Dipyridamole for Early-Onset Preeclampsia: A Pilot Study of Feasibility, Pharmacokinetics, and Biological Effects

NCT07738562 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: Dipyridamole
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Preeclampsia (PE); Hypertension ,Pregnancy

Keywords

Preeclampsia treatment; preeclampsia management; treating mild preeclampsia; Early-onset preeclampsia; hypertensive pregnancy disease; preeclampsia disease-modifying therapy

Outcome Measures

Primary Outcomes (1)

• Protocol Feasibility

  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.

  From enrollment through delivery (estimated 1-5 weeks per participant)

Secondary Outcomes (17)

• 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)

Other Outcomes (2)

• Concentration of Placental Oxidative Stress and Ferroptosis-Related Markers

  At delivery

• Maternal and Fetal Dipyridamole Exposure at Delivery

  At delivery

Study Arms (3)

Dipyridamole 75 mg twice daily (Day 1)

EXPERIMENTAL

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.

Drug: Dipyridamole 75 MG

Dipyridamole 75 mg three times daily (Day 2)

EXPERIMENTAL

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.

Drug: Dipyridamole 75 MG

Dipyridamole 75 mg four times daily (target dose, Day 3 onward)

EXPERIMENTAL

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.

Drug: Dipyridamole 75 MG

Interventions

Dipyridamole 75 MG DRUG

Oral dipyridamole 75 mg tablets, administered via a fixed structured dose escalation across the sequential arms described above (75 mg twice daily → three times daily → four times daily). The escalation schedule is identical for all participants; dosing is not individualized and accelerated escalation is not permitted.

Dipyridamole 75 mg four times daily (target dose, Day 3 onward); Dipyridamole 75 mg three times daily (Day 2); Dipyridamole 75 mg twice daily (Day 1)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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

Sponsors & Collaborators

• Hadassah Medical Organization: lead

Study Sites (1)

Hadassah University Medical Center

Jerusalem, Israel, 9112001, Israel

Location

Related Publications (9)

• Chen X, Shen J, Jiang X, Pan M, Chang S, Li J, Wang L, Miao M, Feng X, Zhang L, Shu G, Liu W, Xu F, Zhang W, Ding Z, Zong H, Liu W, Li D, Chen B, Shao M, Fei G, Zha X, Fan X. Characterization of dipyridamole as a novel ferroptosis inhibitor and its therapeutic potential in acute respiratory distress syndrome management. Theranostics. 2024 Oct 21;14(18):6947-6968. doi: 10.7150/thno.102318. eCollection 2024.

  PMID: 39629132 BACKGROUND

• Zhuang X, Shi S, Liu S, Jiao Y, Huang B, Yang Y, Yang L, Yang X, Wang H, Liang C, Song D, Yu H, Zou D, Sun Q, Yang S, Yin C, Li J, Liu Y, Min J, Wang F, Nian Y, Du L, Chu B. Dipyridamole Acts as Clinical Ferroptosis Inhibitor to Prevent from Tissue Injury. Adv Sci (Weinh). 2025 Jun;12(23):e2500566. doi: 10.1002/advs.202500566. Epub 2025 May 14.

  PMID: 40365742 BACKGROUND

• Edri T, Lianski S, Cohen SM, Beharier O. Placental ferroptosis in preeclampsia: An integrative and comprehensive review. J Reprod Immunol. 2026 Mar;174:104863. doi: 10.1016/j.jri.2026.104863. Epub 2026 Feb 16.

  PMID: 41722450 BACKGROUND

• Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial. Lancet. 1991 Jun 15;337(8755):1427-31. doi: 10.1016/0140-6736(91)93124-r.

  PMID: 1675315 BACKGROUND

• Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet. 1985 Apr 13;1(8433):840-2. doi: 10.1016/s0140-6736(85)92207-x.

  PMID: 2858710 BACKGROUND

• Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020 Jun;135(6):e237-e260. doi: 10.1097/AOG.0000000000003891.

  PMID: 32443079 BACKGROUND

• ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006 May 20;367(9523):1665-73. doi: 10.1016/S0140-6736(06)68734-5.

  PMID: 16714187 BACKGROUND

• Park C, Alahari S, Ausman J, Liu R, Nguyen F, Sallais J, Post M, Caniggia I. Placental Hypoxia-Induced Ferroptosis Drives Vascular Damage in Preeclampsia. Circ Res. 2025 Feb 14;136(4):361-378. doi: 10.1161/CIRCRESAHA.124.325119. Epub 2025 Jan 23.

  PMID: 39846172 BACKGROUND

• Lianski S, Mizrachi T, Barak O, Tsaitlin-Mor L, Elhaik-Goldman S, Yagel S, Goldman-Wohl D, Cohen SM, Hefetz Medina R, Rachmilewitz J, Barr HM, Plotnikov A, Tyurina YY, Tyurin VA, Samovich SN, Kapralov AA, Karumanchi SA, Kagan VE, Bayir H, Sadovsky Y, Beharier O. Antiferroptotic Drugs Reduce sFlt-1 Release and Placenta Damage in Preeclampsia. Hypertension. 2025 Oct;82(10):1705-1718. doi: 10.1161/HYPERTENSIONAHA.125.25003. Epub 2025 Aug 19.

  PMID: 40827397 BACKGROUND

MeSH Terms

Conditions

Pre-Eclampsia; Hypertension, Pregnancy-Induced

Interventions

Dipyridamole

Condition Hierarchy (Ancestors)

Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Prof. Ofer Beharier, Principal Investigator

CONTACT

972+586306700; bofer@hadassah.org.il

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Ofer Beharier, MD, PhD Department of Obstetrics and Gynecology Hadassah University Medical Center, Jerusalem, Israel

Study Record Dates

• First Submitted: May 23, 2026
• First Posted: July 31, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: July 31, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)