Maternal DeathPhase 3NCT03871491
Azithromycin-Prevention in Labor Use Study (A-PLUS)
A Phase 3 study testing Azithromycin in people with Maternal Death and Maternal Infections Affecting Fetus or Newborn, run by NICHD Global Network for Women's and Children's Health at 8 sites in 7 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Maternal Death, Maternal Infections Affecting Fetus or Newborn, Neonatal SEPSIS
- What is being tested?
- Azithromycin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 58,747 participants
- Where
- 8 sitesin 7 countries
- Study dates
- 1 Sep 2020to 30 Sep 2022
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
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- 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].
Who cannot join
- 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.
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- 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.
Trial locations and contacts
8 sites in 7 countries.
8 sites in 7 countries
India2 sites
Jawaharlal Nehru Medical College
Belagām, 590 010
Lata Medical Research Foundation
Nagpur
Democratic Republic of the Congo1 site
Kinshasa School of Public Health
Kinshasa
Guatemala1 site
Institute for Nutrition of Central America and Panama (INCAP)
Guatemala City, 01011
About this study
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
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.
Read the detailed 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
- For all mothers enrolled in the RCT and their infants:
- 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;
- Among a subset of 1000 randomly selected maternal-infant dyads:
- 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).
- Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.
- Conditions
- Maternal Death, Maternal Infections Affecting Fetus or Newborn, Neonatal SEPSIS, Maternal Sepsis During Labor, Neonatal Death, Postpartum Sepsis
- Being tested
- Azithromycin, Placebo
- Keywords
- maternal sepsis, maternal death, neonatal sepsis, neonatal death, azithromycin, Democratic Republic of Congo, Zambia, Guatemala, Bangladesh, India, Pakistan, Kenya, COVID-19
- Medical subject headings
- Maternal Death, Neonatal Sepsis, Perinatal Death, Puerperal Infection, Pregnancy Complications, Infectious, COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzithromycinDrug
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.
PlaceboDrug
Identical appearing placebo, administered as a single oral dose directly after randomization.
| Study group | Role | What they receive |
|---|---|---|
| Intervention | Experimental | The study intervention is a single 2 g dose of directly observed oral azithromycin. Receives: Drug: Azithromycin |
| Placebo | Placebo comparator | By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.
Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
Measured: Within 6 weeks (42 days)
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group
Intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among stillbirths and neonates with 28-day status available born to women randomized. The study includes multiple births so there are more stillbirths and neonates than participants enrolled.
Measured: Within 4 weeks (28 days) post-delivery
Secondary outcomes (21)
Maternal Sepsis
Maternal sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
Measured: Within 42 days post-delivery
Maternal Death Due to Sepsis
Maternal death due to sepsis using the Global Network algorithm for cause of death
Measured: Within 42 days post-delivery
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.
Measured: Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)
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.
Measured: Within 42 days post-delivery
Cesarean Wound Infection
Wound infection (Purulent infection of a 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);
Measured: Within 42 days post-delivery
Perineal Wound Infection
Wound infection (Purulent infection of a perineal 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);
Measured: Within 42 days post-delivery
Other Infections
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). Other bacterial infection.
Measured: Within 42 days post-delivery
Use of Subsequent Maternal Antibiotic Therapy
Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason.
Measured: After randomization to 42 days post-delivery. Randomization occurs between labor onset and delivery (0 to 120 hours before delivery). 42 participants were randomized >120 hours before delivery due to false labor.
Maternal Initial Hospital Length of Stay
Time from drug administration until initial discharge after delivery (time may vary by site).
Measured: Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days)
Maternal Readmissions
Maternal readmissions after delivery discharge and within 42 days of delivery
Measured: After delivery discharge and within 42 days post-delivery
Maternal Admission to Special Care Units
Maternal admission to special care units
Measured: Within 42 days post-delivery (reported during study)
Maternal Unscheduled Visit for Care
Maternal unscheduled visit for care
Measured: Within 42 days post-delivery (reported during study)
Maternal GI Symptoms
Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.
Measured: Within 42 days post-delivery (reported during study)
Neonatal Sepsis
Neonatal sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 28 days post-delivery
Neonatal Death Due to Sepsis
Neonatal death due to sepsis using the Global Network algorithm for causes of death. This outcome is measured among neonates with 28-day status available born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 28 days post-delivery
Other Neonatal Infections
Other neonatal infections (e.g. eye infection, skin infection). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 28 days post-delivery
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). This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Time from delivery to discharge from delivery hospital (0 to 62 days)
Neonatal Readmissions
Neonatal readmissions to facility after delivery discharge and within 42 days of delivery. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: After delivery discharge and within 42 days of delivery
Neonatal Admission to Special Care Units
Neonatal admission to special care units. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 42 days post-delivery (reported during study)
Neonatal Unscheduled Visit for Care
Neonatal unscheduled visit for care. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 42 days post-delivery (reported during study)
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. This outcome is measured among neonates born to women randomized. The study includes multiple births so there are more neonates than maternal participants enrolled.
Measured: Within 42 days post-delivery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2019
- Study start1 Sep 2020
- Primary completion30 Sep 2022
- Study completion30 Sep 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (47)Papers the sponsor has linked to this study.
- Other trials for Maternal DeathStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 58,747 participants (actual)
Sponsor and investigators
- Lead sponsor
- NICHD Global Network for Women's and Children's Health
- Sponsor type
- Research network
- Collaborators
- University of Alabama at Birmingham, University Teaching Hospital, Lusaka, Zambia, University of North Carolina, Chapel Hill, Kinshasa School of Public Health, University of Colorado, Denver, Institute of Nutrition of Central America and Panama, University of Virginia, International Centre for Diarrhoeal Disease Research, Bangladesh, Thomas Jefferson University, Columbia University, Aga Khan University, Boston University, Lata Medical Research Foundation, Nagpur, Indiana University, Moi Univeristy, RTI International, Bill and Melinda Gates Foundation, Jawaharlal Nehru Medical College, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Marion Koso-Thomas, MD, Study director, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03871491
- Sponsor's protocol ID
- CP Azithromycin
- Other IDs
- U24HD092094
- Status last verified
- Oct 2024
- First submitted
- 5 Mar 2019
- Last updated
- 24 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive, following publication of the primary paper.
Publications
World Health Organization. (2015). WHO recommendations for the prevention and treatment of maternal peripartum infections. Retrieved August 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines
Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, Cousens S, Mathers C, Black RE. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015 Jan 31;385(9966):430-40. doi: 10.1016/S0140-6736(14)61698-6. Epub 2014 Sep 30.
PubMed 25280870African Neonatal Sepsis Trial (AFRINEST) group; Tshefu A, Lokangaka A, Ngaima S, Engmann C, Esamai F, Gisore P, Ayede AI, Falade AG, Adejuyigbe EA, Anyabolu CH, Wammanda RD, Ejembi CL, Ogala WN, Gram L, Cousens S. Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial. Lancet. 2015 May 2;385(9979):1767-1776. doi: 10.1016/S0140-6736(14)62284-4. Epub 2015 Apr 1.
PubMed 25842221Baqui AH, Saha SK, Ahmed AS, Shahidullah M, Quasem I, Roth DE, Samsuzzaman AK, Ahmed W, Tabib SM, Mitra DK, Begum N, Islam M, Mahmud A, Rahman MH, Moin MI, Mullany LC, Cousens S, El Arifeen S, Wall S, Brandes N, Santosham M, Black RE; Projahnmo Study Group in Bangladesh. Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial. Lancet Glob Health. 2015 May;3(5):e279-87. doi: 10.1016/S2214-109X(14)70347-X. Epub 2015 Apr 1.
PubMed 25841891Mir F, Nisar I, Tikmani SS, Baloch B, Shakoor S, Jehan F, Ahmed I, Cousens S, Zaidi AK. Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial. Lancet Glob Health. 2017 Feb;5(2):e177-e185. doi: 10.1016/S2214-109X(16)30335-7. Epub 2016 Dec 15.
PubMed 27988146Zaidi AK, Tikmani SS, Sultana S, Baloch B, Kazi M, Rehman H, Karimi K, Jehan F, Ahmed I, Cousens S. Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial. Pediatr Infect Dis J. 2013 Sep;32 Suppl 1(Suppl 1 Innovative Treatment Regimens for Severe Infections in Young Infants):S19-25. doi: 10.1097/INF.0b013e31829ff7aa.
PubMed 23945571Gibbs RS. Clinical risk factors for puerperal infection. Obstet Gynecol. 1980 May;55(5 Suppl):178S-184S. doi: 10.1097/00006250-198003001-00045.
PubMed 6990333World Health Organization. (2015). WHO Statement on Caesarean Section Rates. Retrieved August 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/cs-statement/en/
Mackeen AD, Packard RE, Ota E, Berghella V, Baxter JK. Timing of intravenous prophylactic antibiotics for preventing postpartum infectious morbidity in women undergoing cesarean delivery. Cochrane Database Syst Rev. 2014 Dec 5;2014(12):CD009516. doi: 10.1002/14651858.CD009516.pub2.
PubMed 25479008Smaill FM, Grivell RM. Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev. 2014 Oct 28;2014(10):CD007482. doi: 10.1002/14651858.CD007482.pub3.
PubMed 25350672Gyte GM, Dou L, Vazquez JC. Different classes of antibiotics given to women routinely for preventing infection at caesarean section. Cochrane Database Syst Rev. 2014 Nov 17;2014(11):CD008726. doi: 10.1002/14651858.CD008726.pub2.
PubMed 25402227Tita ATN, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol. 2009 Mar;113(3):675-682. doi: 10.1097/AOG.0b013e318197c3b6.
PubMed 19300334Tita AT, Szychowski JM, Boggess K, Saade G, Longo S, Clark E, Esplin S, Cleary K, Wapner R, Letson K, Owens M, Abramovici A, Ambalavanan N, Cutter G, Andrews W; C/SOAP Trial Consortium. Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. N Engl J Med. 2016 Sep 29;375(13):1231-41. doi: 10.1056/NEJMoa1602044.
PubMed 27682034Oluwalana C, Camara B, Bottomley C, Goodier S, Bojang A, Kampmann B, Ceesay S, D'Alessandro U, Roca A. Azithromycin in Labor Lowers Clinical Infections in Mothers and Newborns: A Double-Blind Trial. Pediatrics. 2017 Feb;139(2):e20162281. doi: 10.1542/peds.2016-2281.
PubMed 28130432World Health Organization. (2017). Statement on maternal sepsis. Retrieved Ausust 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/maternalsepsis-statement/en/
Study at a glance
From the registry record, last updated by the sponsor on 24 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03871491
- Acronym / sponsor ID
- CP Azithromycin
- Conditions
- Maternal Death, Maternal Infections Affecting Fetus or Newborn, Neonatal SEPSIS, Maternal Sepsis During Labor, Neonatal Death, Postpartum Sepsis
- Keywords
- maternal sepsis, maternal death, neonatal sepsis, neonatal death, azithromycin, Democratic Republic of Congo, Zambia, Guatemala
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 58,747 participants (actual)
- Lead sponsor
- NICHD Global Network for Women's and Children's HealthResearch network
- Collaborators
- University of Alabama at Birmingham, University Teaching Hospital, Lusaka, Zambia, University of North Carolina, Chapel Hill, Kinshasa School of Public Health, University of Colorado, Denver, Institute of Nutrition of Central America and Panama, University of Virginia, International Centre for Diarrhoeal Disease Research, Bangladesh, Thomas Jefferson University, Columbia University, Aga Khan University, Boston University, Lata Medical Research Foundation, Nagpur, Indiana University, Moi Univeristy, RTI International, Bill and Melinda Gates Foundation, Jawaharlal Nehru Medical College, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 1 Sep 2020 (actual)
- Primary completion
- 30 Sep 2022 (actual)
- Study completion
- 30 Sep 2022 (actual)
- First posted
- 12 Mar 2019 (actual)
- Results
- Posted 24 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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
- For all mothers enrolled in the RCT and their infants:
- 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;
- Among a subset of 1000 randomly selected maternal-infant dyads:
- 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).
- Serial microbiome collection and storage of specimens for future testing to monitor maternal and newborn microbiome status of selected sites.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.
| Arm | Type | Receives |
|---|---|---|
| Intervention | Experimental | Drug: AzithromycinThe study intervention is a single 2 g dose of directly observed oral azithromycin. |
| Placebo | Placebo comparator | Drug: PlaceboBy random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzithromycinThe 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. | Drug | Intervention |
| PlaceboIdentical appearing placebo, administered as a single oral dose directly after randomization. | Drug | Placebo |
Primary outcome
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group.
Time frame: Within 6 weeks (42 days)
Maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
Intrapartum/Neonatal Death or Sepsis Within 4 Weeks (28 Days) Post-delivery in Intervention vs. Placebo Group
Time frame: Within 4 weeks (28 days) post-delivery
Intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group. This outcome is measured among stillbirths and neonates with 28-day status available born to women randomized. The study includes multiple births so there are more stillbirths and neonates than participants enrolled.
21 secondary outcomes
Maternal Sepsis
Time frame: Within 42 days post-delivery
Maternal Death Due to Sepsis
Time frame: Within 42 days post-delivery
Chorioamnionitis
Time frame: Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)
Endometritis
Time frame: Within 42 days post-delivery
Cesarean Wound Infection
Time frame: Within 42 days post-delivery
Perineal Wound Infection
Time frame: Within 42 days post-delivery
Other Infections
Time frame: Within 42 days post-delivery
Use of Subsequent Maternal Antibiotic Therapy
Time frame: After randomization to 42 days post-delivery. Randomization occurs between labor onset and delivery (0 to 120 hours before delivery). 42 participants were randomized >120 hours before delivery due to false labor.
Maternal Initial Hospital Length of Stay
Time frame: Time from drug administration (which occurs between onset of labor and delivery) and discharge from delivery hospital (0 to 45 days)
Maternal Readmissions
Time frame: After delivery discharge and within 42 days post-delivery
Maternal Admission to Special Care Units
Time frame: Within 42 days post-delivery (reported during study)
Maternal Unscheduled Visit for Care
Time frame: Within 42 days post-delivery (reported during study)
Maternal GI Symptoms
Time frame: Within 42 days post-delivery (reported during study)
Neonatal Sepsis
Time frame: Within 28 days post-delivery
Neonatal Death Due to Sepsis
Time frame: Within 28 days post-delivery
Other Neonatal Infections
Time frame: Within 28 days post-delivery
Neonatal Initial Hospital Length of Stay
Time frame: Time from delivery to discharge from delivery hospital (0 to 62 days)
Neonatal Readmissions
Time frame: After delivery discharge and within 42 days of delivery
Neonatal Admission to Special Care Units
Time frame: Within 42 days post-delivery (reported during study)
Neonatal Unscheduled Visit for Care
Time frame: Within 42 days post-delivery (reported during study)
Pyloric Stenosis Within 42 Days of Delivery
Time frame: Within 42 days post-delivery
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- BackgroundWorld Health Organization. (2015). WHO recommendations for the prevention and treatment of maternal peripartum infections. Retrieved August 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines
- Background: PubMed 25280870Liu L, Oza S, Hogan D, Perin J, Rudan I, Lawn JE, Cousens S, Mathers C, Black RE. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015 Jan 31;385(9966):430-40. doi: 10.1016/S0140-6736(14)61698-6. Epub 2014 Sep 30.
- Background: PubMed 25842221African Neonatal Sepsis Trial (AFRINEST) group; Tshefu A, Lokangaka A, Ngaima S, Engmann C, Esamai F, Gisore P, Ayede AI, Falade AG, Adejuyigbe EA, Anyabolu CH, Wammanda RD, Ejembi CL, Ogala WN, Gram L, Cousens S. Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial. Lancet. 2015 May 2;385(9979):1767-1776. doi: 10.1016/S0140-6736(14)62284-4. Epub 2015 Apr 1.
- Background: PubMed 25841891Baqui AH, Saha SK, Ahmed AS, Shahidullah M, Quasem I, Roth DE, Samsuzzaman AK, Ahmed W, Tabib SM, Mitra DK, Begum N, Islam M, Mahmud A, Rahman MH, Moin MI, Mullany LC, Cousens S, El Arifeen S, Wall S, Brandes N, Santosham M, Black RE; Projahnmo Study Group in Bangladesh. Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial. Lancet Glob Health. 2015 May;3(5):e279-87. doi: 10.1016/S2214-109X(14)70347-X. Epub 2015 Apr 1.
- Background: PubMed 27988146Mir F, Nisar I, Tikmani SS, Baloch B, Shakoor S, Jehan F, Ahmed I, Cousens S, Zaidi AK. Simplified antibiotic regimens for treatment of clinical severe infection in the outpatient setting when referral is not possible for young infants in Pakistan (Simplified Antibiotic Therapy Trial [SATT]): a randomised, open-label, equivalence trial. Lancet Glob Health. 2017 Feb;5(2):e177-e185. doi: 10.1016/S2214-109X(16)30335-7. Epub 2016 Dec 15.
- Background: PubMed 23945571Zaidi AK, Tikmani SS, Sultana S, Baloch B, Kazi M, Rehman H, Karimi K, Jehan F, Ahmed I, Cousens S. Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial. Pediatr Infect Dis J. 2013 Sep;32 Suppl 1(Suppl 1 Innovative Treatment Regimens for Severe Infections in Young Infants):S19-25. doi: 10.1097/INF.0b013e31829ff7aa.
- Background: PubMed 6990333Gibbs RS. Clinical risk factors for puerperal infection. Obstet Gynecol. 1980 May;55(5 Suppl):178S-184S. doi: 10.1097/00006250-198003001-00045.
- BackgroundWorld Health Organization. (2015). WHO Statement on Caesarean Section Rates. Retrieved August 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/cs-statement/en/
- Background: PubMed 25479008Mackeen AD, Packard RE, Ota E, Berghella V, Baxter JK. Timing of intravenous prophylactic antibiotics for preventing postpartum infectious morbidity in women undergoing cesarean delivery. Cochrane Database Syst Rev. 2014 Dec 5;2014(12):CD009516. doi: 10.1002/14651858.CD009516.pub2.
- Background: PubMed 25350672Smaill FM, Grivell RM. Antibiotic prophylaxis versus no prophylaxis for preventing infection after cesarean section. Cochrane Database Syst Rev. 2014 Oct 28;2014(10):CD007482. doi: 10.1002/14651858.CD007482.pub3.
- Background: PubMed 25402227Gyte GM, Dou L, Vazquez JC. Different classes of antibiotics given to women routinely for preventing infection at caesarean section. Cochrane Database Syst Rev. 2014 Nov 17;2014(11):CD008726. doi: 10.1002/14651858.CD008726.pub2.
- Background: PubMed 19300334Tita ATN, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: a systematic review. Obstet Gynecol. 2009 Mar;113(3):675-682. doi: 10.1097/AOG.0b013e318197c3b6.
- Individual participant dataSharing planned: Yes. Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive, following publication of the primary paper.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marion Koso-Thomas, MD study director
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
8 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Azithromycin in people with Maternal Death and Maternal Infections Affecting Fetus or Newborn, run by NICHD Global Network for Women's and Children's Health at 8 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in India, Bangladesh, Democratic Republic of the Congo, Guatemala, Kenya and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maternal Death or Sepsis Within 6 Weeks (42 Days) Post-delivery in Intervention vs. Placebo Group. (time frame: Within 6 weeks (42 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03871491, which also lists 47 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Oct 2024; AzTrials last refreshed its copy on 27 Oct 2026.