Dipyridamole for Early-Onset Preeclampsia: A Pilot Study of Feasibility, Pharmacokinetics, and Biological Effects
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Protocol Feasibility
研究概览
简要总结
Early-onset preeclampsia (PE), defined as preeclampsia presenting before 34 weeks of gestation, is a severe placental disorder associated with significant maternal and perinatal morbidity. There is currently no disease-modifying treatment; management relies on close surveillance and delivery, frequently resulting in extreme prematurity.
Recent laboratory research identified ferroptosis, a form of iron-dependent regulated cell death driven by lipid peroxidation, as a key mechanism of placental injury in early-onset preeclampsia. A high-throughput drug screen identified dipyridamole, an approved oral antiplatelet and vasodilatory agent, as a potent ferroptosis inhibitor in primary human trophoblast cultures (EC50 = 0.146 µM), acting through mechanisms independent of its known phosphodiesterase-inhibitory pharmacology. In preeclamptic placental explants, dipyridamole markedly reduced release of sFlt-1, a central mediator of the maternal syndrome. Dipyridamole carries an established pregnancy safety record supported by randomized trials and a Cochrane meta-analysis of antiplatelet agents in pregnancy.
This is a prospective, single-center, open-label pilot study using a sequential, fixed dose-escalation design. The study will enroll 15 hospitalized pregnant women with early-onset preeclampsia (gestational age 26+0 to 33+6 weeks) and an elevated sFlt-1/PlGF ratio (≥85), for whom expectant management is clinically appropriate. Enrollment proceeds through a staged sentinel design with safety gates reviewed by an independent Safety Monitoring Committee. Participants receive oral dipyridamole added to standard clinical care, using a fixed dose-escalation protocol (75 mg twice daily on Day 1, escalating over 2-3 days to a target dose of 75 mg four times daily, 300 mg/day total). Standard obstetric care continues unchanged, determined entirely on clinical grounds, independent of study participation.
The primary objective is to evaluate the feasibility and clinical implementability of the dipyridamole treatment protocol within routine inpatient obstetric care. Secondary objectives include characterizing the pharmacokinetics of dipyridamole during pregnancy, assessing tolerability, and evaluating longitudinal circulating angiogenic biomarkers (sFlt-1 and PlGF). Exploratory objectives include assessment of placental markers of oxidative stress and ferroptosis-related pathways in tissue obtained at delivery.
Study drug is administered during the antepartum period only and discontinued before delivery. This pilot study is not designed to establish clinical efficacy, but to provide the pharmacokinetic, tolerability, and biological data required to design a subsequent randomized trial.
详细描述
Study Type: Single-center, open-label, pilot interventional study evaluating an approved medication (dipyridamole) in an off-label indication.
Background and Rationale:
Early-onset preeclampsia (PE), typically presenting before 34 weeks of gestation, is the most severe phenotype of hypertensive pregnancy disease and a leading cause of maternal and perinatal morbidity. Once clinically established, there is no disease-modifying therapy; management relies almost exclusively on close surveillance and timely delivery, frequently resulting in extreme prematurity. Early-onset PE is increasingly recognized as a primarily placental disorder, driven by defective placentation, chronic ischemia-reperfusion injury, progressive trophoblast damage, and maladaptive stress responses, in contrast to late-onset disease, which is more strongly influenced by maternal cardiovascular and metabolic susceptibility.
Prior laboratory research identified ferroptosis, a form of regulated cell death driven by iron-catalyzed peroxidation of membrane phospholipids, as a key mechanism of placental injury in early-onset PE. Human trophoblasts were shown to be uniquely vulnerable to ferroptosis due to their high iron content and intense oxidative metabolism. Using redox phospholipidomics, preeclamptic placentas were shown to accumulate specific hydroperoxy-phosphatidylethanolamine species characteristic of ferroptotic cell death; inducing ferroptosis in placental explants drove sFlt-1 release, and ferroptosis inhibitors reversed both tissue damage and sFlt-1 secretion. Multiple independent groups have since confirmed ferroptosis as a driver of placental injury in preeclampsia.
A high-throughput robotic screen of over 6,500 drugs and compounds, designed to identify pregnancy-safe ferroptosis inhibitors in primary human trophoblast cultures, identified dipyridamole as one of the most potent candidates (EC50 = 0.146 μM), acting independently of its known phosphodiesterase-inhibitory pharmacology. In preeclamptic placental explants, dipyridamole treatment led to a marked and reproducible reduction in sFlt-1 release, a central pathogenic mediator of the maternal syndrome.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Singleton pregnancy
- •Established early-onset preeclampsia, with or without severe features, with gestational age from 26+0 to 33+6 weeks at enrollment, confirmed by best obstetric estimate
- •Hospitalization for maternal and/or fetal surveillance
- •Expectant management deemed appropriate by the treating clinical team at the time of enrollment
- •sFlt-1/PlGF ratio ≥85 at screening
- •Confirmed viable fetus without a known or suspected major structural or chromosomal anomaly
- •Baseline platelet count ≥100,000/µL
- •Ability to provide written informed consent
排除标准
- •Immediate indication for delivery at time of screening, including uncontrolled severe hypertension, eclampsia, HELLP syndrome, or severe fetal compromise
- •Active maternal bleeding or clinically significant bleeding disorder
- •Therapeutic-dose anticoagulation (e.g., enoxaparin >1 mg/kg/day)
- •Known hypersensitivity or contraindication to dipyridamole
- •Multiple gestation
- •Known major fetal anomaly or chromosomal abnormality
- •Baseline thrombocytopenia, platelet count <100,000/µL
- •Hemodynamically significant maternal cardiac disease
- •Significant maternal comorbidity that, in the investigator's judgment, precludes safe participation
- •Inability to comply with study procedures
研究组 & 干预措施
Dipyridamole 75 mg twice daily (Day 1)
Initial fixed dose-escalation step. All participants receive oral dipyridamole 75 mg twice daily on Day 1, with clinical monitoring for tolerability prior to escalation to the next dose level.
干预措施: Dipyridamole 75 MG (Drug)
Dipyridamole 75 mg three times daily (Day 2)
Second fixed dose-escalation step. Participants who tolerate the initial dose escalate to dipyridamole 75 mg three times daily on Day 2. The escalation schedule is fixed and identical for all participants; dosing is not individualized and accelerated escalation is not permitted.
干预措施: Dipyridamole 75 MG (Drug)
Dipyridamole 75 mg four times daily (target dose, Day 3 onward)
Target maintenance dose. Participants escalate to dipyridamole 75 mg four times daily (300 mg/day total) from Day 3 onward, continuing throughout the antepartum period. Study drug is discontinued at least 12 hours before planned delivery, and at least 24 hours before planned delivery at which neuraxial anesthesia is anticipated. Temporary hold or de-escalation to a previously tolerated dose level is permitted based on adverse effects or investigator judgment.
干预措施: Dipyridamole 75 MG (Drug)
结局指标
主要结局
Protocol Feasibility
时间窗: From enrollment through delivery (estimated 1-5 weeks per participant)
Composite feasibility endpoint defined as: (1) successful enrollment of ≥10 of 15 planned participants within the recruitment period; (2) completion of the full dose-escalation ramp-up to the target dose of 300 mg/day in ≥70% of enrolled participants; and (3) successful collection of at least the sparse pharmacokinetic sampling set (Day 1 pre-dose + 2 post-dose samples) in ≥70% of participants, within the routine inpatient care setting.
次要结局
- Peak Plasma Concentration (Cmax) of Dipyridamole(Pre-dose through 6-8 hours post-dose on the intensive PK profiling day (after reaching target dose or highest tolerated dose))
- Incidence of Dipyridamole-Related Adverse Events(From first drug administration until six weeks postpartum)
- Change in Serum Soluble fms-Like Tyrosine Kinase-1 (sFlt-1)(Daily for the first 7 days, then every 72 hours until delivery)
- Change in Maternal Blood Pressure(From treatment initiation until delivery (estimated 1-5 weeks))
- Pregnancy Latency from Treatment Initiation to Delivery(From first dose through delivery (estimated 1-5 weeks))
- Uterine Artery Pulsatility Index (UtA-PI)(From enrollment through delivery (estimated 1-5 weeks))
- Trough Plasma Concentration (Ctrough) of Dipyridamole(From treatment initiation through delivery (estimated 1-5 weeks))
- Area Under the Plasma Concentration-Time Curve (AUC) of Dipyridamole(Pre-dose through 6-8 hours post-dose on the intensive PK profiling day)
- Apparent Oral Clearance (CL/F) of Dipyridamole(From treatment initiation through the intensive PK profiling day (estimated 1-5 weeks))
- Terminal Elimination Half-Life (t½) of Dipyridamole(Calculated from PK samples collected on the intensive PK profiling day (up to 6-8 hours post-dose))
- Need for Initiation or Escalation of Antihypertensive Therapy(From treatment initiation until delivery (estimated 1-5 weeks))
- Overall Antihypertensive Medication Burden(From treatment initiation until delivery (estimated 1-5 weeks))
- Change in Serum Placental Growth Factor (PlGF)(Daily for the first 7 days, then every 72 hours until delivery)
- Change in sFlt-1/PlGF Ratio(Daily for the first 7 days, then every 72 hours until delivery)
- Severity of Dipyridamole-Related Adverse Events(From first drug administration until six weeks postpartum)
- Obstetric Indication for Delivery(At delivery)
- Umbilical Artery Pulsatility Index (UA-PI)(From enrollment through delivery (estimated 1-5 weeks))
研究者
Bahrir Ofer
Prof. Ofer Beharier, MD, PhD Department of Obstetrics and Gynecology Hadassah University Medical Center, Jerusalem, Israel
Hadassah Medical Organization