Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study

Background Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40–65 years, for whom 1–10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12–15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63–92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25–0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding Research for Patient Benefit programme, National Institute for Health Research

A Love story

When Philip wakes again it is dayhght; as window, wash-basin, chair and then rucksacks swim into focus, this time he knows where he is: in a room in a pensione in Florence, just a stone\u27s throw from the bridge where Dante saw Beatrice, exams over, his girl beside him. Three months of travelling. Seeing. Voyage to Discovery. New World fmds Old. He turns his head; Alvie is still asleep. Sitting up carefully, he watches a pulse ticking in her neck. Her skin is pale, winter-pale, but across the pillow her hair is a copper fire. She has used the rinse she bought to try out her phrase book Italian. Her lips move; she is smiling. At what, he wonders, sliding out of the bed. What

Tourist

But which shower to choose? There are two on your floor of the pensione, each curtainless, one so small and steamy that you have to leave the door ajar and risk a stranger bursting in — a stranger, probably, who will squawk at you in Italian — the other so eccentric that water sprays all over the walls and your nearly new dressing gown and trickles into the passage. Which shower shall I try today? you would like to ask someone... Which shower shall I try today? you say in your head, jokey, so that whoever is listening can have no inkling of the small panic that underlies the silly question. Perhaps, after all, you should have played safe and booked into a hotel? But, as you put it to them back home in the tea room during one of those sessions when you examined your plans from every angle, hogging the tea break probably but that is a traveller\u27s privilege, of course I can afford a hotel, you said, but pensione in Rome sounds more fun. Well of course a pensione is more fun! came their prompt reply. More fun. More real. Let your hair down properly while you\u27re about it — and you saw them exchange smiles. Be a devil! Take the plunge! Where\u27s your sense of adventure

AB0980 Hand Osteoarthritis: investigating Pain Effects in a randomised placebo-controlled feasibility study of estrogen-containing therapy (HOPE-e): report on the primary feasibility outcomes

Background There is an unmet need for new treatments for hand osteoarthritis (OA). Symptomatic hand OA is more common in women and its incidence increases round the age of menopause. Pre-clinical, epidemiological and post hoc studies in Hormone Replacement Therapy (HRT) trials implicate estrogen deficiency as of likely importance in OA aetiopathogenesis. No clinical trials of HRT have been carried out in hand OA to date. The licensed HRT Duavive (conjugated estrogens + SERM bazedoxifene) was selected on its potential for efficacy and tolerability. Objectives We set out to determine the feasibility and acceptability of this form of HRT in post-menopausal women with hand OA, to generate proof of concept data and refine methods for a full study. Methods ISRCTN12196200. Females aged 40-65 yrs and 1-10yrs after final menstrual period with hand OA fulfilling ACR criteria and 2+ painful hand joints were recruited. Eligibility incorporated best practice for HRT prescription but did not require menopausal symptoms. Recruitment was at 3 sites in primary/secondary care, including directly from the community. Design was parallel group, double-blind 1:1 randomisation of Duavive or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before stopping. Routes and rates of recruitment and the acceptability of randomisation, medication (compliance, retention), and proposed outcomes were measured, and the likelihood of unblinding. Measures related to hand pain and function, menopause symptoms and joint appearance. Patient and Public Involvement actively informed study rationale, design and materials. An end of study questionnaire and 2 participant focus groups provided further acceptability data. Results Recruitment was for 12/possible 18 months, interrupted due to COVID-19. Some study procedures were modified to allow reopening whilst collecting all primary outcomes. 434 enquiries/referrals were received, leading to 96 telephone pre-screens, of which 33 gave written informed consent and attended face to face screening. 28/33 screened (85%) were eligible and randomised. The highest number of randomisations was from study web presence (n=7) followed by SMS text from GP surgeries (n=5). Of 401 not proceeding, 250 (62%) were ineligible, most commonly due to contraindicated medication, followed by medical contraindication, whilst 55 (14%) decided not to take part, for reasons including not wanting to take a hormone-based drug or difficulty attending study visits. Retention and compliance were excellent. All 28 participants completed all study follow ups, with only 3 withdrawals from treatment due to AEs, 2 of these at week 24 and all in the placebo arm. There were no serious AEs. High levels of completeness of all study outcome measures were achieved. Bang’s blinding index suggested that participants/investigators were well blinded. There were overall high/good levels of satisfaction with taking part in the study. 26/28 (92%) would recommend taking part to others with hand OA (irrespective of study arm). Many found the flexibility offered by a combination of remote and face to face visits (due to the pandemic) attractive. Additional insights from focus groups were to include hand stiffness as well as pain measures but to reduce the overall number of questions. Conclusion Despite COVID-19 and a reduced recruitment period, this study recruited sufficient numbers to assess feasibility outcomes. Randomisation of eligible people and retention rates were high. A mixture of remote and face to face visits due to COVID-19 probably improved recruitment and retention and was supported by participants, who were generally satisfied with the study design and medication. The study provided useful insight and improvements that would be incorporated into a future study. Overall, this feasibility study showed that with clear messaging on eligibility and a defined recruitment strategy, recruitment and retention to a study testing this treatment is possible

Treating post-menopausal women with symptomatic hand osteoarthritis with hormone replacement therapy (conjugated estrogens and bazedoxifene): primary report from the HOPE-e randomised placebo-controlled feasibility study

Background: Symptomatic hand osteoarthritis (OA) is more common in women and its incidence increases round the age of menopause, implicating estrogen deficiency. No randomised clinical trials (RCTs) of hormone replacement therapy (HRT) have been carried out in hand OA. We set out to determine the feasibility and acceptability of a RCT of a form of HRT (conjugated estrogens-bazedoxifene) in post-menopausal women with painful hand OA. Methods: ISRCTN12196200. Females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and ≥2 painful hand joints were recruited across three primary/secondary care sites and the community. Design was parallel group, double-blind 1:1 randomisation of conjugated estrogens-bazedoxifene or placebo, orally once daily for 24 weeks, then weaning for 4 weeks before study end. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Secondary outcomes generated proof-of-concept quantitative and qualitative data, assessing acceptability of proposed outcomes for a full trial (hand pain/function/appearance, menopause symptoms), and adverse events (AEs), to refine study design. Analysis was intention-to-treat. Progression criteria were pre-defined. Findings: From May2019-Dec2020, 434 enquiries/referrals were received. 33 individuals gave written informed consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed. Of 96 telephone pre-screens, 28/35 (80%(95%CI 63%,92%)) eligible participants were randomised. All 28 participants completed all follow-ups with high compliance and outcome measure completeness. All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs were reported. Participants/investigators were well blinded (participant index 0·50(95%CI 0·25,0·75)). Interpretation: This first ever feasibility study of a RCT of HRT for painful hand OA met its progression criteria, though not powered to detect an effect. This indicates that a full trial of an HRT in this population is feasible and acceptable, identifying possible further design refinements. Funding: Research for Patient Benefit programme, National Institute for Health Researc

Sources of variation in self-incompatibility in the Australian forest tree, Eucalyptus globulus

† Background and Aims One of the major factors affecting the outcrossing rate in Eucalyptus globulus is thought to be the inherent self-incompatibility (SI) level of the female tree. SI in this species is mainly due to late-acting pre- and post-zygotic mechanisms operating in the ovary, and not S alleles. This study aimed to assess the phenotypic variation in SI levels within E. globulus and determine its genetic control and stability across pollination techniques, sites and seasons. † Methods SI levels were estimated for 105 genotypes originating from across the geographical range of E. globulus over multiple years of crossing. Separate grafted trees of some genotypes growing at the same and different sites allowed the genetic basis of the variation in SI to be tested and its stability across sites and seasons to be determined. The SI level of a tree was measured as the relative reduction in seeds obtained per flower pollinated following selfing compared with outcross pollinations. Thus, if seed set is the same, SI is 0 %, and if no self seed is set, SI is 100 %. † Key Results The average SI in E. globulus was 91% and genotypes ranged from 8 to 100% SI. Most genotypes (.75 %) had SI levels .90 %. There were highly significant differences between genotypes and the within-site broad-sense heritability of percentage SI was high (H2 ¼ 0.80+0.13). However, there was evidence that growing site, and to a lesser extent season, can affect the expression of SI levels. Trees with low reproductive loads produced relatively more seed from selfed flowers. †Conclusions There is a strong genetic basis to the phenotypic variation in SI in E. globulus within a site. However, the level of SI was affected, but to a lesser extent, by the environment, which in part may reflect the higher probability of selfed zygotes surviving on sites or in seasons where competition for resources is less