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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] 294448 0
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 307198 0
Pregnancy 307199 0
Condition category
Condition code
Reproductive Health and Childbirth 306308 306308 0 0
Antenatal care
Cardiovascular 306309 306309 0 0
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] 300737 0
Prevention
Intervention code [2] 300738 0
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] 305321 0
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] 305321 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.
Secondary outcome [1] 344836 0
Incidence of term preeclampsia (preeclampsia subtype diagnosed at =>37 weeks' gestation) according to ISSHP diagnostic criteria.
Timepoint [1] 344836 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.
Secondary outcome [2] 344837 0
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] 344837 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.
Secondary outcome [3] 344838 0
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] 344838 0
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] 344839 0
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] 344839 0
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] 345263 0
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] 345263 0
Assessed after 37 weeks of pregnancy by maternal medical history and clinical pathology review.
Secondary outcome [6] 345264 0
Incidence of early preeclampsia (preeclampsia subtype diagnosed <34 weeks + 0 days of pregnancy) according to ISSHP diagnostic criteria.

Timepoint [6] 345264 0
Assessed after 34 weeks of pregnancy by maternal medical history and clinical pathology review.
Secondary outcome [7] 345290 0
Baby's birth weight (g)

Timepoint [7] 345290 0
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] 345291 0
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] 345291 0
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] 345307 0
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] 345307 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.
Secondary outcome [10] 345311 0
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] 345311 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history review.
Secondary outcome [11] 345312 0
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] 345312 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history review.
Secondary outcome [12] 345985 0
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] 345985 0
Assessed after the puerperium (>6 weeks following birth) by maternal medical history and clinical pathology review.
Secondary outcome [13] 349599 0
Gestational hypertension without preeclampsia
Timepoint [13] 349599 0
Assessed after the puerperium by maternal medical history review
Secondary outcome [14] 349600 0
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] 349600 0
After the puerperium, by medical history review
Secondary outcome [15] 349601 0
Customised neonatal birthweight centile <10% (using the GROW International Customized Centile Calculator)
Timepoint [15] 349601 0
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] 349602 0
Neonatal Intensive Care Unit admission
Timepoint [16] 349602 0
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] 349603 0
Apgar scores at 1 minute and 5 minutes of life
Timepoint [17] 349603 0
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] 349604 0
Length of neonatal hospital stay
Timepoint [18] 349604 0
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
Gender
Females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10478 0
Mercy Hospital for Women - Heidelberg
Recruitment hospital [2] 10479 0
Werribee Mercy Hospital - Werribee
Recruitment hospital [3] 10480 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 22193 0
3021 - St Albans
Recruitment postcode(s) [2] 22192 0
3030 - Werribee
Recruitment postcode(s) [3] 22191 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 10241 0
United Kingdom
State/province [1] 10241 0
Manchester
Country [2] 10242 0
Chile
State/province [2] 10242 0
Santiago

Funding & Sponsors
Funding source category [1] 299075 0
Other
Name [1] 299075 0
Mercy Perinatal
Address [1] 299075 0
Mercy Perinatal
Level 3
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country [1] 299075 0
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] 298320 0
None
Name [1] 298320 0
Address [1] 298320 0
Country [1] 298320 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 300009 0
Mercy Health Human Research Ethics Committee (EC00230)
Ethics committee address [1] 300009 0
Level 6, Mercy Hospital for Women, 163 Studley Road, Heidelberg, 3084, VIC
Ethics committee country [1] 300009 0
Australia
Date submitted for ethics approval [1] 300009 0
06/08/2018
Approval date [1] 300009 0
Ethics approval number [1] 300009 0
Ethics committee name [2] 300994 0
Melbourne Health Human Research Ethics Committee (EC00243)
Ethics committee address [2] 300994 0
Office for Research, Level 2, South West, 300 Grattan Street, Parkville Victoria
Ethics committee country [2] 300994 0
Australia
Date submitted for ethics approval [2] 300994 0
26/09/2018
Approval date [2] 300994 0
Ethics approval number [2] 300994 0

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 82250 0
Prof Stephen Tong
Address 82250 0
University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 82250 0
Australia
Phone 82250 0
+61384584381
Fax 82250 0
+61384584830
Email 82250 0
stephentong1@gmail.com
Contact person for public queries
Name 82251 0
Ms Anna Middleton
Address 82251 0
University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 82251 0
Australia
Phone 82251 0
+61384584381
Fax 82251 0
+61384584830
Email 82251 0
amiddleton@mercy.com.au
Contact person for scientific queries
Name 82252 0
Dr Natalie Hannan
Address 82252 0
University of Melbourne Department of Obstetrics and Gynaecology
Level 4
Mercy Hospital for Women
163 Studley Road
Heidelberg
Victoria 3084
Country 82252 0
Australia
Phone 82252 0
+61384584381
Fax 82252 0
+61384584830
Email 82252 0
nhannan@unimelb.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
None collected for this trial. No participants enrolled.
What supporting documents are/will be available?
No other documents available
Summary results
No Results