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

Study Overview
=================
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.

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

Conditions
-----------------
Preeclampsia

Intervention / Treatment
-----------------
* Drug: 75 mg acetylsalicylic acid
* Drug: 1.5g Metformin
* Drug: 150 mg acetylsalicylic acid
* Drug: Placebo of acetylsalicylic acid and Metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aspirin 75 mg and placebo<br>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. | Drug: 75 mg acetylsalicylic acid<br>* 75 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral<br>* Other names: 75mg Aspirin;Drug: Placebo of acetylsalicylic acid and Metformin<br>* Pills with shape, color and smell same with acetylsalicylic acid and metformin, daily, oral<br>|
| Experimental: Aspirin 150 mg and placebo<br>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. | Drug: 150 mg acetylsalicylic acid<br>* 150 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral<br>* Other names: 150mg Aspirin;Drug: Placebo of acetylsalicylic acid and Metformin<br>* Pills with shape, color and smell same with acetylsalicylic acid and metformin, daily, oral<br>|
| Experimental: Aspirin 75 mg and Metformin 1.5 g<br>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 | Drug: 75 mg acetylsalicylic acid<br>* 75 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral<br>* Other names: 75mg Aspirin;Drug: 1.5g Metformin<br>* up to 1.5 g metformin (C4H11N5, CAS number 657-24-9) daily, Oral Dose increases from 0.5g to 1.0g to 1.5g<br>* Other names: 1.5g Glucophage;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of preterm preeclampsia(<37 weeks) | 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. | ≥20 weeks to <37 weeks of gestation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse outcome of pregnancy at <37 weeks. | including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption. | <37 weeks of gestation | 
| Adverse outcome of pregnancy at <34 weeks. | including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption. | <34 weeks of gestation | 
| Adverse outcome of pregnancy at ≥37 weeks | including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, stillbirth or placental abruption. | ≥37 weeks of gestation | 
| Neonatal mortality | A neonatal death is a death during 0-27 days of life. | During the first 28 days of life (0-27days) | 
| Neonatal morbidity | 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. | During the first 28 days of life (0-27days) | 
| Neonatal birthweight below the 3rd,5th and 10th centile. | Birthweight and birthweight percentile for gestational age at delivery is calculated using a normal range derived in a Chinese population. | At delivery | 
| Stillbirth or neonatal death | 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. | At delivery | 
| <34 weeks and <37 weeks spontaneous preterm 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). | At spontaneous delivery | 
| Gestational age | 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. | At delivery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Preterm preeclampsia, Aspirin, Metformin