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

Preeclampsia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05580523
• Other study ID #: MOST-AVERT
• Status: Recruiting
• Phase: N/A
• Start date: July 3, 2023
• Est. completion date: November 30, 2025

Study information

• Verified date: November 2023
• Source: Chinese University of Hong Kong
• Contact: Chiu Yee, Liona Poon, MD
• Phone: (852) 3505 1290
• Email: liona.poon[@]cuhk.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3000
• Est. completion date: November 30, 2025
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Pre-Eclampsia
• Preeclampsia

Intervention

Drug:
• 75 mg acetylsalicylic acid
75 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral
• 1.5g Metformin
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
• 150 mg acetylsalicylic acid
150 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral
• Placebo of acetylsalicylic acid and Metformin
Pills with shape, color and smell same with acetylsalicylic acid and metformin, daily, oral

Locations

Country	Name	City	State
China	Peking University First Hospital	Beijing	Beijing
China	West China Second University Hospital, Sichuan University	Chengdu	Sichuan
China	Guangzhou Women and Children's Medical Center	Guangzhou	Guangdong
China	The Third Affiliated Hospital of Guangzhou Medical University	Guangzhou	Guangdong
China	Obstetrics and Gynecology Hospital of Fudan University	Shanghai	Shanghai
China	Shanghai First Maternity and Infant Hospital	Shanghai	Shanghai

Sponsors (5)

Lead Sponsor	Collaborator
Chinese University of Hong Kong	Obstetrics & Gynecology Hospital of Fudan University, Peking University First Hospital, Shanghai First Maternity and Infant Hospital, West China Second University Hospital

Country where clinical trial is conducted

China, 

References & Publications (20)

ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):1. doi: 10.1097/AOG.0000000000003018. — View Citation

Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. 2011 Jan;31(1):66-74. doi: 10.1002/pd.2660. Erratum In: Prenat Diagn. 2011 Aug;31(8):832. — View Citation

Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0. — View Citation

Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016 Mar;214(3):356.e1-356.e15. doi: 10.1016/j.ajog.2015.12.019. Epub 2015 Dec 22. — View Citation

Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010 Aug;116(2 Pt 1):402-414. doi: 10.1097/AOG.0b013e3181e9322a. — View Citation

Caron N, Rivard GE, Michon N, Morin F, Pilon D, Moutquin JM, Rey E. Low-dose ASA response using the PFA-100 in women with high-risk pregnancy. J Obstet Gynaecol Can. 2009 Nov;31(11):1022-1027. doi: 10.1016/S1701-2163(16)34346-8. — View Citation

Chaemsaithong P, Pooh RK, Zheng M, Ma R, Chaiyasit N, Tokunaka M, Shaw SW, Seshadri S, Choolani M, Wataganara T, Yeo GSH, Wright A, Leung WC, Sekizawa A, Hu Y, Naruse K, Saito S, Sahota D, Leung TY, Poon LC. Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population. Am J Obstet Gynecol. 2019 Dec;221(6):650.e1-650.e16. doi: 10.1016/j.ajog.2019.09.041. Epub 2019 Oct 4. — View Citation

Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE, Walker BR, Quenby S, Wray S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman JE. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015 Oct;3(10):778-86. doi: 10.1016/S2213-8587(15)00219-3. Epub 2015 Jul 9. — View Citation

Hypertensive Disorders in Pregnancy Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. [Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China(2020)]. Zhonghua Fu Chan Ke Za Zhi. 2020 Apr 25;55(4):227-238. doi: 10.3760/cma.j.cn112141-20200114-00039. Chinese. — View Citation

Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001 Nov 24;323(7323):1213-7. doi: 10.1136/bmj.323.7323.1213. — View Citation

Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH. Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther. 2012;32(3):156-65. doi: 10.1159/000338655. Epub 2012 Jul 26. — View Citation

Rey E, Rivard GE. Is testing for aspirin response worthwhile in high-risk pregnancy? Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):38-42. doi: 10.1016/j.ejogrb.2011.02.026. Epub 2011 Mar 25. — View Citation

Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017 Feb;216(2):110-120.e6. doi: 10.1016/j.ajog.2016.09.076. Epub 2016 Sep 15. — View Citation

Roberge S, Villa P, Nicolaides K, Giguere Y, Vainio M, Bakthi A, Ebrashy A, Bujold E. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther. 2012;31(3):141-6. doi: 10.1159/000336662. Epub 2012 Mar 21. — View Citation

Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28. — View Citation

Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med. 2016 Feb 4;374(5):434-43. doi: 10.1056/NEJMoa1509819. — View Citation

von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143-8. doi: 10.1081/PRG-120021060. — View Citation

Witlin AG, Saade GR, Mattar F, Sibai BM. Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks' gestation. Am J Obstet Gynecol. 2000 Mar;182(3):607-11. doi: 10.1067/mob.2000.104224. — View Citation

Women's Heart Health Group of Chinese Society of Cardiology of Chinese Medical Association; Hypertension Group of Chinese Society of Cardiology of Chinese Medical Association. [Expert consensus on blood pressure management in hypertensive disorders of pregnancy (2019)]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Mar 24;48(3):195-204. doi: 10.3760/cma.j.cn112148-20191024-00652. Chinese. — View Citation

Wright D, Poon LC, Rolnik DL, Syngelaki A, Delgado JL, Vojtassakova D, de Alvarado M, Kapeti E, Rehal A, Pazos A, Carbone IF, Dutemeyer V, Plasencia W, Papantoniou N, Nicolaides KH. Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J Obstet Gynecol. 2017 Dec;217(6):685.e1-685.e5. doi: 10.1016/j.ajog.2017.08.110. Epub 2017 Sep 6. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Neonatal mortality	A neonatal death is a death during 0-27 days of life.	During the first 28 days of life (0-27days)
Secondary	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)
Secondary	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
Secondary	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
Secondary	<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
Secondary	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