Title: EMPOWER: EMesis in Pregnancy - Ondansetron With mEtoclopRamide
Funder: Department of Health and Social Care

Abstract: Design: Double dummy, double masked controlled factorial trial. Setting: Day care or inpatient secondary care settings Target population: Women presenting with severe NVP (nausea and vomiting in pregnancy) before 16+6 weeks gestation. Inclusion/exclusion criteria: Eligible women will have failed firstline antiemetic treatment (as recommended by RCOG). Women with a known fetal anomaly or who have received, or are allergic to, either technology will be excluded. Technologies being assessed: (i) Metoclopramide 10 mg 8 h, (ii) ondansetron 4 mg 8 h. Outcomes: Primary outcome - Failure rate (up to 10 days). Secondary outcomes: (a) Pregnancy Unique Quantification of Emesis and Nausea (PUQE) (b) Intensity of nausea by VAS (Visual analogue scale) (c) NVP specific QoL (quality of life) (d) Relapse rate (i.e. additional antiemetic therapy after 10 days) (e) Re-admission rate (i.e. need for subsequent in-patient and/or day case attendance for NVP) (f) Total in-patient days for (i) NVP and (ii) any indication (g) Additional antiemetic use (h) Edinburgh Postnatal Depression Scale (i) State Trait Anxiety Index (j) Maternity Social Support Scale; (k) Side effects and adverse events (l) Pregnancy and neonatal outcomes An economic evaluation will estimate the incremental cost per treatment failure avoided, from the perspective of the NHS and women/their families, and the net monetary benefit of treatment. A qualitative evaluation of the trial design and process will also be undertaken. Sample size: We have assumed an antiemetic failure rate of 10% based on prior ondansetron studies (with rates of 13% and 7% at 48 hours and 5 days respectively) and our pilot RCT of midwife-led outpatient care where 10% of women had failure of a second line antiemetic (primarily metoclopramide). We have 90% power to detect an increase in failure rate from 10% in either antiemetic group to 20% in either dummy group (based on a two-sided test at the 5% level) if data are available for 266 patients in each comparison (i.e. 133 in each of four treatment combinations). This effect size was felt to be of clinical relevance to co-applicants. Difference between current and planned care pathways: All other aspects of participant care will mirror current care pathways - all participants will receive iv fluid rehydration (2 litres over 6-8 hours). Project timetable: Months 1-5: Study set up. Months 6-11: Internal pilot trial. Months 12-41: Main trial plus follow up. Months 36-44: Data cleaning and analysis. Months 42-48: Write up. Recruitment rate: Based on our experience in the HiPs trial we have estimated we can recruit 3 women/1000 deliveries per annum. We estimate recruitment of 59 women in the pilot (including 20-25 women to the qualitative sub-study) and 53 with data to day 10. To allow for random variation, our stop/go criterion is set just below the 5% point of the Poisson distribution with mean of 53; i.e. the trial would be stopped with 40 or fewer recruits to day 10. The main trial will recruit 25 women per month from up to 20 centres (with ~100,000 deliveries per annum) giving a total of 600 recruits – this allows for 10% data loss. Expertise: The applicant team includes relevant expertise from the fields of obstetrics (Robson, Simpson, Shehmar, Simpson, Tuffnell) obstetric medicine (Nelson-Piercy, Magee) midwifery (McParlin) health economics (Vale), statistics (Muirhead), clinical trials (McColl), pharmacy (Campbell), teratology (Yates) as well as the public (O’Hara, Williams)

Lay abstract: AIM: This research will compare the effectiveness of two drugs (metoclopramide and ondansetron) for treating women with severe symptoms of nausea and vomiting in pregnancy (NVP) who have already tried using one anti-sickness drug but without improvement in their symptoms. BACKGROUND: Around 30% of women suffer from moderate to severe NVP, causing physical and emotional distress and reducing quality of life (QOL). The most severe form, hyperemesis gravidarum (HG), affects up to 3% of women, leading to dehydration, weight loss and nutrient deficiency. Moderate or severe NVP requires medical treatment, but care varies in different hospitals; women have reported feeling unsupported, dissatisfied, anxious and depressed. Two recent reviews of research studies examining treatment effectiveness concluded that there was little good quality research to guide health care professionals and sufferers about which drugs should be used to improve severe NVP. DESIGN: Women attending hospital with severe NVP, 16+6 weeks weeks pregnant or less, who have had little or no improvement whilst taking anti-sickness treatment will be asked to participate. Participants will receive the medical/nursing care they need (examined by a doctor, given fluids into a vein, have blood tests). 600 participants will be randomly allocated to one of four different treatment groups. Researchers, hospital staff and participants will not know which group an individual is in. Group 1: will receive metoclopramide with a placebo (dummy medication). Group 2: will receive ondansetron with a placebo. Group 3: will receive metoclopramide and ondansetron. Group 4: will receive a double placebo. The drugs will initially be given into a vein three times a day for up to four days. Once women are able drink without vomiting, the same drugs will be given by tablet for up to ten days. Participants will be monitored closely by medical and nursing staff. If at any point after 12 hours of treatment a women feels her symptoms have not improved, the study drugs will be deemed to have failed and the medical staff will prescribe an alternative drug (either a higher dose of ondansetron or corticosteroids). When they start the study women will be asked to complete a questionnaire about personal characteristics, symptoms, QOL, support, anxiety and depression. They will be asked about symptoms and side effects after 48 hours and 5 days. After 10 days they will be asked to repeat the questionnaires. If symptoms return after 10 days then participants will be treated according to usual hospital care. Information about further hospital admissions, use of other medication, pregnancy outcome, birth and the health of the baby will also be collected. The costs of treatment will be assessed in each group. A small group of women will be interviewed to understand their reasons for participating/not participating in the study. Failure rates, pregnancy and questionnaire data will then be compared between groups. PATIENT AND PUBLIC INVOLVEMENT: Two women who suffered from severe NVP/HG were involved in the study design, the decision to class treatment failure as the key outcome and advised on other outcomes of importance to sufferers. They will continue to have an advisory role during the study. DISSEMINATION: Results will be published in a Health Technology Assessment report, relevant medical journals, presented at medical conferences and available on websites such as NHS Choices and on social media.

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