Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial

NCT01222247 | Completed Phase 3 Results DMC FDA Drug

• 21 other identifiers: HL98354-HD36801-ALPSU10HD021410U10HD027869U10HD027917U10HD053118U10HD027915U10HD034116U10HD034208U10HD053097U10HD040500U10HD040485U10HD040544U10HD040545U10HD040560U10HD040512U10HD036801U01HL098354U01HL098554U10HD068268U10HD068258U10HD068282
• Study Type: interventional
• Target: 2,831
• Locations: 1 country
• Sites: 17

Brief Summary

This is a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of NICU admissions and improving short-term outcomes in the late preterm infant. The use of antenatal corticosteroids has been shown to be beneficial in women at risk for preterm delivery prior to 34 weeks but has not been evaluated in those likely to deliver in the late preterm period

Conditions

Pregnancy; Respiratory Distress Syndrome; Pregnancy Outcomes; Preterm Birth

Keywords

Betamethasone; Steroids; Perinatology; Late Preterm

Outcome Measures

Primary Outcomes (1)

• Neonatal Composite Outcome

  Need for respiratory support: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 2 hours or more in the first 72 hours, or fraction of inspired oxygen (FiO2) greater than or equal to 0.30 for 4 hours or more in the first 72 hours, or mechanical ventilation in the first 72 hours, or Extracorporeal membrane oxygenation (ECMO) Stillbirth, or neonatal death less than 72 hours of age

  72 hours of life

Secondary Outcomes (28)

• Number of Neonates With Severe Respiratory Complication,

  72 hours of life

• Neonates Needing Immediate Resuscitation After Birth

  Within the first 30 minutes of birth

• Number of Neonates With Respiratory Distress Syndrome

  Delivery

• Number of Neonates With Transient Tachypnea of the Newborn

  by 72 hours after delivery

• Number of Infants With Neonatal Apnea

  72 hours of life

Study Arms (2)

Betamethasone

ACTIVE COMPARATOR

A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart

Drug: Betamethasone

Placebo

PLACEBO COMPARATOR

A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart

Drug: Placebo

Interventions

Betamethasone DRUG

The active study drug, betamethasone. 3 mg per ml betamethasone sodium phosphate 3 mg per milliliter betamethasone acetate The first dose of study drug medication will be administered at randomization as 2 ml injection; the next dose of 2 ml will be administered 24 hours later.

Also known as: Corticosteroid

Betamethasone

Placebo DRUG

Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.

Placebo

Eligibility Criteria

• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Singleton Pregnancy. A twin pregnancy reduced to singleton (either spontaneously or therapeutically) before 14,0 weeks by project gestational age is acceptable
• Gestational age at randomization between 34,0 weeks and 36,5 weeks confirmed by study criteria
• High probability of delivery in the late preterm period (any one of the following):
• Membrane rupture as defined by the occurrence of any two of the following: pooling of fluid in the vaginal vault, positive Nitrazine test, ferning of vaginal fluid, positive AmniSure test; or any one of the following: indigo carmine pooling in the vagina after amnioinfustion, visible leakage of amniotic fluid from the cervix
• Preterm labor with intact membranes. Preterm labor is defined as at least 6 regular uterine contractions in an observation period of no more than 60 minutes and at least one of the following: cervix greater than or equal to 3cm dilated or at least 75% effaced
• Planned delivery by induction of labor or cesarean section in no less than 24 hours and no more than 7 days, as deemed necessary by the provider. An induction must be scheduled to start by 36,5 weeks at the latest, whereas a cesarean delivery must be scheduled by 36,6 weeks at the latest. Therefore the latest gestational age for randomization is 36,4 weeks for a planned induction. The planned delivery may be for any indication, such as the following: prior myomectomy, prior classical cesarean, intrauterine growth restriction (IUGR), oligohydramnios, preeclampsia, nonreassuring fetal heart rate tracing warranting delivery, abruption, placenta previa

You may not qualify if:

• Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group
• Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group
• Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically
• Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops
• Maternal contraindication to betamethasone: hypersensitivity reaction to any components of the medication, idiopathic thromboycytopenic purpura, systemal fungal infection in case of exacerbation by betamethasone, use of amphotericin B due to the possibility of heart failure with concomitant betamethasone
• Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy
• Delivery expected within 12 hours of randomization, because of insufficient time of corticosteroids to confer benefit, including any of the following:
• A. Rupture of Membranes (ROM) does not satisfy protocol criteria - exclude if the patient being evaluated for Preterm Premature Rupture of Membranes (pPROM), does not have preterm labor or planned delivery and does not satisfy the spontaneous membrane rupture criteria (any 2 of: positive Nitrazine test, pooling of fluid in the vaginal vault test or ferning of vaginal fluid; or indigo carmine pooling in the vagina after amnioinfusion; or visible leakage of amniotic fluid from the cervix) B. Rupture of the membranes in the presence of more than 6 contractions per hour or cervical dilation of 3 cm or more, unless oxytocin was withheld for at least 12 hours (other induction agents allowed) C. Chorioamnionitis - exclude if patient is diagnosed with chorioamnionitis D. Cervical dilation ≥ 8 cm E. Evidence of non-reassuring fetal status requiring immediate delivery
• Participation in another interventional study that influences neonatal morbidity and mortality
• Participation in this trial in a previous pregnancy
• Delivery at a non-network hospital
• At 36, 0 weeks to 36, 5 weeks and quota for 36 weeks already met. To ensure there is an adequate proportion of women presenting at 34 to 35 weeks of gestation, enrollment will be restricted so that no more than 50% of the women in the trial present at 36 weeks.

Sponsors & Collaborators

• The George Washington University Biostatistics Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (17)

University of Alabama - Birmingham

Birmingham, Alabama, 35233, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

University of Colorado

Denver, Colorado, 80045, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44109, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

University of Pittsburgh Magee Womens Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Brown University

Providence, Rhode Island, 02905, United States

Location

University of Texas - Southwest

Dallas, Texas, 75235, United States

Location

University of Texas - Galveston

Galveston, Texas, 77555, United States

Location

University of Texas - Houston

Houston, Texas, 77030, United States

Location

University of Utah Medical Center

Salt Lake City, Utah, 84132, United States

Location

Related Publications (26)

• Davidoff MJ, Dias T, Damus K, Russell R, Bettegowda VR, Dolan S, Schwarz RH, Green NS, Petrini J. Changes in the gestational age distribution among U.S. singleton births: impact on rates of late preterm birth, 1992 to 2002. Semin Perinatol. 2006 Feb;30(1):8-15. doi: 10.1053/j.semperi.2006.01.009.

  PMID: 16549207 BACKGROUND

• Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants: a summary of the workshop sponsored by the National Institute of Child Health and Human Development. Pediatrics. 2006 Sep;118(3):1207-14. doi: 10.1542/peds.2006-0018.

  PMID: 16951017 BACKGROUND

• Escobar GJ, Clark RH, Greene JD. Short-term outcomes of infants born at 35 and 36 weeks gestation: we need to ask more questions. Semin Perinatol. 2006 Feb;30(1):28-33. doi: 10.1053/j.semperi.2006.01.005.

  PMID: 16549211 BACKGROUND

• Hamilton BE, Ventura SJ, Martin JA, and Sutton PD. Preliminary births for 2004. Health E-stats. Hyattsville, MD: National Center for Health Statistics. Released October 28, 2005.

  BACKGROUND

• Buus-Frank ME. The great imposter. Adv Neonatal Care. 2005 Oct;5(5):233-6. doi: 10.1016/j.adnc.2005.08.012. No abstract available.

  PMID: 16202965 BACKGROUND

• Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics: 2004. Pediatrics. 2006 Jan;117(1):168-83. doi: 10.1542/peds.2005-2587.

  PMID: 16396875 BACKGROUND

• Dudell GG, Jain L. Hypoxic respiratory failure in the late preterm infant. Clin Perinatol. 2006 Dec;33(4):803-30; abstract viii-ix. doi: 10.1016/j.clp.2006.09.006.

  PMID: 17148006 BACKGROUND

• Laptook A, Jackson GL. Cold stress and hypoglycemia in the late preterm ("near-term") infant: impact on nursery of admission. Semin Perinatol. 2006 Feb;30(1):24-7. doi: 10.1053/j.semperi.2006.01.014.

  PMID: 16549210 BACKGROUND

• Neu J. Gastrointestinal maturation and feeding. Semin Perinatol. 2006 Apr;30(2):77-80. doi: 10.1053/j.semperi.2006.02.007.

  PMID: 16731281 BACKGROUND

• Bhutani VK, Johnson L. Kernicterus in late preterm infants cared for as term healthy infants. Semin Perinatol. 2006 Apr;30(2):89-97. doi: 10.1053/j.semperi.2006.04.001.

  PMID: 16731283 BACKGROUND

• Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008 Jul 17;359(3):262-73. doi: 10.1056/NEJMoa0706475.

  PMID: 18635431 BACKGROUND

• McIntire DD, Leveno KJ. Neonatal mortality and morbidity rates in late preterm births compared with births at term. Obstet Gynecol. 2008 Jan;111(1):35-41. doi: 10.1097/01.AOG.0000297311.33046.73.

  PMID: 18165390 BACKGROUND

• Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA. 2000 Aug 16;284(7):843-9. doi: 10.1001/jama.284.7.843.

  PMID: 10938173 BACKGROUND

• Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically significant behavior problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics. 2004 Sep;114(3):736-43. doi: 10.1542/peds.2003-1150-L.

  PMID: 15342847 BACKGROUND

• Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH, Henriksen TB. Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child. 2006 Aug;91(8):655-60. doi: 10.1136/adc.2005.088872. Epub 2006 Jun 5.

  PMID: 16754656 BACKGROUND

• Clark RH. The epidemiology of respiratory failure in neonates born at an estimated gestational age of 34 weeks or more. J Perinatol. 2005 Apr;25(4):251-7. doi: 10.1038/sj.jp.7211242.

  PMID: 15605071 BACKGROUND

• Stutchfield P, Whitaker R, Russell I; Antenatal Steroids for Term Elective Caesarean Section (ASTECS) Research Team. Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial. BMJ. 2005 Sep 24;331(7518):662. doi: 10.1136/bmj.38547.416493.06. Epub 2005 Aug 22.

  PMID: 16115831 BACKGROUND

• Rubaltelli FF, Dani C, Reali MF, Bertini G, Wiechmann L, Tangucci M, Spagnolo A. Acute neonatal respiratory distress in Italy: a one-year prospective study. Italian Group of Neonatal Pneumology. Acta Paediatr. 1998 Dec;87(12):1261-8. doi: 10.1080/080352598750030951.

  PMID: 9894827 BACKGROUND

• Yoder BA, Gordon MC, Barth WH Jr. Late-preterm birth: does the changing obstetric paradigm alter the epidemiology of respiratory complications? Obstet Gynecol. 2008 Apr;111(4):814-22. doi: 10.1097/AOG.0b013e31816499f4.

  PMID: 18378739 BACKGROUND

• Tita AT, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW, Moawad AH, Caritis SN, Meis PJ, Wapner RJ, Sorokin Y, Miodovnik M, Carpenter M, Peaceman AM, O'Sullivan MJ, Sibai BM, Langer O, Thorp JM, Ramin SM, Mercer BM; Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med. 2009 Jan 8;360(2):111-20. doi: 10.1056/NEJMoa0803267.

  PMID: 19129525 BACKGROUND

• Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics. 2004 Aug;114(2):372-6. doi: 10.1542/peds.114.2.372.

  PMID: 15286219 BACKGROUND

• Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, Barfield W, Weiss J, Evans S. Risk factors for neonatal morbidity and mortality among "healthy," late preterm newborns. Semin Perinatol. 2006 Apr;30(2):54-60. doi: 10.1053/j.semperi.2006.02.002.

  PMID: 16731277 BACKGROUND

• Tomashek KM, Shapiro-Mendoza CK, Weiss J, Kotelchuck M, Barfield W, Evans S, Naninni A, Declercq E. Early discharge among late preterm and term newborns and risk of neonatal morbidity. Semin Perinatol. 2006 Apr;30(2):61-8. doi: 10.1053/j.semperi.2006.02.003.

  PMID: 16731278 BACKGROUND

• Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, Rouse DJ, McKenna DS, Clark EA, Thorp JM Jr, Chien EK, Peaceman AM, Gibbs RS, Swamy GK, Norton ME, Casey BM, Caritis SN, Tolosa JE, Sorokin Y, VanDorsten JP, Jain L; NICHD Maternal-Fetal Medicine Units Network. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med. 2016 Apr 7;374(14):1311-20. doi: 10.1056/NEJMoa1516783. Epub 2016 Feb 4.

  PMID: 26842679 RESULT

• Laptook AR, Chalak L, Pappas A, Davis A, Sanchez PJ, Van Meurs KP, Oh W, Sommers R, Shankaran S, Hensman AM, Rouse DJ, McDonald S, Das A, Goldberg RN, Ambalavanan N, Gyamfi-Bannerman C, Thom EA, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN); Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. The effects of betamethasone on the amplitude integrated EEG of infants born at 34- or 35-weeks gestation. J Perinatol. 2022 Dec;42(12):1615-1621. doi: 10.1038/s41372-022-01415-4. Epub 2022 May 26.

  PMID: 35618748 DERIVED

• McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2020 Dec 25;12(12):CD004454. doi: 10.1002/14651858.CD004454.pub4.

  PMID: 33368142 DERIVED

Related Links

• (The public website of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units (MFMU) Network)

MeSH Terms

Conditions

Respiratory Distress Syndrome; Premature Birth

Interventions

Betamethasone; Adrenal Cortex Hormones

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Elizabeth Thom, Ph.D.
• Organization: The George Washington University Biostatistics Center

e_thom@bsc.gwu.edu

301-881-9260

Study Officials

• Monica Longo, MD

  NICHD Project Scientist

  STUDY DIRECTOR

• Rebecca Clifton, PhD

  George Washington University

  PRINCIPAL INVESTIGATOR

• Cynthia Gyamfi Bannerman, MD

  Columbia University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2010
• First Posted: October 18, 2010
• Study Start: October 1, 2010
• Primary Completion: March 1, 2015
• Study Completion: August 31, 2022
• Last Updated: March 28, 2023
• Results First Posted: January 30, 2019

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

US (17)