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Trial registered on ANZCTR

Registration number

ACTRN12618000690257p

Ethics application status

Not yet submitted

Date submitted

4/04/2018

Date registered

27/04/2018

Date last updated

17/05/2019

Date data sharing statement initially provided

17/05/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

A Prospective, Pre-ecLampsia/Eclampsia Prevention IntervEntion

Scientific title

A Prospective PreecLampsia/Eclampsia Prevention Intervention (APPLE PIE): A randomised controlled trial determining the effect of esomeprazole on the incidence of preeclampsia in a cohort of nulliparous, high BMI women.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1211-3663

Trial acronym

APPLE PIE

Linked study record

None

Health condition

Health condition(s) or problem(s) studied:

Preeclampsia

Pregnancy

Condition category

Condition code

Reproductive Health and Childbirth

Antenatal care

Cardiovascular

Hypertension

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

APPLE PIE study - a prospective, pre-eclampsia/eclampsia prevention intervention. A multi-centre, double blind, randomised, placebo-controlled trial evaluating whether oral esomeprazole tablets (40mg taken once daily from recruitment until delivery) can decrease the incidence of preeclampsia/eclampisa in a cohort of nulliparous women with a BMI =>30kg/m² at the time of hospital booking, when compared to inert placebo. Nulliparity and obesity are two independent risk factors for the development of preeclampsia. Participants will be randomised at recruitment (12-20 weeks' gestation) to either treatment or placebo group, and provided with batches of study tablets for the duration of their pregnancy. Adherence to the study protocol will be assessed by research midwives and obstetric doctors using verbal reports (phone and face-to-face), pill counts and medication diaries completed by the participants. The statistical analysis of the study will use an intention to treat (ITT) analysis, where adherence rates will be discussed. The primary outcome will be the diagnosis of preeclampsia.

Intervention code [1]

Prevention

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Placebo-controlled trial. One inert placebo tablet, identical in appearance to the study treatment, to be taken orally, once daily, from recruitment until delivery of the pregnancy. Placebo tablets will be produced by a contracted cGMP third party. The composition of the placebo treatment will include Microcrystalline Cellulose USP/NF; Colloidal Silicon Dioxide USP/NF; Sodium Starch Glycolate USP/NF; and Sodium Stearyl Fumarate USP/NF. These are standard tablet excipients of GMP grade approved for use worldwide.

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome is the incidence of preeclampsia (using the current guideline of the International Society for the Study of Hypertension in Pregnancy as the diagnostic criteria).

Timepoint [1]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.

Secondary outcome [1]

Incidence of term preeclampsia (preeclampsia subtype diagnosed at =>37 weeks' gestation) according to ISSHP diagnostic criteria.

Timepoint [1]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.

Secondary outcome [2]

Gestation of pregnancy at delivery.

This outcome will be assessed by calculating the difference between the estimated due date (EDD) of pregnancy (confirmed by first trimester ultrasound; or by the clinician's nominated agreed EDD where no ultrasound was completed at <13 weeks' gestation) and the date of delivery.

Timepoint [2]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.

Secondary outcome [3]

Composite of the following fetal/neonatal complications/adverse outcomes: A) Respiratory distress syndrome (defined as the need for oxygen support or supplemental oxygen for >4 hours) B) Clinical diagnosis of intraventricular haemorrhage =>grade II C) Clinical diagnosis of necrotizing enterocolitis resulting in surgery D) Sepsis with confirmed bacteraemia in blood cultures E) Anaemia resulting in blood transfusion F) Retinopathy of prematurity

Timepoint [3]

These complications and adverse events will be assessed by medical history and clinical pathology results review >28 days following the baby's birth, and after their discharge from hospital, in case of the emergence of complications during the neonatal period.

Secondary outcome [4]

Exploratory measurement of preeclampsia-related maternal biomarkers (sFLT-1, sEng, PIGF, ET-1 and VCAM-1) in a subset of participants attending Mercy Hospital for Women for their pregnancy care. This will form a nested longitudinal sub-study within the main study.

Timepoint [4]

Blood samples will be collected at recruitment (12-20 weeks), ~28 weeks and ~36 weeks of pregnancy. The samples will be sent for laboratory analysis as a group within 12 months of the completion of recruitment at Mercy Hospital for Women.

Secondary outcome [5]

Incidence of pre-term preeclampsia (preeclampsia subtype diagnosed between 34 weeks + 0 days - 36 weeks + 6 days of pregnancy) according to ISSHP diagnostic criteria.

This outcome will be expressed as both 95% confidence intervals (CI) of relative risk (RR) and attributable risk (AR). Hypothesis tests will be performed using Chi-squared tests of association. If the study treatment is successful at reducing the incidence of preeclampsia, it could be expected to see a significant reduction (p=<0.05) in the diagnosis of preterm preeclampsia in the treatment group.

Timepoint [5]

Assessed after 37 weeks of pregnancy by maternal medical history and clinical pathology review.

Secondary outcome [6]

Incidence of early preeclampsia (preeclampsia subtype diagnosed <34 weeks + 0 days of pregnancy) according to ISSHP diagnostic criteria.

Timepoint [6]

Assessed after 34 weeks of pregnancy by maternal medical history and clinical pathology review.

Secondary outcome [7]

Baby's birth weight (g)

Timepoint [7]

The first documented bare weight taken after baby's birth, collected during neonatal history review (performed >28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Secondary outcome [8]

Perinatal loss (the still birth OR neonatal death of a participant's baby) Still birth is defined as a fetal death in utero which occurs =>20 weeks of pregnancy up until birth. This includes losses which occur during labour. Neonatal death is defined as the death of a live born infant within the first 28 days of life. For the purposes of this study, we will also classify any death of a baby which occurs beyond 28 days of life, but during the baby's inpatient hospital stay (e.g. a baby admitted at birth to NICU who dies on day 35 of life), as a neonatal death. These incidences are expected to be inevitable, but rare, within the study population of 5500 mother-baby dyads.

Timepoint [8]

Data will be collected during neonatal history review (>28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Secondary outcome [9]

Incidence of preterm delivery (<37 weeks' gestation).

This outcome will be assessed by calculating the difference between the estimated due date (EDD) of pregnancy (confirmed by first trimester ultrasound; or by the clinician's nominated agreed EDD if no ultrasound was completed at <13 weeks' gestation) and the date of delivery.

Timepoint [9]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.

Secondary outcome [10]

Mode of birth (unassisted vaginal birth; forceps assisted vaginal birth; vacuum assisted vaginal birth; elective lower uterine segment caesarean section; emergency lower uterine segment caesarean section; or classical caesarean section).

Timepoint [10]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history review.

Secondary outcome [11]

Maternal gestational weight gain (GWG) in kg.

Assessment of the relative change in maternal weight from recruitment until last documented weight prior to delivery.

Timepoint [11]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history review.

Secondary outcome [12]

Composite of adverse maternal outcomes, including: A) All-cause maternal mortality (from recruitment up to 6 weeks postpartum); B) Eclampsia (diagnosed using ACOG guidelines); C) pulmonary oedaema; D) Severe renal impairment; E) Cerebrovascular event; F) Liver haematoma or rupture; G) Placental abruption

Timepoint [12]

Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.

Secondary outcome [13]

Gestational hypertension without preeclampsia

Timepoint [13]

Assessed after the puerperium by maternal medical history review

Secondary outcome [14]

Indication for delivery. Delivery may occur spontaneously or due to medical intervention (induction or caesarean) for maternal or fetal reasons. This outcome will be assessed from the clinical notes made in the maternal and neonatal medical histories. In cases where more than one indication for delivery existed, each indication will be noted.

Timepoint [14]

After the puerperium, by medical history review

Secondary outcome [15]

Customised neonatal birthweight centile <10% (using the GROW International Customized Centile Calculator)

Timepoint [15]

Data will be collected during neonatal history review (>28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Secondary outcome [16]

Neonatal Intensive Care Unit admission

Timepoint [16]

Data will be collected during neonatal history review (>28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Secondary outcome [17]

Apgar scores at 1 minute and 5 minutes of life

Timepoint [17]

Data will be collected during neonatal history review (>28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Secondary outcome [18]

Length of neonatal hospital stay

Timepoint [18]

Data will be collected during neonatal history review (>28 days post-birth and following hospital discharge; or following still birth/neonatal death).

Eligibility

Key inclusion criteria

• Nulliparous
• BMI of =>30 kg/m² at hospital booking visit
• 12 - 20 weeks of pregnancy at the time of recruitment
• Singleton pregnancy
• Age 18 and above
• Able to comprehend study information

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

• Patient is unable or unwilling to give consent
• Known/suspected major fetal malformation or infection
• Any current use of a PPI
• Contraindications to the use of esomeprazole
• Pre-existing renal impairment
• Pre-existing hepatic impairment
• HIV, Hepatitis B, or Hepatitis C positive

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Central randomisation by computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Simple randomisation table generated by computer software (computerised sequence generation), with stratification for investigational site of recruitment and aspirin use.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

None

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

Sample size calculation:
The sample size was estimated using a baseline incident rate for PE in mothers with BMI =>30 kg/m² of 9.7%. Settings were a power of 0.9, two-sided significance level 0.05 and meaningful attributable risk reduction (AR) allowing detection of a decrease the incidence of PE.

Assuming a drop-out rate of 7% we are aiming for a sample size of 5500 women with the potential to recruit approximately 2000 women per year from our current numbers of women meeting study eligibility criteria at the various investigational sites. Inflation for treatment cross over from placebo to off trial PPI usage has not been accounted for in these calculations.

Statistical analysis plan:
Patient characteristics at randomization, by treatment group, will be summarized as mean (SD), median [25th - 75th percentile], minimum and maximum or number (%) depending upon data type and distribution. The distribution of baseline characteristics between treatment groups will not be subject to hypothesis testing. All analyses will be performed on an intention to treat basis.

The primary outcome, a reduction in PE incidence in the treatment group when compared with the placebo group, will be presented using both 95% confidence intervals (CI) of relative risk (RR) and attributable risk (AR). Analysis will be performed using logistic regression adjusted for site, aspirin usage and metformin usage.

Pre-specified secondary outcomes will be presented using both 95% confidence intervals (CI) of relative risk (RR) and attributable risk (AR). Similar presentation will be made for Continuous variables, sFLT1, sENG, PIGF, ET1, VCAM will be presented using point estimate of group difference & associated 95%CI of difference. Hypothesis tests, where performed, will use Chi-squared tests of association for categorical variables and unpaired t-tests or rank-sum tests for continuous variables according to distribution.

For the primary outcome as per protocol analyses based upon PPI medication actually received will also be performed. Sensitivity analysis, using regression techniques may be performed to assess the effect of any chance covariate imbalance between treatment arms, using propensity score as the sole covariate apart from treatment assignment should covariate distributions vary substantially across treatment arms.
The primary outcome analysis depends upon obtaining information on four items for each mother (presence of pre-eclampsia, group assignment, aspirin usage and metformin usage). Given the nature of the intervention and the prospective follow-up of each mother throughout their gestation we consider that the prevalence of missing data for these items will be very low. Consequently we do not plan to perform imputation for missing data which will only be presented descriptively.

A final analysis will be conducted by the trial Investigators, verified by independent statisticians.
For all outcomes the significance level is two-sided and set at 0.05. Adjustment for inflation of type I error secondary to multiple comparisons of secondary outcomes will be performed using the Holm-Sidak adjusted p-value method. All analyses will be performed using Stata statistical software (currently version 15).

Recruitment

Recruitment status

Withdrawn

Reason for early stopping/withdrawal

Lack of funding/staff/facilities
Other reasons/comments

Other reasons

Difficulties obtaining appropriate indemnity via sponsor's insurer.

Date of first participant enrolment

Anticipated

31/10/2018

Actual

Date of last participant enrolment

Anticipated

31/12/2023

Actual

Date of last data collection

Anticipated

30/06/2024

Actual

Sample size

Target

5500

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [2]

Werribee Mercy Hospital - Werribee

Recruitment hospital [3]

Sunshine Hospital - St Albans

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3030 - Werribee

Recruitment postcode(s) [3]

3021 - St Albans

Recruitment outside Australia

Country [1]

United Kingdom

State/province [1]

Manchester

Country [2]

Chile

State/province [2]

Santiago

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Mercy Perinatal

Address [1]

Mercy Perinatal
Level 3
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country [1]

Australia

Primary sponsor type

University

Name

University of Melbourne (through its Department of Obstetrics and Gynaecology)

Address

University of Melbourne
Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Mercy Health Human Research Ethics Committee (EC00230)

Ethics committee address [1]

Level 6, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, VIC

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/08/2018

Approval date [1]

Ethics approval number [1]

Ethics committee name [2]

Melbourne Health Human Research Ethics Committee (EC00243)

Ethics committee address [2]

Office for Research, Level 2, South West, 300 Grattan Street, Parkville Victoria

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

26/09/2018

Approval date [2]

Ethics approval number [2]

Summary

Brief summary

Preeclampsia is a common, serious complication of pregnancy, affecting 5-8% of pregnancies. It is responsible for 70,000 maternal and 500,000 infant deaths globally every year, with this burden largely shouldered by lower-middle income populations. Currently there is no medical treatment for preeclampsia and the only way to stop disease progression is delivery of the pregnancy. When this occurs at early gestations, the serious potential complications of prematurity are inflicted on the newborn. The establishment of a safe preventative treatment for preeclampsia would therefore be a major advance in the clinical care of pregnant women and their babies.

Laboratory work undertaken by the Translational Obstetrics Group at the University of Melbourne has shown that Proton Pump Inhibitor (PPI) drugs may play an important role in preventing or treating preeclampsia. Esomeprazole, was shown to be particularly effective at reducing high blood pressure associated with preeclampsia in animal studies and when tested on donated human placental tissues. The drugs were also observed to reduce and partially reverse damage to the blood vessel linings (endothelium) caused by preeclampsia. Another study has shown that women who have a high risk of developing preeclampsia and are coincidentally taking PPIs have lower levels of preeclampsia biomarkers present in their bloodstream than other high-risk women who are not taking PPIs. In large studies of >1,000,000 pregnant women, PPIs (commonly prescribed in pregnancy to treat symptoms of acid reflux) have been shown to be safe to take, with no increase in the risk of fetal malformation (structural damage to the baby), premature birth, or miscarriage. 
Given these promising early results, coupled with esomeprazole’s established low-risk harm profile in pregnancy, we propose to progress this concept by undertaking a clinical trial to evaluate esomeprazole as a preventative therapy for preeclampsia.
We plan to recruit a total of 5,500 women with a Body Mass Index (BMI) =>30kg/m² at the time of their first hospital visit, from a number of different hospital sites in Australia, Chile and the UK, leading up to the birth of their first baby. This group of women has been chosen because they have a higher risk of developing preeclampsia than other pregnant women. 
We will randomly allocate these women to either receive 40mg oral esomeprazole, or an inert placebo (sugar pill), each day from recruitment until the birth of their baby. We will monitor for the diagnosis of preeclampsia in these two groups, as well as collecting information about the outcomes of the women and their babies. We will also monitor key biochemical features of preeclampsia in a subset of women who are recruited at the Mercy Hospital for Women. At the completion of this study, we hope to have sufficient evidence to justify recommending routine esomeprazole therapy as a preventative treatment for preeclampsia in pregnant women with a BMI =>30kg/m².

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Stephen Tong

Address

University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61384584381

Fax

+61384584830

stephentong1@gmail.com

Contact person for public queries

Name

Anna Middleton

Address

University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61384584381

Fax

+61384584830

amiddleton@mercy.com.au

Contact person for scientific queries

Name

Natalie Hannan

Address

University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084

Country

Australia

Phone

+61384584381

Fax

+61384584830

nhannan@unimelb.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

None collected for this trial. No participants enrolled.

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Proton Pump Inhibitors Use and Risk of Preeclampsia: A Meta-Analysis.	2022	https://dx.doi.org/10.3390/jcm11164675

N.B. These documents automatically identified may not have been verified by the study sponsor.

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