Clinical trial NCT01222247: Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
Official title: Antenatal Late Preterm Steroids (ALPS): A Randomized Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pregnancy
Respiratory Distress Syndrome
Pregnancy Outcomes
Preterm Birth
Keywords: Betamethasone
Steroids
Perinatology
Late Preterm
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2010-10-18
Enrollment: 2831
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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

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.

Eligibility 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.

Primary outcomes:
measure: Neonatal Composite Outcome
timeFrame: 72 hours of life
Secondary outcomes:
measure: Number of Neonates With Severe Respiratory Complication,
timeFrame: 72 hours of life
measure: Neonates Needing Immediate Resuscitation After Birth
timeFrame: Within the first 30 minutes of birth
measure: Number of Neonates With Respiratory Distress Syndrome
timeFrame: Delivery
measure: Number of Neonates With Transient Tachypnea of the Newborn
timeFrame: by 72 hours after delivery
measure: Number of Infants With Neonatal Apnea
timeFrame: 72 hours of life
measure: Number of Infants withChronic Lung Disease / Bronchopulmonary Dysplasia (BPD) Requiring Supplemental Oxygen
timeFrame: 28 days of life
measure: Neonates With Pneumonia
timeFrame: by 72 hours of life
measure: Number of Neonates Needing Surfactant Administration
timeFrame: Delivery
measure: Neonatal Outcome Composite
timeFrame: 72 hours of life
measure: Number of Neonates With Pulmonary Air Leak
timeFrame: 72 hours post delivery
measure: Neonatal Death After 72 Hours of Delivery
timeFrame: 72 hours after delivery through hospital discharge up to 3 weeks
measure: Birth Weight
timeFrame: Delivery
measure: Birth Weight Less Than 10th Percentile
timeFrame: Delivery
measure: Gestational Age at Delivery
timeFrame: Delivery
measure: Number of Neonates With Necrotizing Enterocolitic (NEC)
timeFrame: Delivery
measure: Number of Infants With Neonatal Sepsis
timeFrame: Delivery
measure: Number of Neonates With Intraventricular Hemorrhage
timeFrame: Delivery
measure: Neonatal Morbidity Composite
timeFrame: Delivery
measure: Number of Neonates With Hypoglycemia
timeFrame: Delivery through hospital discharge up to 3 weeks
measure: Time Until First Neonatal Feeding
timeFrame: Delivery to 36 hours post delivery
measure: Neonatal Feeding Difficulty
timeFrame: Delivery to 36 hours post delivery
measure: Neonatal Hyperbilirubinemia
timeFrame: Delivery
measure: Number of Neonates With Hypothermia
timeFrame: Delivery through discharge up to 3 weeks
measure: Length of NICU or Nursery Stay
timeFrame: Delivery through hospital discharge up to 3 weeks
measure: Median Length of Hospital Stay
timeFrame: Duration of hospital stay following delivery up to 2 weeks
measure: Maternal Outcomes (Participant-based)
timeFrame: Labor and delivery through 72 hours post partum
measure: Hours From Randomization to Delivery
timeFrame: Randomization through delivery
measure: Median Length of Maternal Hospital Stay
timeFrame: Delivery through hospital discharge
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Magee Womens Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Brown University
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas - Southwest
state: Texas
city: Galveston
country: United States
facility: University of Texas - Galveston
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Medical Center
state: Utah
Study officials:
affiliation: NICHD Project Scientist
name: Monica Longo, MD
role: STUDY_DIRECTOR
affiliation: George Washington University
name: Rebecca Clifton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Cynthia Gyamfi Bannerman, MD
role: STUDY_CHAIR
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