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

NCT05580523 | Unknown DMC

• 1 other identifier: MOST-AVERT
• Study Type: interventional
• Target: 3,000
• Locations: 1 country
• Sites: 6

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.

Conditions

Preeclampsia

Keywords

Preterm preeclampsia; Aspirin; Metformin

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Adverse outcome of pregnancy at <37 weeks.

  <37 weeks of gestation

• Adverse outcome of pregnancy at <34 weeks.

  <34 weeks of gestation

• Adverse outcome of pregnancy at ≥37 weeks

  ≥37 weeks of gestation

• Neonatal mortality

  During the first 28 days of life (0-27days)

• Neonatal morbidity

  During the first 28 days of life (0-27days)

Study Arms (3)

Aspirin 75 mg and placebo

EXPERIMENTAL

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; Drug: Placebo of acetylsalicylic acid and Metformin

Aspirin 150 mg and placebo

EXPERIMENTAL

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; Drug: Placebo of acetylsalicylic acid and Metformin

Aspirin 75 mg and Metformin 1.5 g

EXPERIMENTAL

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; Drug: 1.5g Metformin

Interventions

75 mg acetylsalicylic acid DRUG

75 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral

Also known as: 75mg Aspirin

Aspirin 75 mg and Metformin 1.5 g; Aspirin 75 mg and placebo

1.5g Metformin DRUG

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

Also known as: 1.5g Glucophage

Aspirin 75 mg and Metformin 1.5 g

150 mg acetylsalicylic acid DRUG

150 mg acetylsalicylic acid (C9H8O4, CAS number 50-78-2) daily, Oral

Also known as: 150mg Aspirin

Aspirin 150 mg and placebo

Placebo of acetylsalicylic acid and Metformin DRUG

Pills with shape, color and smell same with acetylsalicylic acid and metformin, daily, oral

Aspirin 150 mg and placebo; Aspirin 75 mg and placebo

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: All eligible women with singleton pregnancies
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Chinese University of Hong Kong: lead
• Obstetrics & Gynecology Hospital of Fudan University: collaborator
• Shanghai First Maternity and Infant Hospital: collaborator
• West China Second University Hospital: collaborator
• Peking University First Hospital: collaborator

Study Sites (6)

Peking University First Hospital

Beijing, Beijing Municipality, China

RECRUITING

Guangzhou Women and Children's Medical Center

Guangzhou, Guangdong, China

WITHDRAWN

The Third Affiliated Hospital of Guangzhou Medical University

Guangzhou, Guangdong, China

NOT YET RECRUITING

Obstetrics and Gynecology Hospital of Fudan University

Shanghai, Shanghai Municipality, China

RECRUITING

Shanghai First Maternity and Infant Hospital

Shanghai, Shanghai Municipality, China

RECRUITING

West China Second University Hospital, Sichuan University

Chengdu, Sichuan, China

RECRUITING

Related Publications (21)

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• 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.

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• 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.

  PMID: 21210481 BACKGROUND

• 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.

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• 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.

  PMID: 28657417 BACKGROUND

• 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.

  PMID: 20664402 BACKGROUND

• 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.

  PMID: 22441437 BACKGROUND

• 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.

  PMID: 27640943 BACKGROUND

• 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.

  PMID: 20175340 BACKGROUND

• 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.

  PMID: 21440360 BACKGROUND

• 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.

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• 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.

  PMID: 26721779 BACKGROUND

• 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.

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• 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.

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  PMID: 38631826 DERIVED

MeSH Terms

Conditions

Pre-Eclampsia

Interventions

Aspirin; Metformin

Condition Hierarchy (Ancestors)

Hypertension, Pregnancy-Induced; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Biguanides; Guanidines; Amidines

Study Officials

• Chiu Yee, Liona Poon, MD

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Chiu Yee, Liona Poon, MD

CONTACT

(852) 3505 1290; liona.poon@cuhk.edu.hk

Chi Chiu Wang, PhD

CONTACT

(852) 3505 3099; ccwang@cuhk.edu.hk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: PI, participating research doctors, pharmacists at the local clinical trial pharmacy, project managers and others involved in the trial are all blinded to the investigational medicinal product (IMP). The tablets and capsules will be identical, so it will not be possible to distinguish between the different IMPs.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor (Clinical)

Study Record Dates

• First Submitted: October 12, 2022
• First Posted: October 14, 2022
• Study Start: July 3, 2023
• Primary Completion: January 1, 2025
• Study Completion: November 30, 2025
• Last Updated: November 8, 2023

Record last verified: 2023-11

Locations

CN (6)