Aspirin for Miscarriage and Preeclampsia

(APPLE Trial)

Overseen By Enrique Schisterman, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: University of Pennsylvania

Must be taking: Aspirin

Must not be taking: Anticoagulants, NSAIDs

Disqualifiers: Aspirin allergy, Anticoagulant need, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: From enrollment to delivery, approximately 38 weeks

1150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a specific dose of aspirin taken early in pregnancy can lower the risk of pre-eclampsia (a pregnancy complication with high blood pressure) and pregnancy loss. Participants will take either two low-dose aspirin pills daily or a placebo (a pill with no active ingredient) to compare outcomes. Women who are less than 7 weeks pregnant and have risk factors such as a history of pre-eclampsia, gestational diabetes, or pregnancy loss might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on anticoagulant therapy or need to use NSAIDs regularly during pregnancy, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In a previous study, taking low-dose aspirin early in pregnancy did not increase the risk of serious health problems for mothers, babies, or newborns. Research has shown that aspirin can lower the risk of preeclampsia by 17% without causing major bleeding issues. Another study found that starting aspirin before 11 weeks of pregnancy reduced preeclampsia, though the reduction was not significant.

Aspirin is already approved to help prevent some pregnancy complications, indicating it is generally considered safe when used as directed. Overall, this treatment appears to be well-tolerated in these situations. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using aspirin for preventing miscarriage and preeclampsia because it offers a simple and potentially effective solution with a well-known safety profile. Unlike other treatments that might involve more complex medications or interventions, low-dose aspirin is easily accessible and has been shown to have beneficial effects on blood flow, which is crucial for a healthy pregnancy. Additionally, aspirin's anti-inflammatory properties could help in reducing risks associated with preeclampsia, a condition characterized by high blood pressure and potential organ damage. This approach represents a straightforward and promising strategy in managing these pregnancy complications.

What evidence suggests that this trial's treatments could be effective for miscarriage and preeclampsia?

Research shows that aspirin can lower the risk of preeclampsia, a condition causing high blood pressure during pregnancy. Studies have found that low-dose aspirin reduces the chance of early birth in women at risk for preeclampsia by about 8-14%. Another study found that aspirin might lower the risk of preeclampsia by 17% without causing major bleeding. In this trial, participants in the "Double low-dose aspirin" arm will take two 81mg aspirin tablets daily from trial entry until delivery. Starting aspirin early in pregnancy and at the correct dose is crucial for preventing problems. Overall, strong evidence supports aspirin's role in reducing the risk of preeclampsia in pregnant women. ^{2 3 4 6 7}

Who Is on the Research Team?

Enrique Schisterman, PhD

Principal Investigator

University of Pennsylvania

Kurt Barnhart, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

The APPLE trial is for pregnant women who can start treatment no later than 6 weeks and 6 days into their pregnancy. It's designed to see if early aspirin use can prevent complications like pre-eclampsia or pregnancy loss. Women with certain health conditions or on conflicting medications may not be eligible.

Inclusion Criteria

I can take pills and will follow the aspirin plan.

Provision of signed and dated informed consent form

Patients with a gestation less than or equal to 6 weeks, 6 days (as determined by patient record of LMP or ART date)

Exclusion Criteria

I cannot take aspirin due to asthma, nasal polyps, bleeding disorders, or past stomach ulcers.

I have severe pelvic pain or heavy bleeding needing urgent care.

Known allergies to aspirin or non-steroidal anti-inflammatory agents (NSAID)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants begin taking either 162mg of aspirin or placebo until 12 weeks, then 81mg of aspirin through delivery

From enrollment to delivery, approximately 38 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Aspirin

Trial Overview This study tests whether taking a double low-dose of aspirin (162mg) daily from very early in pregnancy, compared to a standard dose (81mg after the first trimester), reduces the risk of developing pre-eclampsia or experiencing pregnancy loss.

How Is the Trial Designed?

Group I: Double low-dose aspirin Active Control 1 Intervention

Participants will take 2 81mg aspirin tablets daily from entrance into the trial until delivery.

Group II: Standard of Care Placebo Group 1 Intervention

Participants will take 2 placebo pills from entrance into the study until 12 weeks gestational age, they will then take 1 placebo pill and 1 81mg aspirin until delivery.

Aspirin is already approved in European Union, United States, Canada, China for the following indications:

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Low-dose aspirin has been shown to be beneficial in preventing pre-eclampsia in high-risk pregnant women, based on results from four large clinical trials involving over 13,000 participants.

The use of low-dose aspirin is considered safe for mothers and their babies, although its effect on preventing fetal growth retardation is minimal and no significant therapeutic benefits were found.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy in obstetrics. Wallenburg, HC.[2019]

In a study of 41 first-time pregnant women at risk for pregnancy-induced hypertension, those treated with 80 mg of aspirin daily had significantly lower rates of hypertension and preeclampsia compared to the placebo group, with no hypertensive complications in the aspirin group.

The aspirin treatment did not lead to any significant differences in pregnancy duration, birth weight, or fetal health indicators, and there was no increased risk of bleeding for mothers or babies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin in primigravidae with positive roll-over test. Schröcksnadel, H., Sitte, B., Alge, A., et al.[2018]

A quality improvement project in an academic OB/Gyn practice showed that implementing a standardized approach to aspirin (ASA) prescription significantly increased screening rates for preeclampsia risk from 47% to 99% among new obstetric patients.

Post-intervention, 79% of patients who screened positive received an ASA recommendation, demonstrating that the standardized process is effective and equitable, with no significant differences in recommendations based on race.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leveraging quality improvement to promote health equity: standardization of prenatal aspirin recommendations. Gross, ME., Godecker, A., Hughes, A., et al.[2023]

Aspirin is considered safe for use during pregnancy at daily doses not exceeding 100mg and has been shown to effectively prevent pre-eclampsia and fetal growth restriction in high-risk patients.

However, aspirin has not demonstrated benefits for preventing vascular placental disease in low-risk patients or for unexplained recurrent miscarriages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Aspirin: Indications and use during pregnancy]. Belhomme, N., Doudnikoff, C., Polard, E., et al.[2018]

Aspirin therapy significantly reduces the risk of perinatal death and preeclampsia in women with historical risk factors, based on a meta-analysis of 14 trials involving 12,416 women.

The use of aspirin is associated with a decrease in spontaneous preterm birth rates and an increase in mean birth weight, without increasing the risk of placental abruption, highlighting its safety and efficacy as a preventive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin for prevention of preeclampsia in women with historical risk factors: a systematic review. Coomarasamy, A., Honest, H., Papaioannou, S., et al.[2019]

Aspirin is recommended for women at risk of preeclampsia, with guidelines suggesting initiation between 11 to 28 weeks of gestation, and dosages varying from 75 mg to 150 mg depending on the level of risk.

Evidence indicates that higher doses of aspirin (greater than 100 mg daily) started before 16 weeks of gestation may be more effective in reducing the risk of preeclampsia, highlighting the need for further randomized control trials to determine optimal dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose aspirin therapy for the prevention of preeclampsia: time to reconsider our recommendations? Horgan, R., Hage Diab, Y., Waller, J., et al.[2023]

A systematic review of studies indicates that low-dose aspirin (80-150 mg daily) taken in the first trimester (before 16 weeks) may effectively reduce the severity of preeclampsia in at-risk pregnancies.

In contrast, studies administering aspirin later in pregnancy showed mixed results, suggesting that the timing and dosage of aspirin are crucial for its effectiveness in preventing preeclampsia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The Role of Aspirin in Preeclampsia Prevention: State of the Art]. Campos, A.[2018]

Low-dose aspirin has been shown to effectively reduce the risk of preeclampsia and fetal growth restriction in at-risk pregnant populations, but its benefits in low-risk groups remain unclear.

There is ongoing debate among medical organizations regarding the guidelines for aspirin use in pregnancy, with some recommending it only for at-risk women while others suggest it may be more effective and cost-efficient to prescribe it universally from the first trimester.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should we recommend universal aspirin for all pregnant women? Mone, F., Mulcahy, C., McParland, P., et al.[2022]

First-trimester uterine artery Doppler studies can identify 50-65% of women at high risk for severe preeclampsia, which is crucial for early intervention, especially in cases requiring delivery before 35 weeks.

Combining uterine artery Doppler with the serum marker placental protein 13 may enhance detection rates of severe preeclampsia to up to 90%, suggesting a promising approach for screening high-risk pregnancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First trimester screening for preeclampsia. Papageorghiou, AT., Campbell, S.[2016]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12309040/

Effectiveness of low-dose aspirin in reducing the risk ... Aspirin 150 mg was introduced before 11 weeks of gestation. The results showed a non-significant reduction in the incidence of preeclampsia.

2. acog.org acog.org/clinical/clinical-guidance/committee-opinion/articles/2018/07/low-dose-aspirin-use-during-pregnancy

Low-Dose Aspirin Use During Pregnancy Low-dose aspirin has been reported to reduce preterm birth (at less than 37 weeks of gestation) in 8–14% of women at risk of preeclampsia 12 13 14 32. However, ...

3. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2784499

Aspirin Use to Prevent Preeclampsia and Related ... Evidence demonstrates that aspirin use reduces the risk of preeclampsia in high-risk populations. Timing and Dosage. Effective dosages of low-dose aspirin range ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04070573

Low Doses of Aspirin in the Prevention of Preeclampsia Taking ASA (as opposed to placebo) is thought to reduce the risk of preeclampsia by 17%, without increasing the risk of major obstetric bleeding. The number ...

5. ahajournals.org ahajournals.org/doi/10.1161/HYPERTENSIONAHA.121.17448

Effective Aspirin Treatment of Women at Risk for ... Prophylactic low-dose aspirin treatment reduces the rate of preterm preeclampsia in high-risk women, but a significant proportion still develops preeclampsia.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10568740/

The Role of Acetylsalicylic Acid in the Prevention of Pre- ... When ASA is taken after recurrent miscarriages, no reduction of the miscarriage rate is to be expected. In women who had sustained three or more consecutive ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S2589933325001673

Maternal, fetal, and neonatal serious adverse events ... Low-dose aspirin initiated in early pregnancy is not associated with increased risks of serious adverse events for mothers, fetuses, or neonates. Evidence ...