reduce intrapartum/neonatal death or sepsis.

Description:

The A-PLUS Trial is a randomized, placebo-controlled, parallel multicenter clinical trial. The study intervention is a single, prophylactic intrapartum oral dose of 2 g azithromycin, with a comparison with a single intrapartum oral dose of an identical appearing placebo. For the A-PLUS randomized control trial (RCT), a total of 34,000 laboring women from eight research sites in sub-Saharan Africa, South Asia, and Latin America will be randomized with one-to-one ratio to intervention/placebo. In response to the global coronavirus pandemic, research sites will also collect data on COVID-19 signs/symptoms, diagnosis, and treatment in order to estimate the incidence of infection and evaluate the impact of the pandemic on the target population.

Prior to the initiation of the A-PLUS RCT, research sites will conduct an observational pilot study using the RCT's planned infrastructure in order to characterize the current practices at participating research facilities and optimize the identification of suspected infection for the RCT. The information obtained in the pilot study will be used to validate estimates of intrapartum deaths, maternal sepsis, and neonatal sepsis used in the sample size calculations for the RCT. Finally, the pilot study will allow the research sites to inventory and upgrade local capacity to conduct routine cultures during the RCT.

A maximum of 16,000 women, separate from the sample for the main trial, will be enrolled in the pilot, across all eight research sites, with no more than 2000 women enrolled at any individual site. Research sites will be eligible to transition to the RCT when a minimum of 600 participants have been enrolled in the pilot study with evidence of (a) high rates of follow-up; (2) acceptable data quality and completeness; and (3) there are no concerns about identification and reporting of infection.

Given the clinical benefits of intrapartum azithromycin so far reported in two trials and the likelihood that it may become the usual practice if the investigator's large RCT confirms the reported benefits, it is important to monitor antibiotic resistance to determine the safety of azithromycin prophylaxis. Therefore, the RCT will also include an ancillary study (referred to as the antimicrobial resistance (AMR) sub-study) to monitor antimicrobial resistance and maternal and newborn microbiome effects of the single dose of prophylactic azithromycin using the following methodology

1. For all mothers enrolled in the RCT and their infants:

a. Routine clinical monitoring at baseline and three post-partum time points (3 days, 7 days, and 42 days), with culture and sensitivity testing in cases of suspected bacterial infections;

2. Among a subset of 1000 randomly selected maternal-infant dyads:

1. Serial susceptibility monitoring of antimicrobial resistance patterns (including azithromycin resistance) from selected maternal and newborn flora through culture and sensitivity testing. Serial monitoring will be conducted at baseline and three post-partum time points (1 week, 6 weeks, and 3 months).

2. Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 34000
• Est. completion date: September 30, 2024
• Est. primary completion date: October 7, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Pregnant women in labor =28 weeks Gestational Age (GA) (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.

• Admitted to health facility with clear plan for spontaneous or induced delivery.

• Live fetus must be confirmed via a fetal heart rate by Doptone prior to randomization.

• =18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.

• Have provided written informed consent.

• Pregnant women in labor =28 weeks GA (by best estimate) with a pregnancy with one or more live fetuses who plan to deliver vaginally in a facility.

• Admitted to health facility with clear plan for spontaneous or induced delivery.

• Live fetus must be confirmed via presence of a fetal heart rate prior to randomization.

• =18 years of age or minors 14-17 years of age in countries where married or pregnant minors (or their authorized representatives) are legally permitted to give consent.

• Have provided written informed consent [Note: written informed consent may be obtained during antenatal care, but verbal re-confirmation may be needed (per local regulations) at the time of randomization].

Exclusion Criteria:

• Non-emancipated minors (as per local regulations)

• Evidence of chorioamnionitis or other infection requiring antibiotic therapy at time of eligibility (however, women given single prophylactic antibiotics with no plans to continue after delivery should not be excluded).

• Arrhythmia or known history of cardiomyopathy.

• Allergy to azithromycin or other macrolides that is self-reported or documented in the medical record.

• Any use of azithromycin, erythromycin, or other macrolide in the 3 days or less prior to randomization.

• Plan for cesarean delivery prior to randomization.

• Preterm labor undergoing management with no immediate plan to proceed to delivery.

• Advanced stage of labor (>6 cm or 10 cm cervical dilation per local standards) and pushing or too distressed to understand, confirm, or give informed consent regardless of cervical dilation.

• Are not capable of giving consent due to other health problems such as obstetric emergencies (for example, antepartum hemorrhage) or mental disorder.

• Any other medical conditions that may be considered a contraindication per the judgment of the site investigator.

• Previous randomization in the trial.

Related Conditions & MeSH terms

• Death
• Infections
• Maternal Death
• Maternal Infections Affecting Fetus or Newborn
• Maternal Sepsis During Labor
• Neonatal Death
• Neonatal SEPSIS
• Perinatal Death
• Postpartum Sepsis
• Pregnancy Complications, Infectious
• Puerperal Infection
• Sepsis
• Toxemia

Intervention

Drug:
• Azithromycin
The study intervention is a single 2 g dose of directly observed oral azithromycin, to be administered as four 500 mg pills or tablets directly after randomization. By random allocation, participants will receive 2 g of oral azithromycin.
• Placebo
Identical appearing placebo, administered as a single oral dose directly after randomization.

Locations

Country	Name	City	State
Bangladesh	ICDDRB	Dhaka
Congo, The Democratic Republic of the	Kinshasa School of Public Health	Kinshasa
Guatemala	Institute for Nutrition of Central America and Panama (INCAP)	Guatemala City
India	Jawaharlal Nehru Medical College	Belagam
India	Lata Medical Research Foundation	Nagpur
Kenya	Moi University School of Medicine	Eldoret
Pakistan	The Aga Khan University	Karachi
Zambia	University Teaching Hospital	Lusaka

Sponsors (19)

Lead Sponsor

Collaborator

NICHD Global Network for Women's and Children's Health

Aga Khan University, Bill and Melinda Gates Foundation, Boston University, Columbia University, Indiana University School of Medicine, Institute of Nutrition of Central America and Panama, International Centre for Diarrhoeal Disease Research, Bangladesh, Jawaharlal Nehru Medical College, Kinshasa School of Public Health, Lata Medical Research Foundation, Nagpur, Moi Univeristy, RTI International, Thomas Jefferson University, University of Alabama at Birmingham, University of Colorado, Denver, University of North Carolina, Chapel Hill, University of Virginia, University Teaching Hospital, Lusaka, Zambia

Countries where clinical trial is conducted

Bangladesh,  Congo, The Democratic Republic of the,  Guatemala,  India,  Kenya,  Pakistan,  Zambia, 

References & Publications (41)

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* Note: There are 41 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maternal: Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.	Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.	within 6 weeks (42 days)
Primary	Neonatal: Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group	Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group	4 weeks (28 days) post-delivery
Secondary	Incidence of chorioamnionitis	Fever (>100.4°F/38°C) in addition to one or more of the following: fetal tachycardia =160 bpm, maternal tachycardia >100 bpm, tender uterus between contractions, or purulent/foul smelling discharge from uterus prior to delivery.	prior to delivery
Secondary	Incidence of endometritis	Fever (>100.4°F/38°C) in addition to one or more of maternal tachycardia >100 bpm, tender uterine fundus, or purulent/foul smelling discharge from uterus after delivery.	within 42 days post-delivery
Secondary	Incidence of other infections	Wound infection (Purulent infection of a perineal or Cesarean wound with or without fever. In the absence of purulence, requires presence of fever >100.4°F/38°C and at least one of the following signs of local infection: pain or tenderness, swelling, heat, or redness around the incision/laceration); Abdominopelvic abscess (Evidence of pus in the abdomen or pelvis noted during open surgery, interventional aspiration or imaging); Pneumonia (Fever >100.4°F/38°C and clinical symptoms suggestive of lung infection including cough and/or tachypnea >24 breaths/min or radiological confirmation); Pyelonephritis (Fever >100.4°F/38°C and one or more of the following: urinalysis/dip suggestive of infection, costovertebral angle tenderness, or confirmatory urine culture); Mastitis/breast abscess or infection (Fever >100.4°F/38°C and one or more of the following: breast pain, swelling, warmth, redness, or purulent drainage).	within 42 days post-delivery
Secondary	Incidence of use of subsequent maternal antibiotic therapy	Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason.	after randomization to 42 days post-delivery
Secondary	Maternal initial hospital length of stay	Time from drug administration until initial discharge after delivery (time may vary by site).	within 42 days post-delivery
Secondary	Incidence of maternal readmissions	Maternal readmissions within 42 days of delivery	within 42 days post-delivery
Secondary	Incidence of maternal admission to special care units	Maternal admission to special care units	within 42 days post-delivery
Secondary	Incidence of maternal unscheduled visit for care	Maternal unscheduled visit for care	within 42 days post-delivery
Secondary	Incidence of maternal GI symptoms	Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.	within 42 days post-delivery
Secondary	Incidence of maternal death due to sepsis	Maternal death due to sepsis using the Global Network algorithm for cause of death	within 42 days post-delivery
Secondary	Incidence of other neonatal infections (e.g. eye infection, skin infection)	Incidence of other neonatal infections.	within 42 days post-delivery
Secondary	Neonatal initial hospital length of stay	Neonatal initial hospital length of stay, defined as time of delivery until initial discharge (time may vary by site).	within 28 days of delivery
Secondary	Incidence of neonatal readmissions	Neonatal readmissions within 42 days of delivery	within 42 days of delivery
Secondary	Incidence of neonatal admission to special care units	Neonatal admission to special care units	within 28 days of delivery
Secondary	Incidence of neonatal unscheduled visit for care	Neonatal unscheduled visit for care	within 42 days post-delivery
Secondary	Incidence of neonatal death due to sepsis	Neonatal death due to sepsis using the Global Network algorithm for causes of death	within 28 days of delivery
Secondary	Incidence of pyloric stenosis within 42 days of delivery	Pyloric stenosis within 42 days of delivery, defined as clinical suspicion based on severe vomiting leading to death, surgical intervention (pyloromyotomy) as verified from medical records, or radiological confirmation.	within 42 days of delivery