Aspirin Versus Metformin in Pregnancies at High Risk of Preterm Preeclampsia: a 3-arm Randomized Controlled Trial

Not Applicable

Recruiting

• Conditions: Preeclampsia
• Interventions: Drug: 150 mg acetylsalicylic acid; Drug: 75 mg acetylsalicylic acid; Drug: Placebo of acetylsalicylic acid and Metformin; Drug: 1.5g Metformin

• Registration Number: NCT05580523
• Lead Sponsor: Chinese University of Hong Kong

Brief Summary

This is a prospective, multicenter, randomized controlled, double-blind trial of three treatment arms: (1) aspirin 75 mg/day vs. (2) aspirin 150 mg/day vs. (3) aspirin 75 mg/day with metformin 1.5 g/day from the first trimester to compare the incidence of preterm preeclampsia with delivery at \<37 week's gestation between the treatment arms, in order to determine the optimal therapeutic intervention for the prevention of preterm preeclampsia among Chinese women at high-risk of preeclampsia.

Detailed Description

All women with singleton pregnancies who are attending for their routine hospital visit at 11-13 weeks' gestation will be invited to undergo screening for preeclampsia. We use a Bayes theorem-based method that combines maternal characteristics, medical and obstetric history together with mean arterial pressure (MAP) and serum placental growth factor (PlGF) level. Women who are deemed high-risk following first trimester combined screening (cutoff corresponding to a screen positive rate of 10%, e.g ≥1 in 80) will be invited to participate in the 3-arm randomized controlled trial.

Study Timeline

• Study First Submitted: 2022-10-12
• Study First Submitted QC: 2022-10-13
• Study First Posted: 2022-10-14
• Study Start: 2023-07-03
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-05
• Last Update Posted: 2023-11-08
• Primary Completion: 2025-01-01
• Study Completion: 2025-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 3000

Inclusion Criteria

• Singleton pregnancies
• Live fetus at 11-13 weeks' gestation
• High-risk for preterm preeclampsia at 11-13 weeks by the algorithm combining maternal characteristics, medical and obstetric history, MAP and serum PlGF
• Informed and written consent

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Exclusion Criteria

• Age <18 years old
• Multiple pregnancies
• Treatment with low-dose aspirin and metformin at the time of screening
• Pregnancies complicated by major fetal abnormality identified during the first trimester
• Women with learning difficulties, or serious mental illness
• Bleeding disorders such as Von Willebrand's disease
• Active peptic ulceration or gastrointestinal bleeding
• Hypersensitivity to aspirin, metformin hydrochloride and other biguanides
• Treatment with long term nonsteroidal anti-inflammatory medication
• Hyperemesis gravidarum
• Renal, liver or heart failure
• A serious medical condition
• Concurrent participation in another drug trial or at any time within the previous 28 days
• Any other reason the clinical investigators think will prevent the potential participant from complying with the trial protocol.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aspirin 150 mg and placebo	150 mg acetylsalicylic acid	Two capsules of 75 mg aspirin to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery.
Aspirin 75 mg and Metformin 1.5 g	75 mg acetylsalicylic acid	A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin capsules (up to 750 mg) to be taken twice per day from enrolment until delivery
Aspirin 75 mg and placebo	75 mg acetylsalicylic acid	A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery.
Aspirin 75 mg and placebo	Placebo of acetylsalicylic acid and Metformin	A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery.
Aspirin 150 mg and placebo	Placebo of acetylsalicylic acid and Metformin	Two capsules of 75 mg aspirin to be taken orally once per night from enrolment until 36 weeks' gestation and metformin identical-appearing placebo capsules to be taken orally twice per day from enrolment until delivery.
Aspirin 75 mg and Metformin 1.5 g	1.5g Metformin	A capsule of 75 mg aspirin plus an aspirin identical-appearing capsule of placebo to be taken orally once per night from enrolment until 36 weeks' gestation and metformin capsules (up to 750 mg) to be taken twice per day from enrolment until delivery

Primary Outcome Measures

Name	Time	Method
Incidence of preterm preeclampsia(<37 weeks)	≥20 weeks to <37 weeks of gestation	Preeclampsia will be defined as per the International Society for the Study of Hypertension in Pregnancy.The Proportions of delivery with preterm-preeclampsia between different intervention groups will be measured.

Secondary Outcome Measures

Name	Time	Method
Adverse outcome of pregnancy at <37 weeks.	<37 weeks of gestation	including preeclampsia requiring delivery, gestational age (SGA; \<5th percentile) requiring delivery, miscarriage or still birth or placental abruption.
Adverse outcome of pregnancy at <34 weeks.	<34 weeks of gestation	including preeclampsia requiring delivery, gestational age (SGA; \<5th percentile) requiring delivery, miscarriage or still birth or placental abruption.
Neonatal mortality	During the first 28 days of life (0-27days)	A neonatal death is a death during 0-27 days of life.
Stillbirth or neonatal death	At delivery	Stillbirth: the death of a baby before or during birth after 24 weeks of gestation. Neonatal death: the death of a baby within the first 28 days of life.
Neonatal morbidity	During the first 28 days of life (0-27days)	Composite neonatal morbidity (any one of the following): \>grade II intra-ventricular hemorrhage; neonatal sepsis confirmed by cultures; neonatal anemia requiring transfusion; respiratory distress syndrome requiring surfactant and ventilation; necrotising enterocolitis requiring surgical intervention.
Adverse outcome of pregnancy at ≥37 weeks	≥37 weeks of gestation	including preeclampsia requiring delivery, gestational age (SGA; \<5th percentile) requiring delivery, stillbirth or placental abruption.
Neonatal birthweight below the 3rd,5th and 10th centile.	At delivery	Birthweight and birthweight percentile for gestational age at delivery is calculated using a normal range derived in a Chinese population.
<34 weeks and <37 weeks spontaneous preterm delivery	At spontaneous delivery	Spontaneous delivery at \<34 weeks(early preterm) and at \<37 weeks(total preterm) includes those with spontaneous onset of labor and those with preterm pre-labor rupture of membranes (PPROM).
Gestational age	At delivery	Gestation is the period of time between conception and birth. During this time, the baby grows and develops inside the mother's womb. Gestational age is the common term used during pregnancy to describe how far along the pregnancy is. It is measured in weeks, from the first day of the woman's last menstrual cycle to the current date. A normal pregnancy can range from 38 to 42 weeks.

Trial Locations

Locations (6)

The Third Affiliated Hospital of Guangzhou Medical University; 🇨🇳 Guangzhou, Guangdong, China

West China Second University Hospital, Sichuan University; 🇨🇳 Chengdu, Sichuan, China

Obstetrics and Gynecology Hospital of Fudan University; 🇨🇳 Shanghai, Shanghai, China

Peking University First Hospital; 🇨🇳 Beijing, Beijing, China

Guangzhou Women and Children's Medical Center; 🇨🇳 Guangzhou, Guangdong, China

Shanghai First Maternity and Infant Hospital; 🇨🇳 Shanghai, Shanghai, China