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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
Last Update Posted : January 10, 2018
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:

Infants born between 34 and 36 weeks of gestation, known as 'late preterm', are more likely to be admitted to a special care nursery, and more likely to suffer respiratory complications than infants born at term. The use of antenatal corticosteroids has been shown to improve lung function in very premature infants, but has not been evaluated in those likely to deliver in the late preterm period.

This research study will attempt to answer the following primary research question: Do steroids, compared to no steroids, decrease babies' need for oxygen support when given to pregnant women at least 12 to 24 hours before they deliver at 34 weeks to 36 weeks gestation? The research study will also collect information on whether steroids improve the chances that the baby will not get sick from other causes.


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

Detailed Description:

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

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
Primary Completion Date : March 2015
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Active Comparator: Betamethasone 3MG/ML
A course of two 2 mL intramuscular (IM) injections containing 12 mg of betamethasone, 24 hours apart
Drug: Betamethasone 3 MG/ML
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. 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. Maternal outcomes [ Time Frame: Delivery ]
    Chorioamnionitis, Postpartum endometritis, delivery prior to steroids completion, time in hours from initial dose to delivery, length of labor, mode of delivery, indication for delivery, length of stay

  2. Neonatal morbidity / mortality [ Time Frame: 72 hours of life ]
    Major respiratory morbidity: Continuous positive airway pressure (CPAP) or humidified high-flow nasal cannula (HHFNC) for greater than or equal to 12 hours or more in the first 72 hours, or FiO2 greater than or equal to 0.30 for 24 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

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

  5. Need for immediate resuscitation after birth [ Time Frame: Delivery ]
  6. Surfactant use [ Time Frame: Delivery ]
  7. Chronic lung disease (BPD) [ Time Frame: 28 days of life ]
    Infants requiring oxygen at 28 days of life

  8. Necrotizing enterocolitis (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.

  9. 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

  10. Birth weight [ Time Frame: Delivery ]
  11. Hypoglycemia [ Time Frame: Delivery ]
    Glucose < 40 mg%

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

  13. Feeding difficulty [ Time Frame: Delivery ]
    Inability to take all feeds (po), i.e. requiring gavage feeds or IV supplementation. In addition, time to first feed (po) will be recorded.

  14. Hypothermia [ Time Frame: Delivery ]
    Rectal temperature < 36 C

  15. Neonatal infectious morbidity [ Time Frame: Delivery ]
    • Sepsis (within 72hrs and > 72 hrs after birth) OR
    • Suspected sepsis OR
    • Pneumonia

  16. Seizures / encephalopathy [ Time Frame: Delivery ]
  17. Length of hospital stay [ Time Frame: Discharge from hospital ]
    Includes need for NICU or intermediate care admission and length of stay if admitted



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, Senior
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 34,0weeks 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.
  12. No ultrasound < 20 weeks for unsure last menstrual period (LMP). If the patient has an unsure LMP but she had no dating ultrasound before 20 weeks by ultrasound parameters, she is excluded.
  13. No ultrasound < 24 weeks for sure LMP. If the patient has an sure LMP but she had no dating ultrasound before 24 weeks by ultrasound parameters, she is excluded
  14. Multifetal gestation. Exclude if current multifetal gestation or a single gestation resulting from a reduction of a multiple of higher order than twins

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: Uma Reddy, MD, MPH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Principal Investigator: Elizabeth Thom, PhD George Washington University
Study Chair: Cynthia Gyamfi Bannerman, MD Columbia University

Additional Information:
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
Last Update Posted: January 10, 2018
Last Verified: January 2018
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.

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

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
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