drugset / Trial / NCT03871491
Azithromycin-Prevention in Labor Use Study (A-PLUS)
Phase 3
Completed
58747 enrolled
NICHD Global Network for Women's and Children's Health
Aga Khan University · collabBill and Melinda Gates Foundation · collabBoston University · collabColumbia University · collabEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) · collabIndiana University · collabInstitute of Nutrition of Central America and Panama · collabInternational Centre for Diarrhoeal Disease Research, Bangladesh · collabJawaharlal Nehru Medical College · collabKinshasa School of Public Health · collabLata Medical Research Foundation, Nagpur · collabMoi Univeristy · collabRTI International · collabThomas Jefferson University · collabUniversity Teaching Hospital, Lusaka, Zambia · collabUniversity of Alabama at Birmingham · collabUniversity of Colorado, Denver · collabUniversity of North Carolina, Chapel Hill · collabUniversity of Virginia · collab
RandomizedParallel-groupTriple-blindPrevention
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.
Timeline
- Start
- 2020-09-01
- Primary completion
- 2022-09-30
- Completion
- 2022-09-30
Publications
- Background 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
- Background 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.
- Background African 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 Baqui 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 Mir 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 Zaidi 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.
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- Background World 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 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.
- Background Smaill 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 Gyte 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 Tita 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.
- Background Tita 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.
- Background Oluwalana 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.
- Background World Health Organization. (2017). Statement on maternal sepsis. Retrieved Ausust 22, 2018, from http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/maternalsepsis-statement/en/
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- Background van Dillen J, Zwart J, Schutte J, van Roosmalen J. Maternal sepsis: epidemiology, etiology and outcome. Curr Opin Infect Dis. 2010 Jun;23(3):249-54. doi: 10.1097/QCO.0b013e328339257c.
- Background Roca A, Oluwalana C, Bojang A, Camara B, Kampmann B, Bailey R, Demba A, Bottomley C, D'Alessandro U. Oral azithromycin given during labour decreases bacterial carriage in the mothers and their offspring: a double-blind randomized trial. Clin Microbiol Infect. 2016 Jun;22(6):565.e1-9. doi: 10.1016/j.cmi.2016.03.005. Epub 2016 Mar 26.
- Background Harper LM, Kilgore M, Szychowski JM, Andrews WW, Tita ATN. Economic Evaluation of Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. Obstet Gynecol. 2017 Aug;130(2):328-334. doi: 10.1097/AOG.0000000000002129.
- Background Andrews WW, Hauth JC, Cliver SP, Savage K, Goldenberg RL. Randomized clinical trial of extended spectrum antibiotic prophylaxis with coverage for Ureaplasma urealyticum to reduce post-cesarean delivery endometritis. Obstet Gynecol. 2003 Jun;101(6):1183-9. doi: 10.1016/s0029-7844(03)00016-4.
- Background Tita AT, Hauth JC, Grimes A, Owen J, Stamm AM, Andrews WW. Decreasing incidence of postcesarean endometritis with extended-spectrum antibiotic prophylaxis. Obstet Gynecol. 2008 Jan;111(1):51-6. doi: 10.1097/01.AOG.0000295868.43851.39.
- Background Tita AT, Owen J, Stamm AM, Grimes A, Hauth JC, Andrews WW. Impact of extended-spectrum antibiotic prophylaxis on incidence of postcesarean surgical wound infection. Am J Obstet Gynecol. 2008 Sep;199(3):303.e1-3. doi: 10.1016/j.ajog.2008.06.068.
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- Background Emmons SL, Krohn M, Jackson M, Eschenbach DA. Development of wound infections among women undergoing cesarean section. Obstet Gynecol. 1988 Oct;72(4):559-64.
- Background Roberts S, Maccato M, Faro S, Pinell P. The microbiology of post-cesarean wound morbidity. Obstet Gynecol. 1993 Mar;81(3):383-6.
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- Background Andrews WW, Shah SR, Goldenberg RL, Cliver SP, Hauth JC, Cassell GH. Association of post-cesarean delivery endometritis with colonization of the chorioamnion by Ureaplasma urealyticum. Obstet Gynecol. 1995 Apr;85(4):509-14. doi: 10.1016/0029-7844(94)00436-H.
- Background Keski-Nisula L, Kirkinen P, Katila ML, Ollikainen M, Suonio S, Saarikoski S. Amniotic fluid U. urealyticum colonization: significance for maternal peripartal infections at term. Am J Perinatol. 1997 Mar;14(3):151-6. doi: 10.1055/s-2007-994117.
- Background Yoon BH, Romero R, Park JS, Chang JW, Kim YA, Kim JC, Kim KS. Microbial invasion of the amniotic cavity with Ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol. 1998 Nov;179(5):1254-60. doi: 10.1016/s0002-9378(98)70142-5.
- Background Ledger WJ. Prophylactic antibiotics in obstetrics-gynecology: a current asset, a future liability? Expert Rev Anti Infect Ther. 2006 Dec;4(6):957-64. doi: 10.1586/14787210.4.6.957.
- Background Guideline: Managing Possible Serious Bacterial Infection in Young Infants When Referral Is Not Feasible. Geneva: World Health Organization; 2015. Available from http://www.ncbi.nlm.nih.gov/books/NBK321136/
- Background Sutton AL, Acosta EP, Larson KB, Kerstner-Wood CD, Tita AT, Biggio JR. Perinatal pharmacokinetics of azithromycin for cesarean prophylaxis. Am J Obstet Gynecol. 2015 Jun;212(6):812.e1-6. doi: 10.1016/j.ajog.2015.01.015. Epub 2015 Jan 13.
- Background Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics. 2015 Mar;135(3):483-8. doi: 10.1542/peds.2014-2026.
- Background Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90. doi: 10.1056/NEJMoa1003833.
- Background Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013 May 2;368(18):1704-12. doi: 10.1056/NEJMoa1300799.
- Background Hoffman MK, Goudar SS, Kodkany BS, Goco N, Koso-Thomas M, Miodovnik M, McClure EM, Wallace DD, Hemingway-Foday JJ, Tshefu A, Lokangaka A, Bose CL, Chomba E, Mwenechanya M, Carlo WA, Garces A, Krebs NF, Hambidge KM, Saleem S, Goldenberg RL, Patel A, Hibberd PL, Esamai F, Liechty EA, Silver R, Derman RJ. A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study. BMC Pregnancy Childbirth. 2017 May 3;17(1):135. doi: 10.1186/s12884-017-1312-x.
- Background Goldenberg RL, Saleem S, Ali S, Moore JL, Lokangako A, Tshefu A, Mwenechanya M, Chomba E, Garces A, Figueroa L, Goudar S, Kodkany B, Patel A, Esamai F, Nsyonge P, Harrison MS, Bauserman M, Bose CL, Krebs NF, Hambidge KM, Derman RJ, Hibberd PL, Liechty EA, Wallace DD, Belizan JM, Miodovnik M, Koso-Thomas M, Carlo WA, Jobe AH, McClure EM. Maternal near miss in low-resource areas. Int J Gynaecol Obstet. 2017 Sep;138(3):347-355. doi: 10.1002/ijgo.12219. Epub 2017 Jun 13.
- Background Bonet M, Souza JP, Abalos E, Fawole B, Knight M, Kouanda S, Lumbiganon P, Nabhan A, Nadisauskiene R, Brizuela V, Metin Gulmezoglu A. The global maternal sepsis study and awareness campaign (GLOSS): study protocol. Reprod Health. 2018 Jan 30;15(1):16. doi: 10.1186/s12978-017-0437-8.
- Background Albright CM, Has P, Rouse DJ, Hughes BL. Internal Validation of the Sepsis in Obstetrics Score to Identify Risk of Morbidity From Sepsis in Pregnancy. Obstet Gynecol. 2017 Oct;130(4):747-755. doi: 10.1097/AOG.0000000000002260.
- Background Bowyer L, Robinson HL, Barrett H, Crozier TM, Giles M, Idel I, Lowe S, Lust K, Marnoch CA, Morton MR, Said J, Wong M, Makris A. SOMANZ guidelines for the investigation and management sepsis in pregnancy. Aust N Z J Obstet Gynaecol. 2017 Oct;57(5):540-551. doi: 10.1111/ajo.12646. Epub 2017 Jul 3.
- Ramani M, Carlo WA, Mwenechanya M, Chomba E, Goudar SS, Derman RJ, Metgud MC, Kavi A, Bauserman M, Patterson J, Tshefu AK, Lokangaka AL, Krebs NF, Mazariegos M, Barrientos D, Patel AB, Hibberd PL, Bhargav S, Andelkar A, Saleem S, Goldenberg RL, Tikmani SS, Yasmin H, Babineau DC, Hemingway-Foday JJ, Trotta M, Rasco C, McClure EM, Gustafson KE; ABC Study Group. Neurodevelopmental Pediatric Follow-Up After the Azithromycin Prevention in Labor Use Study. Obstet Gynecol. 2026 May 14. doi: 10.1097/AOG.0000000000006301. Online ahead of print.
- 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 Jun;173(3):1562-1568. doi: 10.1002/ijgo.70777. Epub 2026 Jan 13.
- 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.
- 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.
- 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.
- 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.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Azithromycin | Small molecule | 2 g | Oral |