Background Approximately 5% of women will be affected by fetal malposition at full cervical dilatation, with the occiput in transverse or posterior positions. These women are more likely to require assistance to give birth to their babies with either rotational vaginal birth or cesarean birth at full dilatation. Three different rotational methods can be used: rotational (Kielland) forceps, rotational vacuum, and manual rotation. Current evidence supporting the use of the 3 rotational methods is only from observational data. To date, no randomized controlled trial (RCT) of rotational methods has been completed. Objective This study aimed to evaluate whether manual rotation of the fetal head in persistent malposition at full cervical dilatation reduces the risk of severe maternal perineal trauma without substantially increasing the risk of cesarean birth, compared with instrumental rotation. Methods ROTATE is a pragmatic, multicenter, 2-arm parallel group, open-label RCT of manual versus instrumental rotation of the fetal head in malposition at birth with an internal pilot and an embedded qualitative process evaluation. The primary outcome is to evaluate whether manual versus instrumental rotation at full cervical dilatation reduces the risk of severe perineal trauma (superiority outcome), defined as a third- or fourth-degree tear, without substantially increasing the risk of cesarean birth at full dilatation (noninferiority coprimary outcome). A sample size calculation found that 4988 participants are required to detect a clinically meaningful reduction of third- or fourth-degree tears from 6% to 4% with 90% power (α=.05). A total sample size of 5200 participants from approximately 40 sites is anticipated, as loss to follow-up is expected to be about 4%. Neonatal trauma, a composite of potential outcomes relating to intrapartum hypoxia and physical trauma, is a safety signal. The setting is National Health Service consultant–led maternity units across the United Kingdom. Randomization is performed after eligibility has been confirmed and verbal consent has been obtained. Randomization is undertaken via a 24-hour telephone service or web-based system. Participants are randomized at an individual level on a 1:1 ratio to manual or instrumental (forceps or vacuum) rotation. Written consent is sought postnatally. Results Data collection took place between September 9, 2022, and November 5, 2024. The total number of recruits is 321. The data analysis of primary and secondary outcomes is ongoing at the time of submission. Conclusions A multicenter RCT of rotational methods has been conducted in the United Kingdom. Although the trial was closed early due to challenges in meeting recruitment targets, the results are still highly anticipated. Trial Registration ISRCTN ISRCTN10193017; https://www.isrctn.com/ISRCTN10193017 International Registered Report Identifier (IRRID) DERR1-10.2196/72505

Background:People experiencing homelessness face up to 12 times higher mortality rates than the general population. People experiencing homelessness have multiple, unmet health and care needs, including poor physical and mental health, substance use disorder and lack of stable and safe housing, yet they do not find services accessible or tailored to their needs. Aim:The aim of this study was to assess the feasibility of conducting a larger, definitive trial evaluating an integrated clinical pharmacist/homeless third-sector support (Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx) for people experiencing homelessness, in a community pharmacy setting. Design:Randomised, multicentre, open, parallel group external pilot trial with parallel economic and qualitative process evaluation. Methods:People experiencing homelessness ≥ 18 years were recruited from community pharmacies in Glasgow and Birmingham, United Kingdom. Participants were randomised 1 : 1 to receive Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx intervention in addition to usual care or usual care only. The Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx intervention is a collaboration between National Health Service pharmacist independent prescribers and third-sector homelessness charity workers offering weekly community pharmacy and/or outreach-based consultations for people experiencing homelessness to address health (e.g. health screening, treatment and prescribing), housing and social needs (e.g. welfare benefits, housing support). A range of health, social and care outcomes were evaluated at baseline, 3 and 6 months from both usual-care and intervention participants. The primary outcome was to evaluate the feasibility of a subsequent definitive randomised controlled trial according to pre-specified progression criteria classified as green (go ahead), amber (minor amendment in procedures required for definitive trial) and red (substantial changes needed). These related to recruitment; retention; intervention adherence; and collection of clinical and social outcomes data, including emergency department visits, rough sleeping and criminal justice encounters. Results:Progression criteria were met (4 green and 1 amber) as follows: (1) recruitment (target 55% conversion rate): 100 people experiencing homelessness were recruited as planned from 5 community pharmacies, 100/183, that is, 55% eligible consented to participate - green; (2) retention (target 60%): 72 (72%) participants remained in the study at 6 months - green; (3) collection of routine healthcare utilisation data (target 60%): 91 (91%) had emergency department visit and mortality data available at 6 months - green; (4) completion of questionnaire booklet (target 60%): 72 (72%) completed the booklet at 6 months - green; (5) intervention adherence (target 60%). Twenty-six (53%) participants had over half of the planned weekly contacts with the Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx team - amber. Signals of improvements were observed, as there were fewer ambulance call-outs, fewer emergency department visits and hospitalisations; fewer nights slept rough; and improved health-related quality of life in Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx participants compared to the usual-care group at 6 months' follow-up. Qualitative interviews conducted with participants and stakeholders. Participants suggested the Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx intervention was characterised by holistic approach, comprehensiveness, consistency and care. Challenges identified included resource constraints, integration with existing services and concerns about long-term sustainability. Conclusions:Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx community pharmacy pilot randomised controlled trial successfully achieved key progression criteria. If found to be effective and cost-effective in a subsequent definitive randomised controlled trial, it offers promise as an adaptable (United Kingdom and internationally) model of integrated care provision for people experiencing homelessness. Limitations:While small sample size limits generalisability of the, it fulfils the purpose of a pilot study. Temporary absence of intervention worker in one of the study settings constrained intervention delivery. Future trials should plan for contingency measures. Future work:Future research should seek to test and evaluate care models integrating health and voluntary sector care for people experiencing homelessness in various settings, including community pharmacy, street outreach and temporary accommodations. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number NIHR133060.

Antiretroviral therapy (ART) has transformed HIV into a manageable health condition with normal life expectancy. However, people with HIV continue to have poorer mental health compared to background populations, which may be linked to stigma, lack of social support, or socioeconomic challenges. Personalised care aims to improve the outcomes of people with long-term health conditions and the National Health Service (NHS) Long Term Plan looks to implement this (including access to health coaching and social prescribing). The SPHERE trial aims to assess whether a health and well-being coaching and social prescribing intervention improves patient-reported health and well-being among people living with HIV who have psychosocial needs. SPHERE will be conducted across seven HIV outpatient clinics in England and is a pragmatic, two-arm, parallel group randomised controlled trial (RCT) embedding a routine assessment of psychosocial needs in HIV care. Eligibility criteria are people living with HIV aged 18 or older, available for the duration of study follow-up and scoring 16 or more on an assessment of psychosocial need: “Positive-Outcomes-11” (PO-11), covering physical, psychological, social and socioeconomic aspects of health and well-being. The RCT requires 568 participants who will be individually randomised in a 1:1 ratio to either a health and well-being coaching and social prescribing intervention or usual care. The intervention consists of up to eight coaching sessions that will be delivered by health professionals (e.g. HIV nurses) who have received specialist training to become health and well-being coaches. The trial will also include an internal pilot phase, process evaluation (to evaluate intervention feasibility, acceptability and mechanisms of action), economic evaluation (to assess the cost-effectiveness of the intervention and impact on NHS resource use) and parallel observational study (to assess subsequent development of psychosocial needs among those not initially eligible for the trial). The primary outcome is defined as achieving a reduction in PO-11 score of at least 40

Background:Delay in the first stage of labour occurs in approximately 20% of nulliparous women. Recommended treatment is intravenous oxytocin, which shortens labour but does not affect the mode of birth. There is some evidence that a higher dose regimen may decrease the need for caesarean section. Objective:The primary objective was to establish if a high-dose regimen of oxytocin compared to the current standard-dose regimen reduced the need for caesarean section for nulliparous women with confirmed delay in the first stage of labour. Design:Multicentre, randomised double-blind controlled trial. Setting:Twenty-one maternity units in the United Kingdom. Participants:Consenting nulliparous women who had a singleton cephalic pregnancy, gestation of 37-41 weeks inclusive, confirmed delay in labour in first stage, ruptured membranes and for whom the clinical decision has been made to prescribe oxytocin. Interventions:Standard-dose regimen of oxytocin (2 mU/min increasing every 30 minutes to a maximum of 32 mU/min) compared with high-dose regimen (4 mU/min increasing every 30 minutes to a maximum of 64 mU/min). Main outcome measures:The primary outcome was the rate of caesarean section. Secondary outcomes included maternal and neonatal birth outcomes and safety. Results:One hundred and eighteen women were successfully randomised via third-party minimisation from an intended sample size of 1500 between 30 June 2017 and 14 November 2022. The caesarean section rate in the standard-dose group was 34% (20/58) and 27% (16/60) in the high-dose group. The intervention was provided as intended in 96% (113/118) of participants. There was no obvious suggestion that the high-dose regime was unsafe (all neonates were discharged home with mother), but this size of sample prohibited any definitive conclusions. Limitations:The trial did not meet its intended sample size due to a number of challenges. It was difficult for busy clinical staff to recruit women in labour in this acute, but not emergency, situation. The legislative requirements of undertaking research using interventional medicinal products imposed further constraints, and we encountered challenges in the production, blinding and monitoring required. Changes in clinical practice since trial design and commencement 10 years ago have resulted in fewer women going into spontaneous labour (reduced from 66% to 47%), and therefore potentially becoming eligible, due to more women having labour induced (22%-33%) or elective caesarean sections (12%-20%). These challenges were further compounded by a falling birth rate and the impact of the COVID-19 pandemic. Conclusions:The question of the optimum dose of oxytocin for nulliparous women delayed in the first stage of spontaneous labour remains an important unanswered clinical question, and the major challenge is how best to address this within the current regulatory framework. Future work:Future studies should consider whether the option of delayed consent would be suitable in this acute, but not emergency, situation. Funding:This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 14/140/44.

People experiencing homelessness (PEH) are amongst the most marginalised populations in the society. Despite facing extreme health inequalities and poorer outcomes than the general population, they are under-represented in clinical trials. Little is hence known about the physical, mental health and social characteristics of PEH as clinical trial participants. Cross-sectoral complex interventions aiming to mitigate health, wellbeing and wider inequalities faced by PEH are urgently needed. This paper reports on baseline characteristics of PEH from the PHOENIx Community Pharmacy multicentre Pilot randomised controlled trial (RCT) with recruitment from community pharmacies in Glasgow and Birmingham, UK. Participants were randomised 1:1 to receive PHOENIx (collaboration between National Health Service pharmacist independent prescribers and third sector workers) intervention in addition to usual care (UC) or UC only. Data were collected using face-to-face patient questionnaires which included validated tools (e.g. Equation 5D), direct clinical observations (e.g. blood pressure, grip strength) and healthcare utilisation records (e.g. hospital admissions). A total of 100 participants were recruited as planned from five community pharmacies. Participants (n = 99 baseline records for one were lost) were on average 42 years old, mostly white (87, 88

Randomized controlled trials (RCTs) aiming to address the multiple health and social challenges of people experiencing homelessness (PEH) are lacking. Here we report the findings from a multicenter, open, pilot RCT. The intervention involved independent prescriber pharmacist from the National Health Service working on outreach in partnership with dedicated workers from Homeless Voluntary Charity or Social Enterprises (HVCSEs) (Pharmacist and third sector charity worker integrated Homeless Outreach Engagement Non-medical Independent prescriber Rx'-PHOENIx) in low threshold HVCSE venues or temporary accommodation addressing PEH participants' health and wider needs through repeated outreach. The trial aimed to investigate whether sufficient numbers of participants could be recruited, retained, the intervention delivered as planned, and sufficient data collected to inform a subsequent definitive RCT. Clinical outcomes were also collected at follow-up (6 months). Participants were recruited from five community pharmacies and nearby venues in urban centers of Glasgow-Scotland and Birmingham-England, then randomized one-to-one into PHOENIx intervention in addition to usual care (UC) or UC only. A priori progression criteria were achieved: 55% of those assessed as eligible were recruited; at 6 months, 72% remained in the study, 91% had emergency department and mortality data available, and 72% completed questionnaire booklets. Fifty-three percent of participants received at least 50% of the planned PHOENIx intervention consultations (in-person or phone) at 6 months. Signs of improvement in clinical outcomes in the PHOENIx group included fewer ambulance call-outs, ED visits, and hospitalizations; higher outpatient attendances; and higher scores on self-reported health-related quality of life. A definitive RCT is merited.

ObjectivesTo evaluate the cost-effectiveness of long-acting progestogens (LAP), including levonorgestrel-releasing intrauterine system (LNG-IUS) and depot-medroxyprogesterone acetate (DMPA), compared with the combined oral contraceptives pill (COCP) in preventing recurrence of endometriosis-related pain postsurgery.DesignWithin-trial economic evaluation alongside a multicentre, pragmatic, parallel-group, open-label, randomised controlled trial (Preventing Recurrence of Endometriosis by means of Long-Acting Progestogen Therapy trial).SettingThirty-four UK hospitals recruiting participants from November 2015 to March 2019.PatientsFour hundred and five women aged 16–45 years undergoing conservative endometriosis surgery.InterventionsThe ratio of 1:1 randomisation to receive LAPs (LNG-IUS or DMPA) or COCP.Main outcome measuresThe primary evaluation was a cost-utility analysis based on cost per quality-adjusted life-year (QALY) gained at 3 years. We adopted a UK National Health Service perspective. Secondary analyses in the form of cost-effectiveness analysis based on a range of outcomes were also undertaken.ResultsFor the primary analysis, the COCP group incurred an additional cost of £533 (95% CI £52 to £983) per woman compared with LAPs. Treatment with COCP generated additional QALYs of 0.031 (95% CI −0.079 to 0.139) compared with the LAP group over 36-month follow-up. The incremental cost-effectiveness ratio for COCP compared with LAPs is therefore approximately £17 193 per QALY. The probabilistic sensitivity analysis suggested that there was a 54.7% probability that COCP would be cost-effective at the £20 000/QALY threshold. The secondary analyses revealed results more in favour of LAPs.ConclusionAlthough the COCP has a slightly higher probability of being cost-effective at £20 000/QALY threshold, there remains considerable uncertainty, with only marginal differences in outcomes between the two treatments. The lower rates of further surgery and second-line medical treatment for women allocated to LAPs may make this option preferable for some women.Trial registration numberISRCTN 97865475.

Background:Endometriosis affects 1 in 10 women, many of whom have surgery for persistent pain. Recurrence of symptoms following an operation is common. Although hormonal treatment can reduce this risk, there is uncertainty about the best option. Objectives:To evaluate the clinical and cost-effectiveness of long-acting progestogen therapy compared with the combined oral contraceptive pill in preventing recurrence of endometriosis-related pain and quality of life. Design:A multicentre, open, randomised trial with parallel economic evaluation. The final design was informed by a pilot study, qualitative exploration of women's lived experience of endometriosis and a pretrial economic model. Setting:Thirty-four United Kingdom hospitals. Participants:Women of reproductive age undergoing conservative surgery for endometriosis. Interventions:Long-acting progestogen reversible contraceptive (either 150 mg depot medroxyprogesterone acetate or 52 mg levonorgestrel-releasing intrauterine system) or combined oral contraceptive pill (30 µg ethinylestradiol, 150 µg levonorgestrel). Main outcome measures:The primary outcome was the pain domain of the Endometriosis Health Profile-30 questionnaire at 36 months post randomisation. The economic evaluation estimated the cost per quality-adjusted life-years gained. Results:Four hundred and five women were randomised to receive either long-acting reversible contraceptive (N = 205) or combined oral contraceptive pill (N = 200). Pain scores improved in both groups (24 and 23 points on average) compared with preoperative values but there was no difference between the two (adjusted mean difference: -0.8, 95% confidence interval -5.7 to 4.2; p = 0.76). The long-acting reversible contraceptive group underwent fewer surgical procedures or second-line treatments compared with the combined oral contraceptive group (73 vs. 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). The mean adjusted quality-adjusted life-year difference between two arms was 0.043 (95% confidence interval -0.069 to 0.152) in favour of the combined oral contraceptive pill, although this cost an additional £533 (95% confidence interval 52 to 983) per woman. Limitations:Limitations include the absence of a no-treatment group and the fact that many women changed treatments over the 3 years of follow-up. Use of telephone follow-up to collect primary outcome data in those who failed to return questionnaires resulted in missing data for secondary outcomes. The COVID pandemic may have affected rates of further surgical treatment. Conclusions:At 36 months, women allocated to either intervention had comparable levels of pain, with both groups showing around a 40% improvement from presurgical levels. Although the combined oral contraceptive was cost-effective at a threshold of £20,000 per quality-adjusted life-year, the difference between the two was marginal and lower rates of repeat surgery might make long-acting reversible contraceptives preferable to some women. Future work:Future research needs to focus on evaluating newer hormonal preparations, a more holistic approach to symptom suppression and identification of biomarkers to diagnose endometriosis and its recurrence. Trial registration:This trial is registered as ISRCTN97865475. https://doi.org/10.1186/ISRCTN97865475. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/114/01) and is published in full in Health Technology Assessment; Vol. 28, No. 55. See the NIHR Funding and Awards website for further award information. The NIHR recognises that people have diverse gender identities, and in this report, the word 'woman' is used to describe patients or individuals whose sex assigned at birth was female, whether they identify as female, male or non-binary.

INTRODUCTION:There is a paucity of research on and a limited understanding of patient and public involvement (PPI) in the context of research in homelessness and, in particular, direct involvement of people with lived and living experience of homelessness (PEH) as expert advisors. We aim to report on outcomes and reflections from lived experience advisory panel (LEAP) meetings and PPI activities, held throughout the study lifecycle of a pilot randomised-controlled trial (RCT) focused on evaluating integrated health and practical support for PEH. METHODS:Community Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx (PHOENIx Community Pharmacy RCT) is an integrated health and social care intervention for people experiencing homelessness who present to community pharmacy. Intervention includes weekly support from a pharmacist prescriber and a third sector support worker for up to 6 months. PPI activities undertaken throughout the study were documented, including outcomes of LEAP meetings. Outcome reporting followed Guidance for Reporting Involvement of Patients and the Public 2 Short Form (GRIPP2-SF). RESULTS:In total, 17 members were recruited into the LEAP; six meetings (three in two study sites) were held. PPI input was also received through representation from homelessness third sector organisation staff as study co-applicants and core membership in the trial steering committee. Together, the PPI activities helped shape the study proposal, design of study materials, data analysis and dissemination materials. LEAP panel members offered valuable input via their experience and expertise into the delivery and refinement of interventions. Although longitudinal input was received from some LEAP members, ensuring repeat attendance in the pre-planned meetings was challenging. CONCLUSION:People who face social exclusion and marginalisation can provide highly valuable input as equal partners in co-design and delivery of interventions seeking to improve their health and well-being. Fluid membership and flexible methods of seeking and incorporating advice can offer pragmatic approaches to minimising barriers to continued involvement in research. PATIENT OR PUBLIC CONTRIBUTION:This study reports findings and learning relevant to involvement of people with lived and living experience of homelessness as advisors in a research study. It is important for researchers to offer fluid memberships and use diverse methods to receive input from lived experience members, as traditional PPI methodology may be insufficient to ensure inclusivity. Staff and volunteers from third sector organisations were important PPI partners who bring their experience based on frontline service provision, often as the first port of call for people experiencing severe and multiple disadvantage. TRIAL REGISTRATION:ISRCTN88146807.

Objectives: To test whether intraoperative ultrasound can reduce the incidence of early and late complications following surgical removal of products of conception. Design: This was a prospective, multicentre, randomised, open clinical trial to assess feasibility. It was performed in two University Teaching hospitals in the West Midlands, England. The population consisted of women aged 16 years or over who were referred for surgical management of miscarriage. Patients were randomised to surgical management of miscarriage with either continuous intraoperative ultrasound or without intraoperative ultrasound. Process outcomes included the proportion of eligible women screened and proportion of eligible women randomised, attrition rates, evaluation of outcome measurement tools and acceptability. The primary clinical outcome was a composite outcome of unsuccessful procedure or a complication. Results: Fifty-nine women requiring surgical management of miscarriage were randomised. The conversion rate for entry into the trial was 59/79(75 %; 95 %CI = 64-84 %). The composite clinical outcome was attained in 5/ 27(19 %) patients who had surgery without ultrasound and 7/28(25 %) patients who had surgery with ultrasound (RR = 0.74;95 %CI = 0.26, 2.10). When we excluded the patients that could not attend their hysteroscopy appointment, due to COVID-19 pandemic, 5/27(19 %) of patients who had surgery without ultrasound and 5/25 (20 %) of patients who had surgery with ultrasound attained the composite clinical outcome (RR = 0.93;95 %CI = 0.30, 2.90). Conclusions: This multicentre pilot study showed that a large RCT comparing surgical management of miscarriage with and without intraoperative ultrasound is feasible.

OBJECTIVES To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING 34 UK hospitals. PARTICIPANTS 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some.

People experiencing homelessness (PEH) have complex health and social care needs and most die in their early 40 s. PEH frequently use community pharmacies; however, evaluation of the delivery of structured, integrated, holistic health and social care intervention has not been previously undertaken in community pharmacies for PEH. PHOENIx (Pharmacy Homeless Outreach Engagement Non-medical Independent prescribing Rx) has been delivered and tested in Glasgow, Scotland, by NHS pharmacist independent prescribers and third sector homelessness support workers offering health and social care intervention in low threshold homeless drop-in venues, emergency accommodation and emergency departments, to PEH. Building on this work, this study aims to test recruitment, retention, intervention adherence and fidelity of community pharmacy-based PHOENIx intervention. Randomised, multi-centre, open, parallel-group external pilot trial. A total of 100 PEH aged 18 years and over will be recruited from community pharmacies in Glasgow and Birmingham. PHOENIx intervention includes structured assessment in the community pharmacy of health, housing, benefits and activities, in addition to usual care, through weekly visits lasting up to six months. A primary outcome is whether to proceed to a definitive trial based on pre-specified progression criteria. Secondary outcomes include drug/alcohol treatment uptake and treatment retention; overdose rates; mortality and time to death; prison/criminal justice encounters; healthcare utilisation; housing tenure; patient-reported measures and intervention acceptability. Analysis will include descriptive statistics of recruitment and retention rates. Process evaluation will be conducted using Normalisation Process Theory. Health, social care and personal resource use data will be identified, measured and valued. If the findings of this pilot study suggest progression to a definitive trial, and if the definitive trial offers positive outcomes, it is intended that PHOENIx will be a publicly funded free-to-access service in community pharmacy for PEH. The study results will be shared with wider stakeholders and patients in addition to dissemination through medical journals and scientific conferences. International Clinical Trial Registration ISRCTN88146807. Approved protocol version 2.0 dated July 19, 2022.

Background:Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. Ulipristal acetate is prescribed to treat symptoms associated with uterine fibroids. We compared the effectiveness of ulipristal acetate and the levonorgestrel-releasing intrauterine system at reducing the burden of heavy menstrual bleeding, irrespective of the presence of fibroids. Methods:This randomised, open-label, parallel group phase III trial enrolled women over 18 years with heavy menstrual bleeding from 10 UK hospitals. Participants were centrally randomised, in a 1:1 ratio, to either three, 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or a levonorgestrel-releasing intrauterine system. The primary outcome, analysed by intention-to-treat, was quality of life measured by the Menorrhagia Multi-Attribute Scale at 12 months. Secondary outcomes included menstrual bleeding and liver function. The trial is registered with ISRCTN, 20426843. Findings:Between June 5th, 2015 and February 26th, 2020, 236 women were randomised, either side of a recruitment suspension due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate led to early cessation of recruitment but the trial continued in follow-up. The primary outcome substantially improved in both groups, and was 89, (interquartile range [IQR] 65 to 100, n = 53) and 94, (IQR 70 to 100, n = 50; adjusted odds ratio 0.55, 95% confidence interval [CI] 0.26-1.17; p = 0.12) in the ulipristal and levonorgestrel-releasing intrauterine system groups. Rates of amenorrhoea at 12 months were higher in those allocated ulipristal acetate compared to levonorgestrel-releasing intrauterine system (64% versus 25%, adjusted odds ratio 7.12, 95% CI 2.29-22.2). Other outcomes were similar between the two groups and there were no cases of endometrial malignancy or hepatotoxicity due to ulipristal acetate use. Interpretation:Our findings suggested that both treatments improved quality of life. Ulipristal was more effective at inducing amenorrhoea. Ulipristal has been demonstrated to be an effective medical therapeutic option but currently its use has restrictions and requires liver function monitoring. Funding:UK Medical Research Council and National Institute of Health Research EME Programme (12/206/52).

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843.

ObjectiveTo determine treatment options (myomectomy vs. uterine artery embolization (UAE)) for women wishing to avoid hysterectomy. MethodsA multicenter randomized controlled trial was conducted on 254 women and data were collected on fibroid-specific quality of life (UFS-QOL), loss of menstrual blood, and pregnancy. ResultsAt 4 years, the mean difference in the UFS-QOL was 5.0 points (95% confidence interval (CI) -1.4 to 11.5; P = 0.13) in favor of myomectomy. This was not statistically significant as it was at 2 years. There were no differences in bleeding scores, rates of amenorrhea, or heavy bleeding. Of those who were still menstruating, the majority reported regular or fairly regular periods: 36 of 48 (75%) in the UAE group and 30 of 39 (77%) in the myomectomy group. Twelve women after UAE and six women after myomectomy became pregnant (4 years) with seven and five live births, respectively (hazard ratio 0.48, 95% CI 0.18-1.28). There was no difference between the levels of hormones associated with the uterine reserve in each group. ConclusionLeiomyoma are common in reproductive-aged women, causing heavy menses and subfertility. Among women with uterine fibroids, myomectomy resulted in better fibroid-related quality of life at 4 years, compared with UAE but the treatments decreased menstrual bleeding equally. There was also no significant difference in the impact of treatment on ovarian reserve.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND:Uterine fibroids are the most common tumour in women of reproductive age and are associated with heavy menstrual bleeding, abdominal discomfort, subfertility and reduced quality of life. For women wishing to retain their uterus and who do not respond to medical treatment, myomectomy and uterine artery embolisation are therapeutic options. OBJECTIVES:We examined the clinical effectiveness and cost-effectiveness of uterine artery embolisation compared with myomectomy in the treatment of symptomatic fibroids. DESIGN:A multicentre, open, randomised trial with a parallel economic evaluation. SETTING:Twenty-nine UK hospitals. PARTICIPANTS:Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolisation were recruited. Women were excluded if they had significant adenomyosis, any malignancy or pelvic inflammatory disease or if they had already had a previous open myomectomy or uterine artery embolisation. INTERVENTIONS:Participants were randomised to myomectomy or embolisation in a 1 : 1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic. Embolisation of the uterine arteries was performed under fluoroscopic guidance. MAIN OUTCOME MEASURES:The primary outcome was the Uterine Fibroid Symptom Quality of Life questionnaire (with scores ranging from 0 to 100 and a higher score indicating better quality of life) at 2 years, adjusted for baseline score. The economic evaluation estimated quality-adjusted life-years (derived from EuroQol-5 Dimensions, three-level version, and costs from the NHS perspective). RESULTS:A total of 254 women were randomised - 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolisation (98 underwent embolisation). Information on the primary outcome at 2 years was available for 81% (n = 206) of women. Primary outcome scores at 2 years were 84.6 (standard deviation 21.5) in the myomectomy group and 80.0 (standard deviation 22.0) in the uterine artery embolisation group (intention-to-treat complete-case analysis mean adjusted difference 8.0, 95% confidence interval 1.8 to 14.1, p = 0.01; mean adjusted difference using multiple imputation for missing responses 6.5, 95% confidence interval 1.1 to 11.9). The mean difference in the primary outcome at the 4-year follow-up time point was 5.0 (95% CI -1.4 to 11.5; p = 0.13) in favour of myomectomy. Perioperative and postoperative complications from all initial procedures occurred in similar percentages of women in both groups (29% in the myomectomy group vs. 24% in the UAE group). Twelve women in the uterine embolisation group and six women in the myomectomy group reported pregnancies over 4 years, resulting in seven and five live births, respectively (hazard ratio 0.48, 95% confidence interval 0.18 to 1.28). Over a 2-year time horizon, uterine artery embolisation was associated with higher costs than myomectomy (mean cost £7958, 95% confidence interval £6304 to £9612, vs. mean cost £7314, 95% confidence interval £5854 to £8773), but with fewer quality-adjusted life-years gained (0.74, 95% confidence interval 0.70 to 0.78, vs. 0.83, 95% confidence interval 0.79 to 0.87). The differences in costs (difference £645, 95% confidence interval -£1381 to £2580) and quality-adjusted life-years (difference -0.09, 95% confidence interval -0.11 to -0.04) were small. Similar results were observed over the 4-year time horizon. At a threshold of willingness to pay for a gain of 1 QALY of £20,000, the probability of myomectomy being cost-effective is 98% at 2 years and 96% at 4 years. LIMITATIONS:There were a substantial number of women who were not recruited because of their preference for a particular treatment option. CONCLUSIONS:Among women with symptomatic uterine fibroids, myomectomy resulted in greater improvement in quality of life than did uterine artery embolisation. The differences in costs and quality-adjusted life-years are very small. Future research should involve women who are desiring pregnancy. TRIAL REGISTRATION:This trial is registered as ISRCTN70772394. FUNDING:This study was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 22. See the NIHR Journals Library website for further project information.

Context Thyroid peroxidase antibody (TPOAb) positivity is prevalent in women of reproductive age and predisposes to thyroid dysfunction, particularly hypothyroidism, which has adverse effects on pregnancy. Objective This study aimed to report the rate of development of abnormal thyroid function among initially euthyroid TPOAb-positive women recruited into the TABLET trial, to identify factors associated with the development of hypothyroidism, and to compare outcomes between euthyroid and treated hypothyroid individuals. Methods This observational cohort study, conducted at 49 UK hospitals between 2011 and 2016, included euthyroid TPOAb-positive women 16 to 40 years of age with a history of miscarriage or subfertility, planning pregnancy, randomized to levothyroxine 50 mcg daily or placebo. Abnormal thyroid function, conception rate, and live birth rate (LBR) >= 34 weeks were analyzed. Results Among the women, 70/940 (7.4%) developed subclinical (SCH) or overt (OH) hypothyroidism: 27/470 taking levothyroxine and 43/470 placebo (relative risk [RR] 0.63; 95% CI, 0.39-1.00; P = 0.05); 83% of cases emerged prepregnancy. Baseline median serum TSH concentrations and TPOAb titers were significantly higher in those who developed hypothyroidism vs those who did not (P < 0.001). Treated SCH/OH demonstrated a higher failure-to-conceive rate compared with euthyroid women (adjusted RR 2.02 [1.56-2.62]; P < 0.001). The LBR >= 34 weeks was similar in the treated SCH/OH and euthyroid groups (adjusted RR 1.09 [0.77-1.55]; P = 0.6). Conclusion Approximately 7% of euthyroid TPOAb-positive women will develop hypothyroidism within 1 year preconception or in pregnancy. Conception rates are lower in women with treated SCH/OH compared with euthyroid women, but LBR are comparable. Thyroid function in TPOAb-positive women should be monitored regularly, when trying to conceive, to ensure prompt diagnosis and appropriate treatment initiation.