Double blind, randomised, placebocontrolled trial to evaluate the efficacy of esomeprazole to treat early onset pre-eclampsia (PIE Trial): A study protocol

Introduction: Pre-eclampsia is a major complication of pregnancy, globally responsible for 60 000 maternal deaths per year, and far greater numbers of fetal losses. There is no definitive treatment other than delivery. A drug that can quench the disease process could be useful to treat early onset pre-eclampsia, as it could allow pregnancies to safely continue to a gestation where fetal outcomes are significantly improved. We have generated preclinical data to show esomeprazole, a proton pump inhibitor used for gastric reflux, has potent biological effects that makes it a worthwhile therapeutic candidate. Esomeprazole potently decreases soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin secretion from placenta and endothelial cells, and has biological actions to mitigate endothelial dysfunction and oxidative stress. Methods and analysis: We propose undertaking a phase II, double blind, randomised controlled clinical trial to examine whether administering 40 mg esomeprazole daily may prolong gestation in women with early onset pre-eclampsia. We will recruit 120 women (gestational age of 26+0 to 31+6 weeks) who will be randomised to receive either esomeprazole or an identical placebo. The primary outcome will be the number of days from randomisation to delivery. Secondary outcomes include maternal, fetal and neonatal composite and individual outcomes. Maternal outcomes include maternal death, eclampsia, pulmonary oedema, severe renal impairment, cerebral vascular events and liver haematoma or rupture. Neonatal outcomes include neonatal death within 6 weeks after the due date, intraventricular haemorrhage, necrotising enterocolitis and bronchopulmonary dysplasia. We will examine whether esomeprazole can decrease serum sFlt-1 and soluble endoglin levels and we will record the safety of esomeprazole in these pregnancies. Ethics and dissemination: This study has ethical approval (Protocol V.2.4, M14/09/038, Federal Wide assurance Number 00001372, IRB0005239), and is registered with NHREC (ID 3649) and the Pan African Clinical Trial Registry (PACTR201504000771349). Data will be presented at international conferences and published in peer-reviewed journals. The full protocol is included as supplementary information (see online supplementary information 1). Phase II hospital-based, double blind, randomised, placebo-controlled trial. Pregnant women diagnosed with early onset pre-eclampsia at a gestational age between 26+0 and 31+6 weeks at Tygerberg hospital (Western Cape Provence of South Africa) will be invited to participate. To be enrolled, the treating team needs to have determined after their initial assessment that delivery is unlikely to be required within 48 h. A starting point of 26+0 weeks has been chosen as this would be the earliest gestation that Tygerberg Hospital would consider to be viable and are suitable to be offered expectant management. We will recruit women with a singleton pregnancy diagnosed with pre-eclampsia, defined according to the criteria published by the International Society for the Study of Hypertension in Pregnancy (ISSHP).14 We will seek to recruit those with pregnancies at a gestational age between 26+0 and 31+6 weeks, determined by either period dates (if the women is certain of her last menstrual period) or by an early, or mid trimester pregnancy ultrasound. If the gestational age is uncertain, we will recruit participants with an estimated fetal weight between 500 and 1800 g, determined by ultrasound performed at presentation. At Tygerberg Hospital we would not consider a pregnancy to be viable under 500 g and we would not offer expectant management if the fetal weight was above 1800 g. To be eligible for this study, the treating clinicians need to have made an initial assessment and deemed that the patient is suitable for expectant management, that the fetus would benefit from expectant management and that immediate delivery is not required. A full list of the inclusion criteria is shown in box 1. A diagnosis of one of the following: ▸ Pre-eclampsia14 ▸ Gestational hypertension with evidence of pre-eclampsia ▸ Pre-existing hypertension with evidence of pre-eclampsia ▸ Unclassified proteinuric hypertension AND All of the following is present: ▸ Gestational age between 26+0 and 31+6 weeks ▸ Estimated fetal weight by ultrasound between 500 and 1800 g (if gestation is not certain) ▸ Singleton pregnancy ▸ The managing clinicians have made the assessment to proceed with expectant management and that delivery is not expected within 48 h ▸ The managing clinician and neonatologist believe that the fetus could potentially be delivered in a viable condition ▸ No suspicions of a major fetal anomaly or malformation ▸ Patient will be admitted to hospital for expectant management and standardised care Exclusion criteria include women with established maternal or fetal compromise that necessitates delivery, the current use of a proton pump inhibitor, contraindications to the use of a proton pump inhibitor or the use of medications that may interact with proton pump inhibitors. A full list of the exclusion criteria is shown in box 2. Any of the following at the initial assessment: ▸ Patient is unable or unwilling to give consent ▸ Established fetal compromise that necessitates delivery ▸ The presence of: Eclampsia ▸ Severe hypertension ▸ Cerebrovascular event ▸ Posterior reversible encephalopathy syndrome ▸ Severe renal impairment ▸ Pulmonary oedema ▸ Left-sided heart failure ▸ Disseminated intravascular coagulation ▸ Platelet count <50×109 ▸ Haemolysis, elevated liver enzymes and low platelets syndrome ▸ Liver transaminases >500 IU/L ▸ Liver haematoma or rupture ▸ Severe ascites Current use of a proton pump inhibitor ▸ Contraindications or a hypersensitivity reaction to the use of a proton pump inhibitor ▸ Current use of a drug that may be affected by a proton pump inhibitor Randomisation will be done in an equal ratio of esomeprazole to placebo. An online, web-based sequence generator system will be used. It will be linked with codes for placebo and treatment tablets provided by the manufacturer contracted to produce the trial medication. Both the researchers and participants will be blinded. The gestational age at diagnosis is likely to affect allowable length of pregnancy prolongation. To ensure treatment group allocation is balanced for this potential variable, we will stratify randomisation into two strata based on gestational age. Strata 1 includes a gestational age of 26+0 up to and including 28+6 weeks (500–1200 g if gestation is unknown). Strata 2 includes a gestational age of 29+0 up to and including 31+6 weeks (1200–1800 g if gestation is unknown). Thus, randomisation will include blocking within each gestational age stratum. We propose using blocks of 4–6 with the size and order randomly assigned. Once the participants have been randomised, the treatment pack with the same code will be allocated to the participant. All treatment packs will be identical and will contain either active tablets or placebo. The researchers will have no access to the randomisation list. This process will ensure that there is allocation concealment throughout the conduct of the trial. Participants will be identified after they have been admitted to Tygerberg Hospital (tertiary referral centre) with a diagnosis of early onset pre-eclampsia for expectant management. An information leaflet will be given to all potential participants and informed consent will be obtained (see online supplementary information 2 and 3). Each participant will be given an individual treatment pack containing either esomeprazole or placebo which will be produced by a contracted manufacturer IDT pharmaceuticals (http://en.idtaus.com.au). Labelling, storage and preparation will be done according to the requirements of the Medicines for Human Use (Clinical Trials) regulations. Participants will be randomised to daily administration of either active tablets containing 40 mg of esomeprazole or an identical placebo tablet orally once a day. Participants will remain under the care of the hospital treating team, and the study will not alter or interfere with the care given routinely to women with early onset pre-eclampsia, including on when to deliver. Expectant management for early onset pre-eclampsia involves admission to hospital, and close maternal and fetal surveillance. Maternal surveillance includes four hourly blood pressure measurement, twice daily clinical assessment, daily urinalysis and twice weekly assessments with blood tests (full blood count, renal function tests and hepatocellular enzymes if haemolysis, elevated liver enzymes and low platelets syndrome is suspected) and 24 h urinary protein measurement on admission. Fetal surveillance includes ultrasound assessments to assess growth of the fetus, the amniotic fluid index and fetal well-being including Doppler velocimetry of the umbilical artery, the ductus venosus and the middle cerebral artery. If there are no signs of fetal growth restriction or fetal compromise, the ultrasound is repeated two weekly to ensure there has been adequate trajectory of fetal growth. If there are signs of fetal growth restriction or fetal compromise, the frequency of ultrasound surveillance will be increased. Six hourly cardiotocographs are performed to assess the ongoing fetal condition. We will follow the Tygerberg Hospital protocols to monitor preterm fetal growth restriction and delivery may occur on fetal grounds if required. All participants will receive two doses of β-methasone 24 h apart to reduce the risks of neonatal respiratory distress syndrome, intracranial haemorrhage and necrotising enterocolitis. A single repeat dose is usually given 1 week later. Most participants will be on antihypertensive treatment with the aim to stabilise the systolic blood pressure between 140 and 150 mm Hg and the diastolic blood pressure between 90 and 100 mm Hg. The medications used to treat the blood pressure will be documented. All women should already be receiving calcium, iron and folic acid supplementation. Clinical care will be left up to the discretion of the clinical team. The indication for delivery will be a clinical decision. Indications for delivery may include failure to control blood pressure, the development of major maternal or fetal complications, or intrauterine fetal death. Expectant management will usually end at a gestation of 34 weeks. The reported duration that fetuses remain in utero after diagnosis of preterm pre-eclampsia is a mean of 11 days (SD of 7 days) and a median 9 days (range of 1–47 days).15 These data are derived from a descriptive study on expectant management of early onset pre-eclampsia at Tygerberg Hospital, where we propose to undertake this study.15 For 90% power, with a two-sided α set of 0.05, 43 patients are required in each group to identify a gain in gestation of 5 days. Given these data were skewed, the sample size has been multiplied by 1.15 to statistically correct for non-normality.16 This increases the number required to 50 per arm. An additional 10 per arm will be added to allow for drop-outs. Thus, a total of 120 participants will be recruited to provide sufficient power to examine our primary outcome. (Power calculation performed using PASS V.12 software. Hintze, J. (2013). PASS 12. NCSS, LLC. Kaysville, Utah, USA). Blood samples will be routinely collected twice a week. Two sets of specimens will be drawn, the routine pre-eclamptic monitoring samples and the trial samples. The routine blood samples include measurements of the haemoglobin, the platelet count and the urea and creatinine levels. These will be used by the managing clinicians to determine disease severity and may trigger delivery. The second set of samples will be the trial blood samples. These samples will be stored and will only be measured after delivery of the patient. These include measurements of sFlt, sEng and endothelin 1. These results will not be made available to the managing clinicians and will not affect management. There are few data available on the pharmacokinetics of esomeprazole in pregnancy. In healthy males, the plasma elimination half-life is approximately 1–1.5 h and the peak plasma concentration occurs within 1–4 h after dosing. We propose to perform pharmacokinetic testing on a subgroup to determine if there are differences in the pregnant population. Fifteen patients in each group will undergo pharmacokinetic testing, so that blinding and allocation concealment is not affected. Blood will be drawn from an indwelling catheter in a forearm vein at 5 min before the medication is given (reference sample) and then at the following dosing interval: 15, 30 and 45 min and then at 1, 1, 5, 2, 4, 8 and 24 h after the initial dose is given. The sampling will be repeated on day 5. Urine samples will be collected two times per week and sent for spot protein: creatinine ratios. 24 h protein excretion is routinely measured only once on admission but for the purposes of this study we will repeat it weekly. Cord blood and placental samples will be collected at delivery. All participants will be informed that they are free to withdraw from the study at any time, and that this will not affect their clinical care. Basic clinical data and samples already collected will be included in the analyses in accord with the consent obtained at trial entry. It is anticipated that the study can be completed in approximately 4 years (2015–2018). This study has been registered with NHREC (South African Human Research Ethics Committee) and PACTR (Pan African Clinical Trials Registry). Data will be presented at international conferences and published in peer-reviewed journals. Patient confidentiality will be protected according to the regulations set forth by Stellenbosch University’s Human Research Ethics Committee or Institutional Review Board (IRB).