Ondansetron and metoclopramide as second-line antiemetics in women with nausea and vomiting in pregnancy: the EMPOWER pilot factorial RCT

Abstract

Background Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. Objectives To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the incremental cost per treatment failure avoided and the net monetary benefits from the perspectives of the NHS and women. Design This was a multicentre, double-dummy, randomised, double-blinded, dummy-controlled 2 × 2 factorial trial (with an internal pilot phase), with qualitative and health economic evaluations. Participants Thirty-three patients (who were < 17 weeks pregnant and who attended hospital with nausea and vomiting after little or no improvement with first-line antiemetic medication) who attended 12 secondary care NHS trusts in England, 22 health-care professionals and 21 women participated in the qualitative evaluation. Interventions Participants were randomly allocated to one of four treatment groups (1 : 1 : 1: 1 ratio): (1) metoclopramide and dummy ondansetron; (2) ondansetron and dummy metoclopramide; (3) metoclopramide and ondansetron; or (4) double dummy. Trial medication was initially given intravenously and then continued orally once women were able to tolerate oral fluids for a maximum of 10 days of treatment. Main outcome measures The primary end point was the number of participants who experienced treatment failure, which was defined as the need for further treatment because symptoms had worsened between 12 hours and 10 days post treatment. The main economic outcomes were incremental cost per additional successful treatment and incremental net benefit. Results Of the 592 patients screened, 122 were considered eligible and 33 were recruited into the internal pilot (metoclopramide and dummy ondansetron, n = 8; ondansetron and dummy metoclopramide, n = 8; metoclopramide and ondansetron, n = 8; double dummy, n = 9). Owing to slow recruitment, the trial did not progress beyond the pilot. Fifteen out of 30 evaluable participants experienced treatment failure. No statistical analyses were performed. The main reason for ineligibility was prior treatment with trial drugs, reflecting an unpredicted change in prescribing practice at several points along the care pathway. The qualitative evaluation identified the requirements of the study protocol, in relation to guidelines on anti-sickness drugs, and the diversity of pathways to care as key hurdles to recruitment while the role of research staff was a key enabler. No important adverse events or side effects were reported. Limitations The pilot trial failed to achieve the recruitment target owing to unforeseen changes in the provision of care. Conclusions The trial was unable to provide evidence to support clinician decisions about the best choice of second-line antiemetic for nausea and vomiting in pregnancy. Trial registration Current Controlled Trials ISRCTN16924692 and EudraCT 2017-001651-31. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 63. See the NIHR Journals Library website for further project information.

Treatments for hyperemesis gravidarum: A systematic review

“…A small randomized, double‐blind pilot study 44 evaluated the effect of ondansetron in combination with metoclopramide compared with the pharmaceuticals individually or with placebo on the outcomes nausea, vomiting, hospital treatment, and health‐related quality of life. The authors could not conclude any treatment effects.…”

Emesis in pregnancy – a qualitative study on trial recruitment failure from the EMPOWER internal pilot

“…However, despite the best efforts of those involved, including a protocol amendment and an extended pilot phase, the required numbers of pregnant women were not recruited. The overall recruitment rate was 29% of eligible women and this ranged from 11 to 63% across different sites [ 21 ]. Patient recruitment is challenging in a CTIMP involving pregnant women with NVP.…”

“…The qualitative interview study of women approached to participate in the EMPOWER trial was therefore based on the assumption that the success of the trial hinged mainly on their willingness to participate in the trial. While the reasons that women decline participation in the trial are described in more detail in the trial report to commissioners [ 21 ], this paper prioritises the findings from research site staff because of the more extensive and nuanced data collected from their interviews. The findings suggested that there were many other barriers, over and above women’s willingness, to successful recruitment.…”

“…Apart from the characteristics of the study population, there were pertinent contextual and structural features of the trial itself. In particular, the culture of prescribing the study drugs in primary and secondary care varied from site to site and a large proportion of women with severe NVP were ineligible because they had already been treated with one of the study drugs [ 21 ]. A fully informed discussion of the reasons for this practice culture has been provided in the HTA trial report.…”

“…Supplementary themes were identified but are not reported here. Further details are available in the trial report [ 21 ]. The final stage was an additional critically informed, interpretative strand of analysis, wherein the qualitative data were presented according to sociological, concept-led themes drawn from the literature, which are discussed in more detail below.…”