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

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ClinicalTrials.gov Identifier: NCT01222247
Recruitment Status : Active, not recruiting
First Posted : October 18, 2010
Results First Posted : January 30, 2019
Last Update Posted : February 21, 2019
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
The George Washington University Biostatistics Center

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

Condition or disease Intervention/treatment Phase
Pregnancy Respiratory Distress Syndrome Pregnancy Outcomes Preterm Birth Drug: Betamethasone Drug: Placebo Phase 3

Detailed Description:

The rate of preterm birth has steadily increased in the United States over the past 10 years. This increase is driven in part by the rising rate of late preterm birth, defined as those births occurring between 34 and 36 weeks. Late preterm infants experience a higher rate of readmission than their term counterparts, and these infants are more likely to suffer complications such as respiratory distress, kernicterus, feeding difficulties, and hypoglycemia. Late preterm infants also have a higher mortality for all causes when compared to term infants. 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. If shown to reduce the need for respiratory support and thus to decrease the rate of special care nursery admissions and improve short-term outcomes, the public health and economic impact will be considerate.This protocol describes a randomized placebo controlled trial to evaluate whether antenatal corticosteroids can decrease the rate of neonatal respiratory support, thus decreasing the rate of neonatal intensive care unit (NICU) admissions and improving short-term outcomes in the late preterm infant.

Two follow-up studies will be conducted concurrently. The first follow-up study will examine if the positive effects of betamethasone on lung function will persist in children at 6 years of age of mothers randomized to betamethasone with an expected late preterm delivery. Neonatal respiratory morbidity is associated with an increased risk of adverse childhood respiratory disease. Thus it is quite plausible that the effect of betamethasone, in reducing neonatal morbidity, particularly TTN, will translate into improved respiratory morbidity in early childhood.The primary outcome is childhood respiratory disease defined by a composite outcome of abnormal pulmonary function test (PFT) measured by spirometry, physician diagnosis of asthma, or other respiratory illnesses with medication.

The second follow-up study will examine whether late preterm antenatal betamethasone treatment is associated with long-term neurocognitive functioning, and whether there are any long-term consequences of what is believed to be transient neonatal hypoglycemia. Cognitive function will be measured by the Differential Ability Scales 2nd Edition (DAS-II) core components of the general conceptual ability (GCA) that includes verbal ability, non-verbal reasoning ability and spatial ability. The primary outcome is defined as a GCA score of <85 (1 standard deviation below the mean) at 6 years of age or greater.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2831 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
Study Start Date : October 2010
Actual Primary Completion Date : March 2015
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Active Comparator: Betamethasone
A course of two 2mL intramuscular (IM) injections containing 3 mg of betamethasone, 24 hours apart
Drug: Betamethasone
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.
Other Name: Corticosteroid

Placebo Comparator: Placebo
A similar course of an identical appearing placebo: two 2 mL IM injections of placebo, 24 hours apart
Drug: Placebo
Similar course of identical appearing placebo: 2 mL IM injections, 24 hours apart.




Primary Outcome Measures :
  1. Neonatal Composite Outcome [ Time Frame: 72 hours of life ]
    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


Secondary Outcome Measures :
  1. Number of Neonates With Severe Respiratory Complication, [ Time Frame: 72 hours of life ]
    A severe respiratory complication was defined as any of the following occurrences within 72 hours after birth: CPAP or high-flow nasal cannula for at least 12 hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more for at least 24 hours, mechanical ventilation, stillbirth or neonatal death, or the need for ECMO. Except for the duration of CPAP or high-flow nasal cannula and the duration of a fraction of inspired oxygen of 0.30 or more, the criteria for a severe respiratory complication overlap with those of the primary outcome.

  2. Neonates Needing Immediate Resuscitation After Birth [ Time Frame: Within the first 30 minutes of birth ]
    Need for resuscitation after birth: any intervention in the first 30 minutes other than blow-by oxygen

  3. Number of Neonates With Respiratory Distress Syndrome [ Time Frame: Delivery ]
    Respiratory distress defined as the presence of clinical signs of respiratory distress (tachypnea, retractions, flaring, grunting, or cyanosis) with an oxygen requirement and a chest x-ray that shows hypoaeration and reticulogranular infiltrates

  4. Number of Neonates With Transient Tachypnea of the Newborn [ Time Frame: by 72 hours after delivery ]
    TTN is defined as signs of respiratory distress, specifically tachypnea, that are resolved by 72 hours of age. TTN may be diagnosed in the absence of a chest X-ray or with a chest X-ray that is normal or shows signs of increased perihilar interstitial markings

  5. Number of Infants With Neonatal Apnea [ Time Frame: 72 hours of life ]
    Neonatal apnea with respiratory pauses of more than 20 seconds duration resulting in bradycardia or oxygen desaturation below baseline.

  6. Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen [ Time Frame: 28 days of life ]
    Infants requiring supplemental oxygen of more than 0.21 for the first 28 days of life

  7. Neonates With Pneumonia [ Time Frame: by 72 hours of life ]
    Neonatal pneumonia

  8. Number of Neonates Needing Surfactant Administration [ Time Frame: Delivery ]
    Administration of surfactant for neonatal respiratory treatment

  9. Neonatal Outcome Composite [ Time Frame: 72 hours of life ]
    Transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), and apnea

  10. Number of Neonates With Pulmonary Air Leak [ Time Frame: 72 hours post delivery ]
    Neonatal pulmonary air leak syndrome

  11. Neonatal Death After 72 Hours of Delivery [ Time Frame: 72 hours after delivery through hospital discharge up to 3 weeks ]
    Neonatal death after 72 hours of life but before hospital discharge.

  12. Birth Weight [ Time Frame: Delivery ]
    Weight in grams at delivery

  13. Birth Weight Less Than 10th Percentile [ Time Frame: Delivery ]
    Neonates whose birth weight is less than the 10th percentile at delivery

  14. Gestational Age at Delivery [ Time Frame: Delivery ]
    Number of neonates delivered at ≤ 34 weeks 6 days, between 35 weeks 0 days and 35 weeks 6 days, between 36 weeks 0 days and 36 weeks 6 days, between 37 weeks 0 days and 38 weeks 6 days, or on or after 39 weeks 0 days

  15. Number of Neonates With Necrotizing Enterocolitic (NEC) [ Time Frame: Delivery ]
    Defined as modified Bell Stage 2 or 3. Stage 2: Clinical signs and symptoms with pneumatosis intestinalis on radiographs. Stage 3: Advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation.

  16. Number of Infants With Neonatal Sepsis [ Time Frame: Delivery ]
    Clinical suspicion of systemic infection with a positive blood, cerebral spinal fluid, or catheterized/suprapubic urine culture; or, in the absence of positive cultures, clinical evience of cardiovascular collapse or an X-ray confirming infection.

  17. Number of Neonates With Intraventricular Hemorrhage [ Time Frame: Delivery ]
    Grade 3 or 4 Intraventricular Hemorrhage

  18. Neonatal Morbidity Composite [ Time Frame: Delivery ]
    A composite endpoint of morbidities known to be affected by steroid administration will also be evaluated. Specifically, this composite will include RDS, intraventricular hemorrhage (IVH), and NEC

  19. Number of Neonates With Hypoglycemia [ Time Frame: Delivery through hospital discharge up to 3 weeks ]
    Glucose < 40 mg per deciliter (2.2 mmol per liter) at any time

  20. Time Until First Neonatal Feeding [ Time Frame: Delivery to 36 hours post delivery ]
    Median length of time from delivery until the first neonatal feeding

  21. Neonatal Feeding Difficulty [ Time Frame: Delivery to 36 hours post delivery ]
    Inability of the neonate to take all feeds (po), i.e. requiring gavage feeds or IV supplementation.

  22. Neonatal Hyperbilirubinemia [ Time Frame: Delivery ]
    Peak total bilirubin of at least 15 mg% or the use of phototherapy.

  23. Number of Neonates With Hypothermia [ Time Frame: Delivery through discharge up to 3 weeks ]
    Rectal temperature < 36 C at any time

  24. Length of NICU or Nursery Stay [ Time Frame: Delivery through hospital discharge up to 3 weeks ]
    Includes need for NICU or intermediate care admission and length of stay if admitted. For analysis purposes, death before discharge is assigned maximum rank

  25. Median Length of Hospital Stay [ Time Frame: Duration of hospital stay following delivery up to 2 weeks ]
    Median length of maternal hospital stay following delivery

  26. Maternal Outcomes (Participant-based) [ Time Frame: Labor and delivery through 72 hours post partum ]
    Chorioamnionitis: clinical diagnosis and a body temperature of at least 100.4 degrees F., Endometritis: persistent postpartum temperature greater than 100.4 degrees F with uterine tenderness, cesarean delivery

  27. Hours From Randomization to Delivery [ Time Frame: Randomization through delivery ]
    Median interval of hours from randomization to delivery

  28. Median Length of Maternal Hospital Stay [ Time Frame: Delivery through hospital discharge ]
    Median length of maternal hospital stay in days



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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

or

  • 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

or

  • 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

Exclusion Criteria:

  1. Any prior antenatal corticosteroid course during the pregnancy because of potential contamination of the placebo group
  2. Candidate for stress dose corticosteroids because of chronic steroid therapy to prevent suppression of adrenal gland, because of potential contamination of the placebo group
  3. Twin gestation reduced to a singleton gestation at or after 14 weeks 0 days by project gestational age either spontaneously or therapeutically
  4. Fetal demise, or known major fetal anomaly, including cardiac anomaly and hydrops
  5. 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
  6. Pre-gestational diabetes - exclude if the patient was on medication (insulin, glyburide) prior to pregnancy
  7. 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

  8. Participation in another interventional study that influences neonatal morbidity and mortality
  9. Participation in this trial in a previous pregnancy
  10. Delivery at a non-network hospital
  11. 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.

Information from the National Library of Medicine

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): NCT01222247


Locations
United States, Alabama
University of Alabama - Birmingham
Birmingham, Alabama, United States, 35233
United States, California
Stanford University
Stanford, California, United States, 94305
United States, Colorado
University of Colorado
Denver, Colorado, United States, 80045
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, New York
Columbia University
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599
Duke University
Durham, North Carolina, United States, 27710
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44109
Ohio State University
Columbus, Ohio, United States, 43210
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
University of Pittsburgh Magee Womens Hospital
Pittsburgh, Pennsylvania, United States, 15213
United States, Rhode Island
Brown University
Providence, Rhode Island, United States, 02905
United States, Texas
University of Texas - Southwest
Dallas, Texas, United States, 75235
University of Texas - Galveston
Galveston, Texas, United States, 77555
University of Texas - Houston
Houston, Texas, United States, 77030
United States, Utah
University of Utah Medical Center
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
The George Washington University Biostatistics Center
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
Study Director: Menachem Miodovnik, MD NICHD Project Scientist
Principal Investigator: Rebecca Clifton, PhD George Washington University
Study Chair: Cynthia Gyamfi Bannerman, MD Columbia University

Additional Information:
Publications of Results:
Other Publications:
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.

Responsible Party: The George Washington University Biostatistics Center
ClinicalTrials.gov Identifier: NCT01222247     History of Changes
Other Study ID Numbers: HL98354-HD36801-ALPS
U10HD021410 ( U.S. NIH Grant/Contract )
U10HD027869 ( U.S. NIH Grant/Contract )
U10HD027917 ( U.S. NIH Grant/Contract )
U10HD053118 ( U.S. NIH Grant/Contract )
U10HD027915 ( U.S. NIH Grant/Contract )
U10HD034116 ( U.S. NIH Grant/Contract )
U10HD034208 ( U.S. NIH Grant/Contract )
U10HD053097 ( U.S. NIH Grant/Contract )
U10HD040500 ( U.S. NIH Grant/Contract )
U10HD040485 ( U.S. NIH Grant/Contract )
U10HD040544 ( U.S. NIH Grant/Contract )
U10HD040545 ( U.S. NIH Grant/Contract )
U10HD040560 ( U.S. NIH Grant/Contract )
U10HD040512 ( U.S. NIH Grant/Contract )
U01HD036801 ( U.S. NIH Grant/Contract )
U01HL098354 ( U.S. NIH Grant/Contract )
First Posted: October 18, 2010    Key Record Dates
Results First Posted: January 30, 2019
Last Update Posted: February 21, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared after completion and publication of the main analyses per NIH policy. Requests can be sent to mfmudatasets@bsc.gwu.edu.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by The George Washington University Biostatistics Center:
Betamethasone
Steroids
Perinatology
Late Preterm

Additional relevant MeSH terms:
Premature Birth
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Betamethasone benzoate
Betamethasone-17,21-dipropionate
Betamethasone
Betamethasone Valerate
Betamethasone sodium phosphate
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents