Title: Calcium Supplementation for Prevention of Pre-eclampsia in High Risk Women: CaPE Trial
Funder: Department of Health and Social Care

Abstract: Pre-eclampsia affects around one in thirty pregnancies. It is diagnosed when pregnant women develop high blood pressure and protein in their urine. The complications of this disorder can be very serious. Pre-eclampsia can result in severe problems for the mother such as fits and bleeding. The baby may also be affected, with reduced growth or being born too early. In severe cases, the mother or baby may even die. The impact of the disease on women and their families is often considerable. This is related to the effect on their wellbeing and the upheaval of needing additional tests, admission to hospital and early delivery. This is also costly for the NHS. _x000D_ _x000D_ We currently use low-dose aspirin to try and prevent pre-eclampsia in women who are more likely to develop the disease. But it only reduces the chances of getting pre-eclampsia by around 10-20%. At the moment, the only cure is delivery. _x000D_ _x000D_ We know from previous studies that a simple treatment, calcium tablets, might help to reduce the risk of a woman getting pre-eclampsia, and also of having an early birth and other important complications. These studies have been done in other places around the world, most of them in women who do not have much calcium in their diet and are not at high risk of developing pre-eclampsia. We don’t know whether calcium would help to prevent pre-eclampsia in the UK in women who are at higher risk of getting it, as it is thought that most women in the UK have normal amounts of calcium in their diet. _x000D_ _x000D_ The aim of our study, called the CaPE trial, is to find out whether giving calcium tablets, alongside all the usual care that women receive in pregnancy, will reduce pre-eclampsia and the complications in women and their babies. In order to make sure that it is a fair test of calcium, half of the women in the study will be given calcium tablets, and the other half will be given lookalike dummy tablets (called placebos). This is a common way to test if a new treatment works. _x000D_ _x000D_ We currently recommend aspirin treatment to around 10% of women as we think that they are at higher risk of getting pre-eclampsia. This is based on risk factors such as having pre-existing high blood pressure, diabetes, previous pre-eclampsia or having two medium risk factors such as being pregnant for the first time, being older, having twins. These women are already seen by a doctor or midwife in the first half of pregnancy and offered aspirin. We will offer the CaPE trial to the same group of women and then follow them up through pregnancy to find out how they get on with the treatments and what happens to them and their baby. _x000D_ _x000D_ In order to find out whether calcium works for pregnant women in the UK, we need to enroll around 7800 women in the CaPE trial. We have done studies of this size before and we know that pregnant women are often willing to take part in research like this. This will tell us whether calcium tablets can reduce a woman’s risk of pre-eclampsia by 20%. _x000D_ _x000D_ We have put together a strong team to run this study, including specialists in pregnancy care, newborn babies, and looking at the costs. We have a representative from the two main patient groups in this area who will contribute to all aspects of designing and running the trial as part of the core team. When we have completed the trial, we will make sure that we make the findings available to women and everyone involved in pregnancy care.

Lay abstract: Research question: HTA commissioned call to investigate the clinical and cost-effectiveness of calcium supplementation plus usual care compared with usual care alone in women at high risk of pre-eclampsia. _x000D_ _x000D_ Background: epidemiological studies and RCTs suggest calcium may reduce risk of pre-eclampsia. However, most studies have been conducted in populations with low dietary calcium intake, so findings have not been viewed as applicable to a population with adequate calcium intake, such as in the UK. Moreover, little research has focused on impact of calcium on women at high risk of pre-eclampsia._x000D_ _x000D_ Primary objective: (1) to determine whether calcium during pregnancy plus usual care (including aspirin) is more effective than usual care alone in reducing risk of pre-eclampsia in high risk women. Secondary objectives: to assess (1) impact on other important outcomes for mother and baby; (2) cost-effectiveness (3) adherence (4) which subgroups would benefit most._x000D_ _x000D_ Design: randomised, triple-masked, placebo-controlled multi-centre trial in 40 maternity units across the UK, with a 12 month internal pilot and a health economic evaluation. Central randomisation in 1:1 ratio, with minimisation. _x000D_ _x000D_ Participants: women at high risk of pre-eclampsia, deemed eligible for aspirin based on NICE guideline criteria (single high risk factor or two or more moderate risk factors). Exclusions: contraindications to regular calcium intake, or any medication with potential severe interactions with calcium, use of calcium supplements or regular high dose Vitamin D._x000D_ _x000D_ Intervention: Calcium 2 g/day commenced from 12 to 22 weeks’ gestation, taken until delivery, plus usual care (including aspirin) compared with placebo tablets plus usual care._x000D_ _x000D_ Outcomes: based on Core Outcome Set and the commissioning brief. Primary: pre-eclampsia. Secondary: for the woman: death, eclampsia, stroke, cortical blindness, pulmonary oedema, acute kidney injury, liver capsule haematoma, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, ITU admission, intubation, mechanical ventilation, gestational and severe hypertension, early onset pre-eclampsia <34 weeks, need for elective delivery, mode of delivery, composite morbidity, adverse effects. For the baby: death before hospital discharge, gestational age at delivery, birthweight, small for gestational age, admission to neonatal unit and level of care, number of admission days, neonatal brain injury syndromes, respiratory support, preterm birth <34 and <37 weeks, chronic lung disease, necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity, and composite neonatal morbidity/mortality. Follow up to hospital discharge or 40 weeks gestation plus four weeks, whichever is sooner. Health economic outcomes and consent for data linkage studies for long term outcomes._x000D_ _x000D_ Sample size: 7756 women, to detect a 20% reduction in the occurrence of pre-eclampsia from 11.5% to 9.2% with 90% power (p=0.05), allowing for 5% loss to follow up. _x000D_ _x000D_ Timelines: 6 month set up, with 12 month pilot; site opening at 3/month through the pilot to around 34 sites. Main trial: further 22 months of recruitment from 40 sites; 8 months closing down for data collection, 6 months of analysis and reporting (total 4.5 years)._x000D_ _x000D_ Impact/dissemination: findings will have direct application to clinical practice. Results will be presented at conferences, published in a journal and made available via open source methods.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH