Title: Oxybutynin or venlafaxine for hot flushes in women who cannot or choose not to use hormone replacement therapy: randomised trial and economic evaluation (the BLUSH trial)
Funder: Department of Health and Social Care

Abstract: BACKGROUND: _x000D_ _x000D_ Most menopausal women experience hot flushes and/ or night sweats, called vasomotor symptoms. The frequency and severity of flushes vary between women, but those who have had breast cancer and are taking tamoxifen or similar drugs tend to have severe symptoms. Hormone replacement therapy (HRT) is the most effective treatment and is recommended by the National Institute for Health and Care Excellence (NICE). However, HRT should not be taken by women who have/ had breast cancer. Also, some women, or their GPs, may be concerned about the potential side-effects of HRT or prefer not to take it. _x000D_ _x000D_ Non-hormonal treatments for hot flushes, suggested by guidelines, include medicines that are also used as antidepressants, a blood pressure medicine, and a type of painkiller. These are all less effective than HRT and associated with greater side-effects. A less frequently used treatment is oxybutynin, a medicine used to treat an overactive bladder. _x000D_ _x000D_ We conducted a survey of doctors and found more than 9 out of 10 gynaecologists and GPs offer antidepressants as the first treatment choice to women who cannot or do not want to use HRT. Very few are aware of the potential of oxybutynin. All agree more information is needed to help women decide which treatment is best overall. _x000D_ _x000D_ RESEARCH PLAN: _x000D_ _x000D_ We plan to undertake a research study with 480 women who cannot take HRT for medical reasons and 480 women who prefer not to take HRT, in two parallel studies. Women taking part will be assessed by hospital doctors, asked to record their hot flushes and night sweats in a diary and complete questionnaires about their symptoms. They will be randomly allocated to take either oxybutynin or an anti-depressant called venlafaxine. Neither the women nor their doctors will be able to choose, but the women will know what treatment they are taking. This is called an ‘open randomised controlled trial’ and is a highly reliable way of deciding the value of two treatments. We will ask women about their symptoms after 1, 3, 6 and 12 months, using paper or online diaries and questionnaires. The questionnaires will ask about menopause symptoms, bladder function, sleep, their working and social life and the acceptability of the treatment. We will also look at the costs of treatment and the improvements they bring to women’s lives and work out which offers value for money to the NHS. _x000D_ _x000D_ PATIENT/ PUBLIC INVOLVEMENT _x000D_ _x000D_ We have worked closely with patient groups Women’s Health Concern, the Independent Cancer Patients’ Voice and the website Menopause Matters in developing this proposal. A survey of women via Menopause Matters highlighted the outcomes of most importance and showed the need for proven alternatives to HRT. We will ask a group of women to advise us on the patient information, design of the questionnaires, and how to promote the trial to a wide range of women, including those who tend not to seek medical treatment. _x000D_ _x000D_ DISSEMINATION _x000D_ _x000D_ The results of the trial will be published in leading journals, presented at medical conferences and will feed into the national guidelines for the NHS. Information to help women decide about non-hormonal treatment for menopausal symptoms will be prepared for the patient groups and websites such as NHS Choices.

Lay abstract: RESEARCH QUESTION_x000D_ Is oxybutynin more effective and better value for money than venlafaxine at controlling vasomotor symptoms (VMS) in two groups of women: those who prefer not to use menopausal Hormone Replacement Treatment (HRT), and those with contraindications to HRT._x000D_ _x000D_ BACKGROUND_x000D_ Most menopausal women experience VMS, including hot flushes and night sweats, lasting several years. VMS are more frequent and intense in women taking breast cancer treatment, which can reduce compliance. All alternatives are less effective than HRT and have side effects._x000D_ _x000D_ METHODS_x000D_ Design:_x000D_ Multi-centre, randomised, open, parallel, superiority trial with internal pilot, and a parallel economic evaluation. To be adequately powered to detect clinically meaningful effects in both populations, we will conduct two randomised controlled trials in parallel under a single master protocol._x000D_ _x000D_ Setting:_x000D_ Women will be identified in gynaecology clinics, by oncology and GP databases searches and via direct to patient marketing_x000D_ _x000D_ Target population:_x000D_ Women with menopausal VMS who are either unable to take, or prefer not to take, HRT_x000D_ _x000D_ Health technologies being assessed:_x000D_ Oxybutynin: Extended release, oral, starting dose 5mg, max 15mg_x000D_ Venlafaxine: Modified release, oral, starting dose 37.5mg, max 75mg_x000D_ _x000D_ Primary Outcome:_x000D_ The average Hot Flush (HF) score (frequency x severity) over one week, at week 12_x000D_ _x000D_ Secondary Outcomes:_x000D_ All measured at baseline, week 12, and 6 and 12 months and additional stated timepoints:_x000D_ Average HF score (also in weeks 4 and 8)_x000D_ Frequency and severity, individually, of hot flushes/night sweats (also in weeks 4 and 8)_x000D_ Time to onset of symptom relief_x000D_ Individual domains and total score of MENQOL-I (also at week 4) _x000D_ Health related quality of life (EQ-5D-5L) and capability-wellbeing (ICECAP-A)_x000D_ Patient acceptability of treatment (5-point Likert scale, also at week 4)_x000D_ Patient-reported global improvement_x000D_ Urinary urgency, frequency and incontinence (ICIQ-OAB)_x000D_ Sleep quality (PSQI)_x000D_ Work productivity and absenteeism (WHO HPQ)_x000D_ Common known side effects of each drug_x000D_ Change or cessation of treatment, and for cancer population, continuation of endocrine therapy_x000D_ _x000D_ Sample size:_x000D_ Both trials have been powered to detect a 4-point mean difference in HF Score (SD=12) at 12 weeks, with 90% power, 5% 2-sided significance and 1:1 allocation. To allow for ~20% loss to follow-up and treatment discontinuation, 480 participants will be recruited per trial._x000D_ _x000D_ Economic evaluation:_x000D_ From the perspectives of the NHS/social care, and of the wider society, cost-effectiveness will be evaluated using cost-consequence (including impact on individuals’ capability and productivity) and cost-utility (incremental costs per QALY) analyses._x000D_ _x000D_ TIMELINES_x000D_ M1-M6: Protocol and database development, approvals, site set-up_x000D_ M7-M37: Clinic/ GP practice database searches and direct to patient adverts_x000D_ M10-M18 Pilot recruitment_x000D_ M19 Stop-go decision_x000D_ M19-M39 Continued recruitment_x000D_ M53 End of 1-year follow-up, data cleaned_x000D_ M54–M60 Data analysis, economic evaluation, reporting_x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ The results will enable women to make informed decisions about treatments for VMS, and may indirectly improve adherence with breast cancer treatment._x000D_ We will actively engage with all appropriate professional societies to appraise them of progress and outcome of the trial. Women’s Health Concern and Independent Cancer Patient Voices will lead on patient involvement.

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