Clinical trial NCT06249178: EV Based Platform for Monitoring Therapeutics Response During Pregnancy (ARISE)
Official title: Developing Extracellular Vesicle Based MPRINT Translational Resource Platform for Monitoring Therapeutics Response During Pregnancy
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Preeclampsia
Keywords: Extracellular vesicles proteome profile
Aspirin treatment
Pregnancy
Preeclampsia
Lead sponsor: Ohio State University
Sponsor class: OTHER
Collaborators: name: University of Texas
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2024-02-08
Enrollment: 1000
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Pregnant women greater than 18 years of age at risk of preeclampsia (PE), receiving aspirin to prevent PE or a candidate to receive aspirin.

Brief summary: The goal of this prospective observational cohort study of pregnant people at-risk of preeclampsia receiving aspirin as part of clinical care or a planned randomized controlled trial of 81mg vs. 162mg of aspirin is to generate proteomic data to show a distinct maternal and fetal Extracellular Vesicle (EV) proteome profile with aspirin treatment, and develop and validate a multi-marker panel for the monitoring of placental function in people at-risk of Preeclampsia and in response to aspirin treatment. The primary research question is:

1. Does the maternal and fetal Positive for Placental Alkaline Phosphatase (PLAP+) Extracellular Vesicle (EV) proteome profile in the 2nd and 3rd trimester of pregnancy differ between people who receive aspirin and develop (or not) preeclampsia?

Participants will be asked to give blood samples up to four times during and at the end of their pregnancy.

Detailed description: Pregnant and lactating people remain therapeutic orphans as they are excluded from the vast majority of clinical drug development and therapeutic trials. Moreover, current practices in drug evaluation in pregnancy have been hindered by the lack of effective biomarkers and innovative study designs. There is a need to develop novel placental-specific biomarkers in order to assess placental function and response to therapeutics, as a way to inform on their safety and efficacy. An example of these novel biomarkers is placental (fetal) specific extracellular vesicles (EVs). Recent advances in characterizing the cargo content of these EVs demonstrated their potential to be used as placental biomarkers. Fourteen proteins found in EVs significantly correlated with aspirin use (FDR\<0.1) in at-risk people, but that more power is needed to confidently assess the relationship with aspirin dosage and pregnancy outcomes. In addition, prior studies showed that aspirin affects endothelial and trophoblast cells, thus potentially modulating exosome derived from these cells and their cargo contents.

The main goal is to develop a novel platform using exosome profiling, as novel biomarkers, to monitor placental mediated adverse pregnancy outcomes and response to therapeutics.

Specific Aim 1: Develop and validate a multi-marker panel/Extracellular Vesicle (EV) proteome profile (maternal and fetal) for monitoring of placental function in people at-risk of Preeclampsia (PE) and in response to aspirin treatment.

Specific Aim 2: Demonstrate that maternal and fetal Positive for Placental Alkaline Phosphatase (PLAP+) EV proteome profile in the 2nd and 3rd trimester of pregnancy differ between people who develop (or not) preeclampsia and correlate with aspirin dose and salicylic acid concentrations.

Specific Aim 3: Demonstrate that the changes in maternal and fetal EV proteome profiles (baseline to 2nd-3rd trimester) correlate with the changes in inflammatory and angiogenic imbalance profiles associated with PE, and with other clinical outcomes such as Preterm Birth (PTB) and Fetal Growth Restriction (FGR).

Eligibility criteria: Inclusion Criteria:

Participants will be eligible to participate if they meet the following study inclusion criteria:

1. pregnant individuals age ≥18 years
2. enrolled ≤16M6/7 weeks of gestation based on the best obstetric estimate as defined by ACOG criteria
3. singleton live intrauterine gestation
4. Any of the following:

   1. At least one of the high-risk criteria for HDP (per US Preventive Services Task Force Recommendation Statement \[USPSTF\]); i) any prior pregnancy complicated by Preeclampsia ii) current pregnancy complicated by chronic hypertension diagnosed before randomization iii) chronic kidney disease iv) autoimmune disease (e.g., antiphospholipid syndrome, lupus)
   2. Two or more moderate-risk criteria for HDP (per USPSTF); i) nulliparity (no prior delivery at or after 20 weeks 0 days of gestation) ii) obesity (body mass index ≥30 kg/m2 at time of enrollment) iii) age ≥35 years (at time of expected estimated due date) iv) sociodemographic characteristics (Black race, government-assisted insurance) v) Personal risk factors (previous pregnancy with low birth weight or SGA infant, previous adverse pregnancy outcome \[unexplained stillbirth\], placental abruption, interval \>10 years between pregnancies).
   3. or participating in another clinical RCT of 81mg vs. 162mg aspirin for prevention of hypertensive disorders of pregnancy

Exclusion Criteria:

1. age \< 18 years,
2. involuntarily confined or detained
3. considered as having a diminished decision-making capacity
4. multifetal gestation
5. pregestational diabetes mellitus or gestational diabetes diagnosed \< 20 weeks due to the impact on exosome response
6. known or suspected fetal aneuploidy or major congenital abnormality, fetal demise, or planned pregnancy termination
7. known allergy or hypersensitivity to aspirin or any medical condition where aspirin is contraindicated (e.g., peptic ulcer disease, nasal polyps, NSAID-induced asthma, gastrointestinal bleeding, G6PD deficiency, severe hepatic dysfunction, bleeding disorders)
8. plan to deliver at another center or participating in another intervention study that influences the primary outcome in this study, without prior approval

Primary outcomes:
measure: multi-marker panel
timeFrame: From enrollment till delivery; up to 29 weeks
Secondary outcomes:
measure: Preeclampsia
timeFrame: From enrollment to deliver; up to 29 weeks
measure: Preterm birth < 37 weeks gestation
timeFrame: From enrollment to deliver; up to 25 weeks
measure: Preterm birth < 34 weeks gestation
timeFrame: From enrollment to deliver; up to 22 weeks
measure: Preeclampsia with severe features
timeFrame: From enrollment to deliver; up to 29 weeks
measure: Gestational hypertension
timeFrame: From enrollment to deliver, up to 29 weeks
measure: Fetal growth restriction
timeFrame: From enrollment to deliver; up to 29 weeks
measure: Birthweight
timeFrame: at delivery
measure: PlGF
timeFrame: 28 to 41 weeks
measure: sFLT-1
timeFrame: 28 to 41 weeks
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center OB/GYN Maternal and Fetal Medicine
state: Ohio
Study officials:
affiliation: Ohio State University
name: Maged Costantine, MD, MBA
role: PRINCIPAL_INVESTIGATOR
References: