Clinical trial NCT06980025: Aspirin Dose Escalation for the Prevention of Recurrent Preterm Delivery Trial
Official title: A Dose Escalation Study of Low Dose Aspirin for the Prevention of Recurrent Preterm Birth
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Preterm Delivery
Obstetrical Complications
Keywords: Preterm Delivery
Stillbirth
Maternal Morbidity
Neonatal Morbidity
Prevention
Lead sponsor: The George Washington University Biostatistics Center
Sponsor class: OTHER
Collaborators: name: Columbia University
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2025-05-20
Enrollment: 1800
Sex: FEMALE
Minimum age (years): 14
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Individuals will be randomized between 10 weeks, 0 days gestation and 15 weeks, 6 days gestation to either aspirin 162 mg or aspirin 81 mg daily and continue the study intervention through 36 weeks, 6 days gestation. Randomization will be stratified by clinical site.
Primary purpose: PREVENTION

Brief summary: This is a phase-III multi-center double-blind randomized clinical trial of 1,800 individuals with a history of prior preterm birth at less than 35 weeks gestation who are randomized to either 162 mg aspirin or 81 mg aspirin daily. The study drug will be initiated between 10 and 15 weeks gestation and continued through 36 weeks, 6 days gestation. The primary endpoint is recurrent preterm delivery or fetal death prior to 35 weeks, 0 days gestation.

Detailed description: This is a phase-III multi-center double-blind randomized clinical trial of 1,800 individuals with a history of prior preterm birth at less than 35 weeks gestation who are randomized to either 162 mg aspirin or 81 mg aspirin daily.

The primary objective is to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing recurrent preterm delivery or fetal death before 35 weeks, 0 days gestation in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with spontaneous preterm delivery (sPTB), ischemic placental disease (IPD), or stillbirth. Ischemic placental disease includes small for gestational age, preeclampsia, or placental abruption.

The secondary objective is to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing ischemic placental disease in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with sPTB, IPD, or stillbirth.

Tertiary /Exploratory objectives are 1) to assess the efficacy of daily 162 mg of aspirin compared to 81 mg aspirin in reducing adverse maternal and neonatal outcomes, and 2) to assess maternal and neonatal safety in individuals with a proximal birth between 20 weeks, 0 days and 34 weeks, 6 days gestation with sPTB, IPD, or stillbirth.

Individuals will be randomized between 10 and 15 weeks gestation to either 162mg or 81mg of aspirin daily and continue the study intervention through 36 weeks, 6 days gestation. Participants will have monthly virtual or in-person visits through 37 weeks gestation to assess study intervention compliance, side effects, medication use, and unscheduled hospitalization. Maternal blood will be collected in a subset of the population. Research staff will abstract maternal and neonatal outcomes following delivery and discharge from the hospital.

Eligibility criteria: Inclusion Criteria:

* 14 years or older
* Singleton gestation. Twin gestation reduced to a singleton, either spontaneously or therapeutically, is not eligible unless the reduction occurred before 13 weeks 6 days project gestational age. Higher-order multifetal gestations reduced to singletons are not eligible.
* Gestational age at randomization between 10 weeks 0 days and 15 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
* Prior preterm birth between 20 weeks 0 days and 34 weeks 6 days with one of the following in the proximal birth reaching 20 weeks or greater:

  * Spontaneous preterm birth is defined as spontaneous preterm labor or premature rupture of membranes
  * Ischemic placental disease is defined as preeclampsia, small for gestational age, fetal growth restriction, or placental abruption, as defined clinically.
  * Stillbirth excluding those with known genetic disorders or major congenital anomalies.

Exclusion Criteria:

* Known allergy or hypersensitivity to aspirin or any medical condition where aspirin is contraindicated (e.g., history of peptic ulcer disease, nasal polyps, NSAID-induced asthma, history of gastrointestinal bleeding, known G6PD deficiency, severe hepatic dysfunction, bleeding disorders, and consumption of 3 or more alcoholic drinks per day)
* Taking other anticoagulants such as Heparin or Low-Molecular weight Heparin
* Thrombocytopenia defined as a platelet count defined as a platelet count \<100,000 microliters
* Gastric bypass surgery, regardless of type
* Aspirin use \>81 mg daily during the current pregnancy who are not willing or able to go through a 2-week washout before randomization.
* Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or uterine septum not resected) due to increased risk of preterm delivery.
* Known fetal genetic disease or major malformations
* Fetal demise or planned termination of pregnancy. Selective reduction by 13 weeks 6 days gestation, from twins to singleton, is not an exclusion.
* Any fetal/maternal condition requiring invasive in-utero assessment or treatment, for example, significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia.
* Patients with any of the following medical conditions because of increased risk for adverse pregnancy outcome or indicated preterm birth:

  * Treated hypertension requiring more than one agent
  * Chronic renal disease with baseline serum creatinine ≥1.5 mg/dL
  * Conditions treated with chronic oral glucocorticoid therapy (e.g., systemic lupus erythematosus)
  * Uncontrolled hyper- and hypothyroid disease
  * New York Heart Association (NYHA) stage II or greater cardiac disease
* Planned indicated delivery prior to 37 weeks.
* Participation in another interventional study that influences the primary outcome in this study (gestational age at delivery).
* Participation in this trial in a previous pregnancy.
* Delivery planned at a non-participating site

Primary outcomes:
measure: Rate of recurrent preterm delivery or fetal death prior to 35 weeks 0 days gestation
timeFrame: Between randomization and 35 weeks, 0 days gestation (a period of up to 25 weeks)
Secondary outcomes:
measure: Rate of ischemic placental disease
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
Other outcomes:
measure: Rate of recurrent preterm delivery or fetal death at <28 weeks
timeFrame: Between randomization and delivery (a period of up to 18 weeks)
measure: Rate of recurrent preterm delivery or fetal death at <37 weeks
timeFrame: Between randomization and delivery (a period of up to 27 weeks)
measure: Rate of ischemic placental disease with delivery prior to 28 weeks
timeFrame: Between randomization and delivery (a period of up to 18 weeks)
measure: Rate of ischemic placental disease with delivery prior to 35 weeks
timeFrame: Between randomization and delivery (a period of up to 25 weeks)
measure: Rate of Ischemic Placental Disease with Delivery Prior to 37 weeks
timeFrame: Between randomization and delivery (a period of up to 27 weeks)
measure: Rate of preeclampsia
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of preeclampsia with severe features
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of placental abruption
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Number of emergency room visits or hospitalizations
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Number of days between randomization and delivery or fetal death
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of stillbirth
timeFrame: Between 20 weeks gestation and delivery (a period of up to 22 weeks)
measure: Rate of small for gestational age at less than 5th percentile
timeFrame: At delivery
measure: Rate of small for gestational age at less than 10th Percentile
timeFrame: At delivery
measure: Rate of neonatal death
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal intensive care unit (NICU) admission
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Neonatal Length of Hospital Stay
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal ventilator or continuous positive airway pressure (CPAP use
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal oxygen use
timeFrame: Between delivery and 72 hours post birth
measure: Rate of neonatal seizure
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal hyperbilirubinemia
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal infectious morbidity
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of perinatal composite outcome
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of minor bleeding
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of thrombocytopenia
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of aspirin allergy
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of gastric ulcer disease
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of persistent epistaxis
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of clinically meaningful bleeding
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Estimated blood loss
timeFrame: Delivery
measure: Rate of estimated blood loss greater than 1000ml
timeFrame: Delivery
measure: Rate of transfusion of packed red blood cells
timeFrame: Between delivery admission and hospital discharge (a period of up to 120 days)
measure: Rate of cesarean hysterectomy
timeFrame: Delivery
measure: Rate of intensive care unit (ICU) admission
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of intracranial hemorrhage
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of congenital malformation
timeFrame: Between randomization and hospital discharge (a period of up to 49 weeks)
measure: Rate of oligohydramnios
timeFrame: Between randomization and delivery (a period of up to 32 weeks)
measure: Rate of neonatal primary pulmonary hypertension
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
measure: Rate of neonatal intracranial hemorrhage
timeFrame: Between delivery and hospital discharge (a period of up to 120 days)
Locations:
city: Birmingham
country: United States
facility: University of Alabama - Birmingham
state: Alabama
city: San Francisco
country: United States
facility: Regents of the University of California San Francisco
state: California
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
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: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Magee Women's Hospital of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Brown Univeristy
state: Rhode Island
city: Houston
country: United States
facility: Baylor College of Medicine
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: The George Washington University Biostatistics Center
name: Rebecca G Clifton, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: ChristianaCare Center for Women & Children's Health Research
name: Matthew K Hoffman, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Columbia University
name: Uma M Reddy, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Robert Wood Johnson Medical School - Rutgers Health
name: Cande Ananth, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
References: