Award Title: Pregnancy AntihyperteNsive Drugs: which Agent is best? (giant PANDA study)
Funder: Department of Health and Social Care

Abstract: What is the aim of the study?_x000D_
The aim of this study is to find out which blood pressure medication is best for pregnant women with high blood pressure._x000D_
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Why is this important?_x000D_
Around 10% of pregnant women in the UK are diagnosed with high blood pressure before or during pregnancy. Without treatment, high blood pressure can cause damage to the heart and kidneys, and rarely, complications such as a stroke. Sometimes we need to admit women to hospital with very high blood pressure. If we cannot bring the blood pressure down with medication, we may need to deliver the baby, even if premature, to avoid complications for mum and her baby. In pregnancy, we take particular care to treat high blood pressure to try and avoid all complications. A recent report summarised all the studies that have compared blood pressure medication in pregnancy. It found that there haven’t been enough large studies to say which is the best blood pressure medication to use and that researchers need to do more work to find this out._x000D_
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We want to find out which of two different treatments currently used in the NHS work best at controlling blood pressure in pregnant women without having troublesome side-effects for the woman or baby. The medications we will compare are called labetalol and nifedipine. Both have been widely used by pregnant women in the UK for many years and are considered safe to use in pregnancy but prescribing varies widely around the country because we do not know which one works best._x000D_
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What does the study involve?_x000D_
We will approach around 2300 women in 40-50 maternity units in the UK who have high blood pressure in pregnancy and need treatment. We will offer these women information about the study and give them time to decide if they would like to take part. Women will be asked for their consent and we will then randomly allocate them to one of the two blood pressure medications using a computer. This means that their treatment will be chosen by chance, a bit like tossing a coin, and is the fairest way to test treatments. The women and their doctors will know which medication they are getting to ensure they are taking the correct dose._x000D_
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All women will continue to have their usual antenatal care (including their blood pressure measurements) and their doctors will be able to change blood pressure medications as needed, for example to change the dose. Two weeks after joining the study we will contact the women and ask them to complete a short study survey about how they find the blood pressure medication. The women and their babies will be followed up through the pregnancy until they leave hospital after delivery._x000D_
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What do other women think of the study?_x000D_
We have asked women who have/had high blood pressure in pregnancy what they thought of this study. They were very supportive of the need for this study and told us what endpoints they thought were important to pregnant women and their families. We have used this information to help design this study and will continue to involve women who have experienced high blood pressure in our work to ensure women’s viewpoints are at the heart of our research._x000D_
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The results of this study will help to understand which drug gives the best blood pressure control for the woman and is safe for the baby. The results will be published in widely respected journals and will help doctors and pregnant women with high blood pressure decide which medication is best for each woman.

Lay Abstract: Research question: In women with pregnancy hypertension (P), what is the effect of a treatment initiation strategy with nifedipine (I) versus labetalol (C) on severe maternal hypertension (O) and a composite of perinatal loss or neonatal unit admissions (O)?_x000D_
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Design: Prospective, late phase, pragmatic, parallel group, open-label, multicentre, two-arm randomised controlled trial of treatment initiation with nifedipine or labetalol in women with pregnancy hypertension._x000D_
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Setting: 40-50 UK consultant-led maternity units._x000D_
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Population: Pregnant women with hypertension._x000D_
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Inclusion criteria: Pregnancy (=34+0 weeks’ gestation); pregnancy hypertension (chronic or gestational hypertension or pre-eclampsia); decision made to initiate or continue use of antihypertensive; aged =18 years; written informed consent._x000D_
Exclusion criterion: Contraindication to either agent; already taking both agents and not able (or willing) to be switched onto single agent._x000D_
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Health technologies: Treatment initiation with any preparation of modified release nifedipine, a calcium channel blocker, (intervention arm) vs. labetalol, a mixed alpha/ beta blocker, (active control arm) by random allocation (1:1). All other aspects of antenatal and delivery care will follow the usual care pathways underpinned by NICE 2019 guidelines for pregnancy hypertension. _x000D_
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Co-primary outcomes: _x000D_
Maternal: Severe hypertension (proportion of healthcare professional measured systolic blood pressure readings (=160mmHg) up to delivery). _x000D_
Perinatal: Perinatal death (stillbirth after 20 weeks’ gestation or neonatal death up to 7 days) or neonatal unit admission up to hospital discharge. Secondary maternal and perinatal outcomes include clinical and patient-reported outcomes in addition to health care resource use._x000D_
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Sample size: 2,300 pregnant women with hypertension.  Assuming 90% power, 2.5% one-sided significance for non-inferiority, a control group event rate for the co-primary outcome of neonatal unit admission of 25%, 5% loss to follow up, a total of approximately 2,300 women would be required to detect a clinically meaningful non-inferiority margin of 6%. For the maternal co-primary outcome, a sample size of 2,190 will allow the detection of a 2.3% superiority difference between the mean proportions of clinic and hospital systolic blood measurements =160mmHg. This is equivalent to an effect size of 0.14 of a standard deviation, based on a two-sample t-test (5% two-sided alpha, 90% power) e.g. from around a mean of 9.6% to 11.9%. _x000D_
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Economic evaluation: A cost-effectiveness analysis using a decision analytical model with a lifetime horizon and an NHS perspective, and a cost-consequence analysis up to hospital discharge._x000D_
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Difference between pathways: Standard care pathways advise antihypertensive treatment; both nifedipine and labetalol are currently used in practice. In the trial, choice of antihypertensive treatment will be randomly allocated, but other care will follow usual antenatal care pathways._x000D_
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Timetable: Months 1-8: set-up; Months 9-17: internal pilot; Months 18-33: recruitment; Months 34-41: follow-up; Months 42-48: analysis and write-up._x000D_
Expertise in team: The multidisciplinary team draws on UK-wide clinical academic expertise across the health professional spectrum with extensive trials experience in pregnancy hypertension, a PPI co-applicant (experience of pregnancy hypertension) and an experienced Clinical Trials Unit._x000D_
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Dissemination and impact: Academic outputs (presentations, papers) and active engagement with public and patient dissemination routes. For impact, the trial is intended to provide definitive evidence to inform guidelines and linked shared decision-making tools for early uptake into clinical practice.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH