Azithromycin-Prevention in Labor Use Study (A-PLUS)
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| ClinicalTrials.gov Identifier: NCT03871491 |
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Recruitment Status :
Recruiting
First Posted : March 12, 2019
Last Update Posted : September 16, 2020
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| Condition or disease | Intervention/treatment | Phase |
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| Maternal Death Maternal Infections Affecting Fetus or Newborn Neonatal SEPSIS Maternal Sepsis During Labor Neonatal Death Postpartum Sepsis | Drug: Azithromycin Drug: Placebo | Phase 3 |
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
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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;
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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 Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 34000 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention 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 (Participant, Care Provider, Investigator) |
| Masking Description: | Both the azithromycin and placebo will be procured from the same manufacturer. The packaging will be standardized across sites and will be labeled as: "Azithromycin 2 g or Placebo", with the expiration data and a unique identifier. Clinical and research staff as well as the women will be masked to treatment status unless there is a serious adverse event potentially related to the treatment modality that requires unmasking for safety reasons. There will be one pharmacist at each site who will monitor randomization, drug supply, and safety. If concerns about randomization or participant safety are identified, the data coordinating center will authorize and instruct the study pharmacist to apply un-masking procedures. |
| Primary Purpose: | Prevention |
| 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 |
| Actual Study Start Date : | September 1, 2020 |
| Estimated Primary Completion Date : | September 1, 2023 |
| Estimated Study Completion Date : | September 1, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Intervention
The study intervention is a single 2 g dose of directly observed oral azithromycin.
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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. |
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Placebo Comparator: Placebo
By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.
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Drug: Placebo
Identical appearing placebo, administered as a single oral dose directly after randomization. |
- Maternal: Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group. [ Time Frame: within 6 weeks (42 days) ]Incidence of maternal death or sepsis within 6 weeks (42 days) post-delivery in intervention vs. placebo group.
- Neonatal: Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group [ Time Frame: 4 weeks (28 days) post-delivery ]Incidence of intrapartum/neonatal death or sepsis within 4 weeks (28 days) post-delivery in intervention vs. placebo group
- Incidence of chorioamnionitis [ Time Frame: prior to delivery ]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.
- Incidence of endometritis [ Time Frame: within 42 days post-delivery ]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.
- Incidence of other infections [ Time Frame: within 42 days post-delivery ]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).
- Incidence of use of subsequent maternal antibiotic therapy [ Time Frame: after randomization to 42 days post-delivery ]Use of subsequent maternal antibiotic therapy after randomization to 42 days postpartum for any reason.
- Maternal initial hospital length of stay [ Time Frame: within 42 days post-delivery ]Time from drug administration until initial discharge after delivery (time may vary by site).
- Incidence of maternal readmissions [ Time Frame: within 42 days post-delivery ]Maternal readmissions within 42 days of delivery
- Incidence of maternal admission to special care units [ Time Frame: within 42 days post-delivery ]Maternal admission to special care units
- Incidence of maternal unscheduled visit for care [ Time Frame: within 42 days post-delivery ]Maternal unscheduled visit for care
- Incidence of maternal GI symptoms [ Time Frame: within 42 days post-delivery ]Maternal GI symptoms including nausea, vomiting, and diarrhea and other reported side effects.
- Incidence of maternal death due to sepsis [ Time Frame: within 42 days post-delivery ]Maternal death due to sepsis using the Global Network algorithm for cause of death
- Incidence of other neonatal infections (e.g. eye infection, skin infection) [ Time Frame: within 42 days post-delivery ]Incidence of other neonatal infections.
- Neonatal initial hospital length of stay [ Time Frame: within 28 days of delivery ]Neonatal initial hospital length of stay, defined as time of delivery until initial discharge (time may vary by site).
- Incidence of neonatal readmissions [ Time Frame: within 42 days of delivery ]Neonatal readmissions within 42 days of delivery
- Incidence of neonatal admission to special care units [ Time Frame: within 28 days of delivery ]Neonatal admission to special care units
- Incidence of neonatal unscheduled visit for care [ Time Frame: within 42 days post-delivery ]Neonatal unscheduled visit for care
- Incidence of neonatal death due to sepsis [ Time Frame: within 28 days of delivery ]Neonatal death due to sepsis using the Global Network algorithm for causes of death
- Incidence of pyloric stenosis within 42 days of delivery [ Time Frame: 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.
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| Ages Eligible for Study: | 18 Years to 45 Years (Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | Yes |
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.
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): NCT03871491
| Contact: Elizabeth McClure, PhD | 919 316 3773 | mcclure@rti.org | |
| Contact: Tracy Nolen, DrPH | 919 541 7467 | tnolen@rti.org |
| Bangladesh | |
| ICDDRB | Not yet recruiting |
| Dhaka, Bangladesh, 1212 | |
| Contact: Site Principal Investigator rhaque@icddrb.org | |
| Principal Investigator: Rashidul Haque, MD | |
| Congo, The Democratic Republic of the | |
| Kinshasa School of Public Health | Not yet recruiting |
| Kinshasa, Congo, The Democratic Republic of the | |
| Contact: Antoinette Tshefu, MD, MPH, PhD antotshe@yahoo.com | |
| Principal Investigator: Antoinette Tshefu, MD | |
| Guatemala | |
| Institute for Nutrition of Central America and Panama (INCAP) | Not yet recruiting |
| Guatemala City, Guatemala, 01011 | |
| Contact: Lester Figueroa, MD lfigueroa@incap.int | |
| Principal Investigator: Lester Figueroa, MD | |
| India | |
| Jawaharlal Nehru Medical College | Recruiting |
| Belagavi, India, 590 010 | |
| Contact: Shivaprasad S. Goudar, MD, MHPE 011 91 831 2409 2055 sgoudar@jnmc.edu | |
| Principal Investigator: Shivaprasad S. Goudar, MD, MHPE | |
| Lata Medical Research Foundation | Not yet recruiting |
| Nagpur, India | |
| Contact: Archana Patel, MD, DNB, MSCE dr_apatel@yahoo.com | |
| Principal Investigator: Archana Patel, MD, DNB, MSCE | |
| Kenya | |
| Moi University School of Medicine | Not yet recruiting |
| Eldoret, Kenya, 30100 | |
| Contact: Fabian Esamai, MBChB, MMed, PhD 011 254 733 836 410 fesamai2007@gmail.com | |
| Principal Investigator: Fabian Esamai, MBChB, MMed, PhD | |
| Pakistan | |
| The Aga Khan University | Not yet recruiting |
| Karachi, Pakistan, 74800 | |
| Contact: Sarah Saleem, MD Sarah.saleem@aku.edu | |
| Principal Investigator: Sarah Saleem, MD | |
| Zambia | |
| University Teaching Hospital | Not yet recruiting |
| Lusaka, Zambia | |
| Contact: Elwyn Chomba, MBChB, DCH, MRCP echomba@zamnet.zm | |
| Principal Investigator: Elwyn Chomba, MBChB, DCH, MRCP | |
| Study Director: | Marion Koso-Thomas, MD | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| Responsible Party: | NICHD Global Network for Women's and Children's Health |
| ClinicalTrials.gov Identifier: | NCT03871491 |
| Other Study ID Numbers: |
CP Azithromycin |
| First Posted: | March 12, 2019 Key Record Dates |
| Last Update Posted: | September 16, 2020 |
| Last Verified: | August 2020 |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
| Product Manufactured in and Exported from the U.S.: | No |
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maternal sepsis maternal death neonatal sepsis neonatal death azithromycin Democratic Republic of Congo Zambia |
Guatemala Bangladesh India Pakistan Kenya COVID-19 |
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Infection Sepsis Toxemia Neonatal Sepsis Pregnancy Complications, Infectious Puerperal Infection Perinatal Death Maternal Death Death Systemic Inflammatory Response Syndrome |
Inflammation Pathologic Processes Infant, Newborn, Diseases Pregnancy Complications Parental Death Puerperal Disorders Azithromycin Anti-Bacterial Agents Anti-Infective Agents |