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Endothelial dysfunction and defective placental vascularization are hypothesized to be significant causes of preeclampsia. In preeclampsia, due to vascular endothelial dysfunction, vasoconstriction and platelet activation can result in severe features which alter pregnancy outcomes. However, studies have shown that acetylsalicylic acid (Aspirin) can decrease endothelial dysfunction leading to decreased platelet aggregation which reduces adverse outcomes. The objective of our study is to determine if Aspirin has a dose-dependent response for modifying biomarkers reflective of maternal endothelial dysfunction when indicated for preeclampsia prevention in a cohort of women identified at risk for developing preeclampsia.
Pregnant women who are at risk for preeclampsia will be randomized to receive either 81mg Aspirin or 162mg Aspirin daily starting from 11-16 weeks of gestation until 36 weeks of gestation. A third, control group of women at low risk for preeclampsia will not receive aspirin. All women will be assessed with uterine artery Doppler studies and mean arterial blood pressures at three time points during pregnancy. Blood, urine, and cord blood samples will also be collected.
Eligible women will be identified in the late first or early second trimesters. Once recruited, women will be randomly assigned to either 81 mg or 162 mg per day dosing schedules. The randomization scheme will vary based on the body mass index (BMI) with separate schemes for women <=30 kg/m2 versus >30 kg/m2. Ultrasonographic assessment of biophysical biomarkers will be obtained at 11-16 weeks, 18-22 weeks, and 28-32 weeks gestation. Biologic samples of serum and urine will be obtained at the 11-16 week and 28-32 week visit. Upon delivery, cord blood and a placental specimen will also be obtained. Medication treatment will continue until 36 weeks gestation. Pregnancy and neonatal outcome data will be recorded.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control Group | Active Comparator | Patients will receive standard of care. |
|
| Acetylsalicylic Acid 81mg | Experimental | Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). |
|
| Acetylsalicylic Acid 162mg | Experimental | Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetylsalicylic Acid 81 mg | Drug | Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Pulsatility Index (PI) | Uterine artery doppler is used to assess impedance to flow in the uterine artery three times: 11-16 weeks gestation(baseline), 18-22 weeks gestation (event 2), 28-32 weeks gestation (event 3). Data reported as change between 11-16 weeks gestation (baseline) and either 18-22 weeks gestation (event 2) or 28-32 weeks gestation (event 3). difference in uterine artery pulsatility index (PI) is calculated as the difference in PI for each patient between each trimester visit. PI at each visit will be calculated by averaging left-side and right-side PIs from each of three (or all available) images on each side for each patient using ultrasound technology. Unit of measure is a ratio: difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity Relative change in uterine artery pulsatility index is a measure of flow to the uterus. A greater difference from the baseline value represents a greater improvement in placental perfusion. | Three times between 11 and 32 weeks of gestation. |
| Measure | Description | Time Frame |
|---|---|---|
| Onset of Pre-eclampsia | Frequency of Disease during pregnancy and postpartum as defined by American College of Obstetrics and Gynecology (ACOG) criteria | From enrollment at 11 weeks throughout pregnancy and postpartum ( 6 weeks after delivery), approximately 35 weeks |
| Severity of Pre-eclampsia |
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Inclusion Criteria (control)
• No risk factors for preeclampsia
Inclusion Criteria (pre-eclampsia)
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| John M O'Brien, MD | University of Kentucky | Principal Investigator |
| Katherine Vignes, MD | University of Kentucky | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Kentucky | Lexington | Kentucky | 40536 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28657417 | Background | Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28. | |
| 17512048 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Control Group | Patients will receive standard of care. Control: Standard of Care |
| FG001 | Acetylsalicylic Acid 81mg | Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 81 mg: Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
| FG002 | Acetylsalicylic Acid 162mg | Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 162 mg: Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | Control Group | Patients will receive standard of care. Control: Standard of Care |
| BG001 | Acetylsalicylic Acid 81mg | Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 81 mg: Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Pulsatility Index (PI) | Uterine artery doppler is used to assess impedance to flow in the uterine artery three times: 11-16 weeks gestation(baseline), 18-22 weeks gestation (event 2), 28-32 weeks gestation (event 3). Data reported as change between 11-16 weeks gestation (baseline) and either 18-22 weeks gestation (event 2) or 28-32 weeks gestation (event 3). difference in uterine artery pulsatility index (PI) is calculated as the difference in PI for each patient between each trimester visit. PI at each visit will be calculated by averaging left-side and right-side PIs from each of three (or all available) images on each side for each patient using ultrasound technology. Unit of measure is a ratio: difference between the peak systolic and end-diastolic velocities divided by the mean flow velocity Relative change in uterine artery pulsatility index is a measure of flow to the uterus. A greater difference from the baseline value represents a greater improvement in placental perfusion. | Participants delivered or lost to follow up not included | Posted | Mean | Standard Deviation | ratio | Three times between 11 and 32 weeks of gestation. |
|
29 weeks
Adverse Events were assessed from enrollment until delivery
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Control Group | Patients will receive standard of care. Control: Standard of Care |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hemorrhage | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headaches | Nervous system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. John M. O'Brien | University of Kentucky | 8592575158 | john.obrien2@uky.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 27, 2025 | Jun 27, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D011225 | Pre-Eclampsia |
| ID | Term |
|---|---|
| D046110 | Hypertension, Pregnancy-Induced |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
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| ID | Term |
|---|---|
| D001241 | Aspirin |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
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|
| Acetylsalicylic Acid 162 mg | Drug | Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
|
|
| Control | Other | Standard of Care |
|
Frequency women are identified with Severe Features of the disease |
| From enrollment at 11 weeks throughout pregnancy and immediate postpartum ( 6 weeks after delivery), approximately 35 weeks |
| Composite Neonatal Outcomes Including Frequency of Intraventricular Hemorrhage (IVH), Bronchopulmonary Dysplasia (BPD), Respiratory Distress Syndrome (RDS), Necrotising Enterocolitis(NEC) | Frequency of adverse neonatal outcomes | Neonatal period ( first 28 days after birth) |
| Change in s-ICAM Levels Over Time | Serial biologic samples will be obtained in the first (baseline), second (event 2), and third (event 3) trimesters to measure changes in soluble Intercellular Adhesion Molecule (s-ICAM) levels over time. | Three times between 11 and 32 weeks of gestation |
| Change in PIGF Levels Over Time | Serial biologic samples will be obtained in the first (baseline), second (event 2), and third (event 3) trimesters to measure changes in placental growth factor (PIGF) levels over time. | Three times between 11 and 32 weeks of gestation |
| Change in CRP Levels Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in C-reactive protein (CRP) levels over time. | Three times between 11 and 32 weeks of gestation |
| Change in IL-6 Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in interleukin 6 (IL-6) levels over time. | Three times between 11 and 32 weeks of gestation |
| Change in TNF Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in tumor necrosis factor (TNFα) levels over time. | Three times between 11 and 32 weeks of gestation |
| Gestational Age at Delivery | measured in weeks, from the first day of the last menstrual cycle to delivery | At Delivery, up to 41 weeks |
| Background |
| Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0. |
| 29138036 | Background | Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018 Mar;218(3):287-293.e1. doi: 10.1016/j.ajog.2017.11.561. Epub 2017 Nov 11. |
| Discontinued Intervention |
|
| BG002 | Acetylsalicylic Acid 162mg | Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 162 mg: Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI at enrollment | Mean | Standard Deviation | kg/m2 |
|
| Method of Conception | Count of Participants | Participants |
|
| Title |
|---|
| Description |
|---|
| OG000 | Control Group | Patients will receive standard of care. Control: Standard of Care |
| OG001 | Acetylsalicylic Acid 81mg | Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 81 mg: Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
| OG002 | Acetylsalicylic Acid 162mg | Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 162 mg: Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. |
|
|
| Secondary | Onset of Pre-eclampsia | Frequency of Disease during pregnancy and postpartum as defined by American College of Obstetrics and Gynecology (ACOG) criteria | Participants delivered or lost to follow up not included | Posted | Count of Participants | Participants | From enrollment at 11 weeks throughout pregnancy and postpartum ( 6 weeks after delivery), approximately 35 weeks |
|
|
|
| Secondary | Severity of Pre-eclampsia | Frequency women are identified with Severe Features of the disease | Participants delivered or lost to follow up not included | Posted | Count of Participants | Participants | From enrollment at 11 weeks throughout pregnancy and immediate postpartum ( 6 weeks after delivery), approximately 35 weeks |
|
|
|
| Secondary | Composite Neonatal Outcomes Including Frequency of Intraventricular Hemorrhage (IVH), Bronchopulmonary Dysplasia (BPD), Respiratory Distress Syndrome (RDS), Necrotising Enterocolitis(NEC) | Frequency of adverse neonatal outcomes | Participants lost to follow up not included | Posted | Count of Participants | Participants | Neonatal period ( first 28 days after birth) |
|
|
|
| Secondary | Change in s-ICAM Levels Over Time | Serial biologic samples will be obtained in the first (baseline), second (event 2), and third (event 3) trimesters to measure changes in soluble Intercellular Adhesion Molecule (s-ICAM) levels over time. | Serum specimens were not collected for all patients at individual timepoints related to issues such as patient refusal for venipuncture. Some elected to discontinue participation | Posted | Mean | Standard Deviation | ng/ml | Three times between 11 and 32 weeks of gestation |
|
|
|
| Secondary | Change in PIGF Levels Over Time | Serial biologic samples will be obtained in the first (baseline), second (event 2), and third (event 3) trimesters to measure changes in placental growth factor (PIGF) levels over time. | Serum specimens were not collected for all patients at individual timepoints related to issues such as patient refusal for venipuncture. Some elected to discontinue participation | Posted | Mean | Standard Deviation | pg/ml | Three times between 11 and 32 weeks of gestation |
|
|
|
| Secondary | Change in CRP Levels Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in C-reactive protein (CRP) levels over time. | Serum specimens were not collected for all patients at individual timepoints related to issues such as patient refusal for venipuncture. Some elected to discontinue participation. | Posted | Mean | Standard Deviation | mg/L | Three times between 11 and 32 weeks of gestation |
|
|
|
| Secondary | Change in IL-6 Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in interleukin 6 (IL-6) levels over time. | Not enough serum from samples to run these measures | Posted | Three times between 11 and 32 weeks of gestation |
|
|
| Secondary | Change in TNF Over Time | Serial biologic samples will be obtained in the first, second, and third trimesters to measure changes in tumor necrosis factor (TNFα) levels over time. | Not enough serum from samples to run these measures | Posted | Three times between 11 and 32 weeks of gestation |
|
|
| Secondary | Gestational Age at Delivery | measured in weeks, from the first day of the last menstrual cycle to delivery | Posted | Mean | Standard Deviation | weeks | At Delivery, up to 41 weeks |
|
|
|
| 0 |
| 65 |
| 8 |
| 65 |
| 3 |
| 65 |
| EG001 | Acetylsalicylic Acid 81mg | Patients will receive low dose (81mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 81 mg: Patients will receive 81mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. | 0 | 68 | 12 | 68 | 3 | 68 |
| EG002 | Acetylsalicylic Acid 162mg | Patients will receive low dose (162mg) acetylsalicylic acid (Aspirin). Acetylsalicylic Acid 162 mg: Patients will receive 162mg acetylsalicylic acid daily, initiated between 11 and 16 weeks of gestation and continued until 36 weeks of gestation. | 0 | 75 | 15 | 75 | 2 | 75 |
| Intrauterine Fetal Demise | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
|
| Placental Abruption | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
|
| Previable Delivery | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
|
| Nose bleeds | Blood and lymphatic system disorders | Systematic Assessment |
|
| Allergic reaction | Immune system disorders | Systematic Assessment |
|
| Emesis | Gastrointestinal disorders | Systematic Assessment |
|
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| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| Baseline and Event 3 |
|
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| Baseline and Event 3 |
|
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| Baseline and Delivery |
|
|