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

NCT03871491 | Completed Phase 3 Results DMC

• 2 other identifiers: CP AzithromycinU24HD092094
• Study Type: interventional
• Target: 58,747
• Locations: 7 countries
• Sites: 8

Brief 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.

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; Bangladesh; India; Pakistan; Kenya; COVID-19

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Within 4 weeks (28 days) post-delivery

Secondary Outcomes (21)

• Maternal Sepsis

  Within 42 days post-delivery

• Maternal Death Due to Sepsis

  Within 42 days post-delivery

• Chorioamnionitis

  Between date/time of randomization and date/time of delivery (up to 120 hours before delivery)

• Endometritis

  Within 42 days post-delivery

• Cesarean Wound Infection

  Within 42 days post-delivery

Study Arms (2)

Intervention

EXPERIMENTAL

The study intervention is a single 2 g dose of directly observed oral azithromycin.

Drug: Azithromycin

Placebo

PLACEBO COMPARATOR

By random allocation, participants will receive four oral placebo pills containing a non-antimicrobial agent directly after randomization.

Drug: Placebo

Interventions

Azithromycin DRUG

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.

Intervention

Placebo DRUG

Identical appearing placebo, administered as a single oral dose directly after randomization.

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• NICHD Global Network for Women's and Children's Health: lead
• University of Alabama at Birmingham: collaborator
• University Teaching Hospital, Lusaka, Zambia: collaborator
• University of North Carolina, Chapel Hill: collaborator
• Kinshasa School of Public Health: collaborator
• University of Colorado, Denver: collaborator
• Institute of Nutrition of Central America and Panama: collaborator
• University of Virginia: collaborator
• International Centre for Diarrhoeal Disease Research, Bangladesh: collaborator
• Thomas Jefferson University: collaborator
• Columbia University: collaborator
• Aga Khan University: collaborator
• Boston University: collaborator
• Lata Medical Research Foundation, Nagpur: collaborator
• Indiana University School of Medicine: collaborator
• Moi Univeristy: collaborator
• RTI International: collaborator
• Bill and Melinda Gates Foundation: collaborator
• Jawaharlal Nehru Medical College: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (8)

ICDDRB

Dhaka, 1212, Bangladesh

Location

Kinshasa School of Public Health

Kinshasa, Democratic Republic of the Congo

Location

Institute for Nutrition of Central America and Panama (INCAP)

Guatemala City, 01011, Guatemala

Location

Jawaharlal Nehru Medical College

Belagām, 590 010, India

Location

Lata Medical Research Foundation

Nagpur, India

Location

Moi University School of Medicine

Eldoret, 30100, Kenya

Location

The Aga Khan University

Karachi, 74800, Pakistan

Location

University Teaching Hospital

Lusaka, Zambia

Location

Related Publications (46)

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• Sidze L, Moore JL, Carlo WA, Mwenechanya M, Chomba E, Hemingway-Foday JJ, Kavi A, Metgud MC, Goudar SS, Derman R, Lokangaka AL, Tshefu AK, Bauserman MS, Bose CL, Shivkumar P, Waikar M, Patel AB, Hibberd PL, Nyongesa P, Esamai F, Ekhaguere OA, Bucher SL, Jessani S, Tikmani SS, Saleem S, Goldenberg RL, Billah SM, Lennox R, Haque R, Petri WA, Figueroa L, Mazariegos M, Krebs NF, Nolen TL, Koso-Thomas M, McClure EM, Tita ATN; A-PLUS Trial Group. Intrapartum oral azithromycin for maternal infection prophylaxis and the risk of postpartum hemorrhage: A secondary analysis of the A-PLUS trial. Int J Gynaecol Obstet. 2026 Jan 13. doi: 10.1002/ijgo.70777. Online ahead of print.

  PMID: 41527950 DERIVED

• Carlo WA, Tita ATN, Moore JL, Mwenechanya M, Chomba E, Hemingway-Foday JJ, Kavi A, Metgud MC, Goudar SS, Derman RJ, Lokangaka A, Tshefu A, Bauserman M, Patterson JK, Shivkumar P, Waikar M, Patel A, Hibberd PL, Nyongesa P, Esamai F, Ekhaguere OA, Bucher S, Jessani S, Tikmani SS, Saleem S, Goldenberg RL, Billah SM, Lennox R, Haque R, Petri W, Mazariegos M, Krebs NF, Babineau DC, McClure EM, Koso-Thomas M; A-PLUS Trial Group. Effectiveness of intrapartum azithromycin to prevent infections in planned vaginal births in low-income and middle-income countries: a post-hoc analysis of data from a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Glob Health. 2025 Apr;13(4):e689-e697. doi: 10.1016/S2214-109X(24)00562-X.

  PMID: 40155106 DERIVED

• Patterson JK, Neuwahl S, Kirsch S, Moore JL, Tita ATN, Carlo WA, Lokangaka A, Tshefu A, Mwenechanya M, Chomba E, Kavi A, Metgud MC, Goudar SS, Derman RJ, Shivkumar P, Waikar M, Patel A, Hibberd PL, Nyongesa P, Esamai F, Ekhaguere OA, Bucher S, Jessani S, Tikmani SS, Saleem S, Wylie BJ, Goldenberg RL, Billah SM, Lennox R, Haque R, Petri WA, Mazariegos M, Krebs NF, Hemingway-Foday JJ, Babineau D, Koso-Thomas M, McClure EM, Bauserman M. Cost-effectiveness of intrapartum azithromycin to prevent maternal infection, sepsis, or death in low-income and middle-income countries: a modelling analysis of data from a randomised, multicentre, placebo-controlled trial. Lancet Glob Health. 2025 Apr;13(4):e679-e688. doi: 10.1016/S2214-109X(24)00517-5.

  PMID: 40155105 DERIVED

• Hemingway-Foday J, Tita A, Chomba E, Mwenechanya M, Mweemba T, Nolen T, Lokangaka A, Tshefu Kitoto A, Lomendje G, Hibberd PL, Patel A, Das PK, Kurhe K, Goudar SS, Kavi A, Metgud M, Saleem S, Tikmani SS, Esamai F, Nyongesa P, Sagwe A, Figueroa L, Mazariegos M, Billah SM, Haque R, Shahjahan Siraj M, Goldenberg RL, Bauserman M, Bose C, Liechty EA, Ekhaguere OA, Krebs NF, Derman R, Petri WA, Koso-Thomas M, McClure E, Carlo WA. Prevention of maternal and neonatal death/infections with a single oral dose of azithromycin in women in labour in low-income and middle-income countries (A-PLUS): a study protocol for a multinational, randomised placebo-controlled clinical trial. BMJ Open. 2023 Aug 30;13(8):e068487. doi: 10.1136/bmjopen-2022-068487.

  PMID: 37648383 DERIVED

• Tita ATN, Carlo WA, McClure EM, Mwenechanya M, Chomba E, Hemingway-Foday JJ, Kavi A, Metgud MC, Goudar SS, Derman R, Lokangaka A, Tshefu A, Bauserman M, Bose C, Shivkumar P, Waikar M, Patel A, Hibberd PL, Nyongesa P, Esamai F, Ekhaguere OA, Bucher S, Jessani S, Tikmani SS, Saleem S, Goldenberg RL, Billah SM, Lennox R, Haque R, Petri W, Figueroa L, Mazariegos M, Krebs NF, Moore JL, Nolen TL, Koso-Thomas M; A-PLUS Trial Group. Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. N Engl J Med. 2023 Mar 30;388(13):1161-1170. doi: 10.1056/NEJMoa2212111. Epub 2023 Feb 9.

  PMID: 36757318 DERIVED

MeSH Terms

Conditions

Maternal Death; Neonatal Sepsis; Perinatal Death; Puerperal Infection; Pregnancy Complications, Infectious; COVID-19

Interventions

Azithromycin

Condition Hierarchy (Ancestors)

Parental Death; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Sepsis; Infections; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Puerperal Disorders; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Elizabeth McClure
• Organization: RTI International

mcclure@rti.org

919-316-3773

Study Officials

• Marion Koso-Thomas, MD

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Randomized, placebo-controlled, parallel multicenter clinical trial. Women in labor will be randomized with one-to-one ratio to intervention/placebo.

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 12, 2019
• Study Start: September 1, 2020
• Primary Completion: September 30, 2022
• Study Completion: September 30, 2022
• Last Updated: October 24, 2024
• Results First Posted: October 24, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: No more than one year after publication of the primary paper. No end date.
• Access Criteria: Deidentified participant data will be made available through the NICHD Data and Specimen Hub (N-DASH) system, a publicly accessible online archive. Investigators interested in data and access are required to submit their request through N-DASH, per the requirements of the DASH policy. This includes a brief description of the proposed use of the research data, a signed NICHD DASH Data Use Agreement, and IRB approval, exemption, or declaration that the research does not involve human subjects.

Locations

KE (1); GU (1); BA (1); IN (2); PA (1); ZA (1); DE (1)