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

Primary Purpose

Preeclampsia

Status

Not yet recruiting

Phase

Not Applicable

Locations

China

Study Type

Interventional

Intervention

Aspirin 75mg

Metformin 1.5g

Aspirin 150 mg

Placebo

About this trial

This is an interventional prevention trial for Preeclampsia focused on measuring Preterm preeclampsia, Aspirin, Metformin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

Peking University First Hospital
Guangzhou Women and Children's Medical Center
The Third Affiliated Hospital of Guangzhou Medical University
Obstetrics and Gynecology Hospital of Fudan University
Shanghai First Maternity and Infant Hospital
West China Second University Hospital, Sichuan University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Aspirin 75 mg and placebo

Aspirin 150 mg and placebo

Aspirin 75 mg and Metformin 1.5 g

Arm Description

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.

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

Adverse outcome of pregnancy at ≥37 weeks

including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, stillbirth or placental abruption.

Neonatal mortality

A neonatal death is a death during 0-27 days of life.

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.

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.

Stillbirth or neonatal death

<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).

Gestational age

Full Information

NCT ID

NCT05580523

First Posted

October 12, 2022

Last Updated

May 18, 2023

Sponsor

Chinese University of Hong Kong

Collaborators

Obstetrics & Gynecology Hospital of Fudan University, Shanghai First Maternity and Infant Hospital, West China Second University Hospital, Peking University First Hospital

1. Study Identification

Unique Protocol Identification Number

NCT05580523

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

June 2023 (Anticipated)

Primary Completion Date

January 2025 (Anticipated)

Study Completion Date

February 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Chinese University of Hong Kong

Collaborators

Obstetrics & Gynecology Hospital of Fudan University, Shanghai First Maternity and Infant Hospital, West China Second University Hospital, Peking University First Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Preeclampsia

Keywords

Preterm preeclampsia, Aspirin, Metformin

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

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.

Allocation

Randomized

Enrollment

3000 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Aspirin 75 mg and placebo

Arm Type

Experimental

Arm Description

Arm Title

Aspirin 150 mg and placebo

Arm Type

Experimental

Arm Description

Arm Title

Aspirin 75 mg and Metformin 1.5 g

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Aspirin 75mg

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Metformin 1.5g

Intervention Description

up to 1.5 g metformin (C4H11N5, CAS number 657-24-9).

Intervention Type

Drug

Intervention Name(s)

Aspirin 150 mg

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

placebo

Primary Outcome Measure Information:

Title

Incidence of preterm preeclampsia(<37 weeks)

Description

Time Frame

≥20 weeks to <37 weeks of gestation

Secondary Outcome Measure Information:

Title

Adverse outcome of pregnancy at <37 weeks.

Description

including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption.

Time Frame

<37 weeks of gestation

Title

Adverse outcome of pregnancy at <34 weeks.

Description

including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, miscarriage or still birth or placental abruption.

Time Frame

<34 weeks of gestation

Title

Adverse outcome of pregnancy at ≥37 weeks

Description

including preeclampsia requiring delivery, gestational age (SGA; <5th percentile) requiring delivery, stillbirth or placental abruption.

Time Frame

≥37 weeks of gestation

Title

Neonatal mortality

Description

A neonatal death is a death during 0-27 days of life.

Time Frame

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

Title

Neonatal morbidity

Description

Time Frame

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

Title

Neonatal birthweight below the 3rd,5th and 10th centile.

Description

Birthweight and birthweight percentile for gestational age at delivery is calculated using a normal range derived in a Chinese population.

Time Frame

At delivery

Title

Stillbirth or neonatal death

Time Frame

At delivery

Title

<34 weeks and <37 weeks spontaneous preterm delivery

Description

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).

Time Frame

At spontaneous delivery

Title

Gestational age

Time Frame

At delivery

10. Eligibility

Sex

Female

Gender Based

Yes

Gender Eligibility Description

All eligible women with singleton pregnancies

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Liona Prof Poon, MD

Phone

(852) 3505 1290

liona.poon@cuhk.edu.hk

First Name & Middle Initial & Last Name or Official Title & Degree

Ronald Prof Wang

Phone

(852) 3505 3099

ccwang@cuhk.edu.hk

Facility Information:

Facility Name

Peking University First Hospital

City

Beijing

State/Province

Beijing

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Xueyin Wang, PhD

Phone

+86-1083573227

xueyin0925@163.com

First Name & Middle Initial & Last Name & Degree

Yuchun Zhu, MD

Phone

+86-13911102732

zhu_yuchun@163.com

Facility Name

Guangzhou Women and Children's Medical Center

City

Guangzhou

State/Province

Guangdong

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yanmin Jiang, MD

Phone

13189081153

13189081153@163.com

First Name & Middle Initial & Last Name & Degree

Di Mao, MD

Phone

+86-15986442004

melodygz2019@gmail.com

Facility Name

The Third Affiliated Hospital of Guangzhou Medical University

City

Guangzhou

State/Province

Guangdong

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Zhihua Li, MD

Phone

18998321631

zhihuali2004@163.com

First Name & Middle Initial & Last Name & Degree

Dunjin Chen, MD

Phone

18928916722

gzdrchen@gzhmc.edu.cn

Facility Name

Obstetrics and Gynecology Hospital of Fudan University

City

Shanghai

State/Province

Shanghai

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Weirong Gu, MD,PhD

Phone

+86-13501674753

guweirong1237@fckyy.org.cn

First Name & Middle Initial & Last Name & Degree

Qiongjie Zhou, MD,PhD

Phone

+86-13671558865

zhouqiongjie1732@fckyy.org.cn

Facility Name

Shanghai First Maternity and Infant Hospital

City

Shanghai

State/Province

Shanghai

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hao Ying, MD

Phone

+86 13371985049

stephenying_2011@163.com

First Name & Middle Initial & Last Name & Degree

Xiang Jiang, MD

Phone

+86 18502129988

jiangxiang79@163.com

Facility Name

West China Second University Hospital, Sichuan University

City

Chengdu

State/Province

Sichuan

Country

China

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yanping Zhang, MD

Phone

18280173971

1187256353@qq.com

First Name & Middle Initial & Last Name & Degree

Rong Zhou, MD

Phone

18180609085

zhourong_hx@scu.edu.cn

12. IPD Sharing Statement

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

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