Is Treating Post-Menopausal Women With Symptomatic Hand Osteoarthritis With Hormone Replacement Therapy Feasible?: Results From The Hope-E Randomised, Placebo-Controlled Feasibility Study

Purpose: Hand osteoarthritis (OA) is more common in women. Hand OA incidence increases further in females around the age of 50, the typical age of menopause. Estrogen-deficient states are associated with increased musculoskeletal pain and inflammation and with increased rates of symptomatic OA. Estrogen replacement and selective estrogen receptor modulators (SERMs) can improve pain and structure in some pre-clinical models of OA associated with estrogen loss, and in exploratory analysis from hormone replacement therapy (HRT) trials. However, no randomised clinical trials (RCTs) of HRT had been performed in symptomatic OA populations, specifically hand OA. By carrying out a RCT feasibility study of a form of HRT (conjugated estrogens (CE)-bazedoxifene) in post-menopausal women with painful hand OA, we set out to determine the feasibility and acceptability of this. We also aimed to generate proof-of concept data on likely outcomes, calculate a sample size and refine methods for a full trial. Method(s): We recruited females aged 40-65 years and 1-10 years after final menstrual period with definite hand OA and >=2 painful hand joints across three primary/secondary care sites and from the community. Medical exclusions included those typical for clinical HRT use. Design was parallel group, double-blind 1:1 randomisation of CE-bazedoxifene or placebo, taken orally once daily for 24 weeks, then tapering for 4 weeks before study end at Week 28. Primary feasibility outcomes were rates of eligible participant identification, recruitment, randomisation, retention, compliance, and likelihood of unblinding. Adverse events (AEs) were collected. Secondary clinical outcomes included the anticipated primary outcome in a full trial of mean hand pain over 14 days prior to each visit, scored on a 0-10 numerical rating scale (NRS) where 10 is worst pain possible, as well as hand function, appearance and menopause symptoms. Progression criteria to a full RCT were: (i) recruitment >=30 participants across all sites in 18 months (or proportionate to time open);(ii) a drop-out rate of <=30% of randomised individuals;and (iii) acceptability to the majority of participants, including acceptable AE rates. All clinical outcomes were analysed on an intention-to-treat basis. Though not powered to detect a treatment difference, change and treatment effects (the difference in the outcome between the two groups) were indicated with 95% CIs, with all models adjusted for clinical subtype of painful hand joint, study site, and baseline values. The sample size for a full trial was estimated using the standard deviation (SD) of week 24 mean hand pain. Result(s): Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. From May 2019 to December 2020, 434 enquiries/referrals were received. Of 96 telephone pre-screens, 35 individuals were potentially eligible and of these, 33 gave consent to participate. Of the remaining, 250/401 (62%) were ineligible, whilst 55/401 (14%) chose not to proceed, with the most common reason being not wanting to take HRT. 28/35 (80% (95%CI 63%,92%)) eligible participants were randomised to study medication. All 28 participants completed all follow-ups with high compliance (100% active, 13/14[93%] placebo) and outcome measure completeness (100%, mean hand pain). All three AE-related treatment withdrawals were on placebo when unblinded. No serious AEs occurred. Participants/investigators were well blinded (participant blinding index 0.50[95%CI 0.25 to 0.75]). All three prespecified progression criteria were therefore met for a full trial. The treatment effect difference over 24 weeks in mean hand pain between active and placebo was -0.71 (95% CI -2.20 to 0.78) (Fig 1A). During tapering/stopping medication, mean hand pain increased by 1.31 points in the active arm compared with 0.17 in the placebo arm, indicating a possible effect of cessation of medication (Fig 1A). Furthermore, 6/13 (46%) participants in the active group reported worsening pain at week 28 compared with week 24, but only 2/12 (17%) were worse on withdrawing placebo (Fig 1B). The sample size for a full trial was estimated as 296 (based on MCID 0.8 on NRS, SD 2.0, 90% power, 10% drop-out, alpha 5%). Conclusion(s): This first study of a RCT of HRT for painful hand OA met its progression criteria, indicating that a full trial of an HRT in this population is feasible and acceptable. Although not powered to detect an effect, there was a trend towards improvement in hand pain on treatment and worsening of hand pain on tapering in the active arm only. This adds to proof-of-concept data in this area, justifying more work.ISRCTN12196200. Funded by Research for Patient Benefit programme, National Institute for Health Research (UK) PB-PG-0416-20023 [Formula presented]Copyright © 2023

A rare case of central post-stroke pain in a patient with migraine and lacunar infarcts in the medulla oblongata

Studies about headaches associated with acute ischemic stroke in patients suffering from migraine were limited, and therefore we present a clinical case of central post-stroke pain (CPSP) in a 47-year-old woman with migraine and lacunar infarcts in the medulla oblongata and also possible mechanisms of CPSP in patients with migraine. Magnetic resonance imaging of the brain revealed lacunar infarction in the medulla oblongata on the right (vertebral artery basin) and a single focus of gliosis in the parietal lobe on the right. Magnetic resonance angiography of cerebral vessels showed the fetal type of structure of both posterior cerebral arteries. This clinical case is a complex clinical situation of a combination of secondary headaches (post-stroke) in a patient with a primary headache (migraine), which was successfully treated by the combined administration of first-line drugs for the treatment of neuropathic pain in a patient with lacunar infarcts in the medulla oblongata. The treatment of CPSP is a difficult task due to the insufficiently unexplored mechanisms of development, the most effective approaches are those aimed at reducing the increased excitability of neurons.Copyright © 2023, Indian Association of Biomedical Scientists. All rights reserved.

Exogenous estrogen use for contraception and hormone replacement therapy and the risk of thrombosis in women with COVID-19

Background: The thrombotic risk associated with SARS-CoV- 2 (COVID-19) is well documented, although there is limited information on how additional prothrombotic risk factors impact persons who contract COVID-19. Certain estrogen containing contraceptives and hormone replacement therapies are also well known to increase the risk of thrombosis. It is unknown if the risks of these agents and concurrent COVID-19 infection are additive. Aim(s): To investigate the relationship between COVID-19 infection and concurrent exogenous estrogen on the rate of thrombotic events. Method(s): A retrospective analysis including all adult female patients diagnosed with COVID-19 between January 2020-2022 at our center also treated with hormone therapy. Female patients on hormone replacement therapy (HRT) for post-menopausal symptoms were included in this analysis. HRT was defined as any treatment consisting of an estrogen analog with or without a progesterone. Thrombotic events were defined as any venous thromboembolism (VTE), cerebrovascular accident (CVA), myocardia infarction (MI), or any arterial clot/embolic event. Events were included if they were recorded as current SNOMED/ICD codes in the same encounter as the diagnosis of COVID-19. Inpatients and outpatients were included in the analysis. Result(s): 92 patients were identified who were diagnosed with COVID-19 while on hormone therapy at the time of diagnosis. 18 of the patients were hospitalized. Mean age was 42 years and 59 years for all patients and hospitalized patients, respectively. The most common estrogen therapies were norethindrone-estradiol (38%) and conjugated estrogen (14.1%). There were 3 (3.2%) total thrombotic events which all occurred in hospitalized patients. 2 patients experienced VTE while 1 patient experienced a cerebrovascular event with arterial clot. Conclusion(s): This retrospective study demonstrates a low rate of thrombosis in patients treated with exogenous estrogen and with COVID-19. The rate of thrombosis in the outpatient setting was low while thrombotic events occurred in hospitalized older patients. Further studies are warranted to explore this association.

Hormone Replacement Therapy and COVID-19 Outcomes in Kidney Transplant Recipients Compared With the General Population

Background: In the non-immunosuppressed (non-IS) population, female sex is protective against adverse COVID-19 (C19) outcomes, possibly due to estrogenrelated immunity. Sex-based risk is attenuated in IS kidney transplant recipients (KTRs). Exogenous estrogen is associated with reduced C19 mortality in non-IS postmenopausal females. Here, we aimed to study the impact of estrogen or testosterone hormone replacement therapy (HRT) on C19 outcomes in KTRs compared to the general population. Method(s): We studied adult (>45 yrs) KTRs from across the US with C19 from 05-01-20 to 05-12-22, using EHR data from the National COVID Cohort Collaborative. Female and male patients were classified as no HRT, or HRT use in the last 6 months (exogenous systemic estrogens for females;testosterone for males). Using MV cox proportional hazards models and logistic regression, we determined the risk of developing a major adverse renal or cardiac event (MARCE), mortality, and other 90-day post-C19 outcomes. We repeated this analysis in a non-IS control group for comparison. Result(s): Over the study period, 11,498 KTRs and >1.9M non-IS patients were diagnosed with C19. In non-IS, relative to no HRT use, HRT use in the last 6 months was associated with significantly lower risk of MARCE (Hazard Ratio [HR] 0.54, 95% Confidence Interval [CI] 0.51-0.59, for females;0.63, 0.56-0.70, for males), mortality (HR 0.45, CI 0.40-0.51, for females;0.55, 0.45-0.66, for males), and all secondary events for males and females (Figure 1). In KTRs, HRT was not associated with any post-C19 outcome in either males or females;there was a trend towards lower risk in males on HRT vs not on HRT, for most outcomes. Conclusion(s): HRT was protective against adverse C19 outcomes in older non-IS males and females, but not in KTRs. The modifying effects of IS on the benefits of HRT requires further investigation.

A RARE PRESENTATION OF COVID-19-ASSOCIATED CENTRAL VENOUS THROMBOSIS

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Due to a wide range of clinical presentations, central venous thrombosis (CVT) is a rare neurologic condition that can be difficult to diagnose. Since the COVID-19 pandemic, more cases of venous thromboembolic events have emerged and been found associated with COVID-19. We detail a potential case of COVID-19 associated CVT. CASE PRESENTATION: A 28-year-old female with past medical history of obesity, polycystic ovary syndrome, recurrent sinusitis, and presumed history of COVID-19 infection with anosmia, ageusia, and sinusitis symptoms three- months prior presented to the hospital with 1-month history of worsening, right-sided pain behind her ear, eye, head, posterior neck and shoulder, nausea, and photophobia, which had worsened in the last 5 days. She initially tried over-the-counter medications with no improvement. Vital signs were unremarkable. Examination was notable for frontal sinus and right postauricular tenderness to palpation. C- reactive protein was elevated at 26.2 mg/L. Non- contrasted brain computed tomography (CT) was concerning for right transverse sinus and superior sagittal sinus thrombosis. Brain magnetic resonance imaging (MRI) showed early signs of cortical edema and venous infarction and findings concerning for right mastoiditis. Intracranial venous MRI showed complete thrombosis of the right transverse and sigmoid sinus, superior sagittal sinus, and most of the superior draining cortical veins. Heparin drip was started. Initial empiric antibiotics for mastoiditis were stopped. Hyper-coagulopathy work-up with beta- 2 glycoprotein 1 antibodies and phospholipid antibodies were negative. As there were no other inciting factors for CVT found and no history of positive COVID-19 test, a COVID-19 antibody immunoassay was obtained and returned positive. The patient did not have a history of COVID vaccination. She was discharged on warfarin and enoxaparin. Anticoagulation was stopped after 6 months with repeat imaging showing resolution of clot burden. DISCUSSION: Usual risk factors associated with CVT are morbid obesity, hormone replacement therapy, oral contraceptive use, hereditary thrombophilia, and pregnancy. Literature on CVT related to COVID-19 is limited. In 41 documented cases, the average age of incidence is 50 years old and median onset of neurological symptoms from initial COVID-19 diagnosis is 7 days [0 to 21 days]. Our patient's neurological symptoms began about 3 months after her initial diagnosis, potentially making it the first known case of COVID-19 associated CVT with symptom onset past 21 days. Anticoagulation is the mainstay treatment for CVT, and duration depends on the presence of provoking factor. CONCLUSIONS: In patients with new neurologic symptoms and recent diagnosis of COVID-19, CVT should be considered in the differential diagnosis as it can initially present in a subtle manner. Early recognition could improve patient morbidity and mortality. Reference #1: Abdalkader, M., Shaikh, S. P., Siegler, J. E., Cervantes-Arslanian, A. M., Tiu, C., Radu, R. A., Tiu, V. E., Jillella, D. v., Mansour, O. Y., Vera, V., Chamorro, Á., Blasco, J., López, A., Farooqui, M., Thau, L., Smith, A., Gutierrez, S. O., Nguyen, T. N., Jovin, T. G. (2021). Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature. Journal of Stroke and Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105733 Reference #2: Idiculla, P. S., Gurala, D., Palanisamy, M., Vijayakumar, R., Dhandapani, S., Nagarajan, E. (2020). Cerebral Venous Thrombosis: A Comprehensive Review. European Neurology (Vol. 83, Issue 4). https://doi.org/10.1159/000509802 Reference #3: Ostovan VR, Foroughi R, Rostami M, et al. Cerebral venous sinus thrombosis associated with COVID-19: a case series and literature review. Journal of Neurology. 2021 Oct;268(10):3549-3560. DOI: 10.1007/s00415-021-10450-8. PMID: 33616740;PMCID: PMC7897893. DI CLOSURES: No relevant relationships by Shu Xian Lee No relevant relationships by Arif Sarwari No relevant relationships by Benita Wu

At-risk patient and healthcare provider perspectives on clinical trial participation for ductal carcinoma in situ

Background: Significant challenges exist in recruiting newly diagnosed ductal carcinoma in situ (DCIS) patients to participate in presurgical intervention trials. Perceived motivators and barriers to participation have not been formally studied from the patient or healthcare provider (HCP) perspective. Based on our experience in the Promise Study (NCT02694809), we hypothesized that delaying surgery and concern for side effects are barriers to trial participation and that access to new treatments and financial benefits are motivators. To improve recruitment, we conducted focus groups to better understand barriers and motivators for trial participation in our patient population. Methods: Three focus groups with post-menopausal women (PMW) without history of DCIS, one focus group with patients previously treated for DCIS, and two HCP focus groups were conducted. Due to COVID-19, the focus groups took place online via videoconferencing and included participants from across the United States. A thirdparty facilitator generated discussion on predetermined topics including knowledge of DCIS, clinical trial recruitment materials, hormone replacement therapy, healthcare delivery and clinical trials during COVID-19, and perceived motivators and barriers to trial participation in general and specifically for women with DCIS. Here, we focus on comparing perceived influential factors for patient participation in DCIS clinical trials in PMW and HCP focus groups. Qualitative thematic analysis was completed on focus group transcripts in NVivo. Results: PMW had no knowledge of DCIS prior to the focus groups and believed DCIS should be removed promptly. PMW believed barriers to DCIS clinical trial participation included the potential for the study drug to cause harm, distrust of medicine, and the fact that DCIS is not life-threatening. PMW identified helping future DCIS patients, accessing better treatment, and easing anxiety as motivators for DCIS trial participation. HCPs believed patients were motivated by increased monitoring by the medical team, financial incentive, and access to newer treatment. HCPs believed that delays in DCIS surgery, the potential for the intervention to be harmful or ineffective, and the trial causing patient anxiety were barriers. Neither group emphasized time commitment as a barrier to DCIS trial participation. PMW were not motivated by financial incentives. Conclusions: Knowledge about DCIS is lacking in PMW. PMW and HCPs agreed that the risk of harm caused by study interventions is a deterrent to trial participation and that access to superior treatment is a motivator. However, PMW and HCPs did not agree on other motivators and barriers which could lead to missed recruitment opportunities. Providing educational materials on DCIS and addressing motivators and barriers to clinical trial participation may increase recruitment to presurgical DCIS trials.

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 osteoarthri-tis (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 defciency 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 refne methods for a full study. Methods: ISRCTN12196200. Females aged 40-65 yrs and 1-10yrs after fnal menstrual period with hand OA fulflling 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 modifed 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 fexibility 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 satisfed 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 defned recruitment strategy, recruitment and retention to a study testing this treatment is possible.

Characteristics of COVID-19 in peri-and postmenopausal women. Role of hormone replacement therapy

A literature review on the effect of peri-and postmenopausal period on the course of novel coronavirus infection and post-COVID-19 syndrome was performed. The aspects of hormone replacement therapy against the background of therapy for COVID-19 and post-COVID-19 syndrome were studied. The postmenopausal period in women was found to be a risk factor for a more severe course of COVID-19. Estradiol may act as a protective factor for women with COVID-19 by regulating cellular and humoral immunity factors such as interleukin-2,-6,-8, tumor necrosis factor-α and C3. Prolonged course of COVID-19, persistence of its symptoms and development of severe post-COVID-19 syndrome are associated with female sex, with women in peri-and postmenopausal period being most vulnerable. Symptoms of estrogen deficiency and menopause may be similar to the manifestations of post-COVID-19 syndrome, and these conditions can coexist and aggravate each other. According to international experts, the use of hormone replacement therapy will help to improve the well-being of women, their quality of life, and relieve the symptoms typical of menopause and post-COVID-19 syndrome.

FEASIBILITY OF THE FOCUM STUDY, A PILOT OBSERVATIONAL COHORT STUDY ABOUT THE INFLUENCE OF MENOPAUSE ON THE DEVELOPMENT OF OSTEOARTHRITIS

Purpose: After the age of fifty years, the incidence of osteoarthritis (OA) increases rapidly in women, suggesting an effect of menopause on the development of OA. Because it is still unclear how menopause precisely influences the development of OA, we aim to investigate this in a novel human model: the Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM) model. This model consists of women between fifty and sixty years of age, who are currently using a combined oral contraceptive (OC) and aim to stop OC use at short term. When these women stop using OC, a rapid change in hormones is expected, modelling a “sudden menopause”. Therefore, this model provides an opportunity to study changes occurring during menopausal transition. Because the FOCUM model is new, it is unknown if women want to participate, are willing to stop OC use shortly, and will not start hormone replacement after stopping OC use. Therefore, we aim to investigate the feasibility of the FOCUM study. We define the study to be feasible when: 1) 50 participants are included within one year and received their baseline measurements (including questionnaires, blood samples and Magnetic Resonance Imaging (MRI) assessments), 2) the loss of follow-up at 6 weeks is less than 5%, and 3) no hormone replacement therapy is used by the participants at 6 weeks follow-up. Methods: For the inclusion of participants, pharmacies in and nearby Rotterdam were invited to participate. Pharmacies were asked to search in their information systems to identify all possible eligible subjects, based on age and OC use. All eligible subjects received an invitation letter with information about the study. Interested subjects were contacted by the researchers for more information. Inclusion criteria were: 1) woman, 2) between 50 and 60 years of age, 3) currently using a combined OC (with Anatomical Therapeutic Chemical (ATC) code G03AA or G03AB), and 4) started OC use before the age of 45. Exclusion criteria were: 1) already known with osteoarthritis (self-reported or registered by their general practitioner), 2) already known with another inflammatory rheumatic condition, 3) having a contra-indication for MRI assessment, 4) having a terminal or mental illness, and 5) not being able to give informed consent. In this study, measurements are performed at baseline, just before stopping OC use (T0 = 0 to 30 days), and after (T1 = 6 weeks;T2 = 6 months;T3 = 1 year;T4 = 2 years) stopping OC use. At every time point, a digital questionnaire is filled in and a blood sample is drawn. At T0 and T4, also an MRI of one of the knees is performed. Results: In January 2020, invitations were sent to 106 pharmacies of which 48 were willing to participate. Due to COVID restrictions, the first invitations to possible eligible subjects were sent in July 2020. Until April 2021, a total of 1037 invitation letters were sent. 206 subjects replied positively, of which 175 were screened by the researchers. After screening for in- and exclusion criteria, 85 subjects were eligible. The most common reason why subjects were not eligible, was because they did not use their OC anymore. Eventually, 54 subjects gave informed consent and were all seen for their baseline measurements between August 2020 and July 2021. All baseline questionnaires, blood samples and MRI assessments were available. At 6 weeks follow-up, all 54 subjects were still participating in the study. From one participant the blood sample has not been drawn at 6 weeks follow-up and one participant started hormone replacement therapy after baseline measurements (see flowchart 1). [Formula presented] Conclusions: We reached the number of 54 participants within one year, which is more than the initially targeted number of 50. All baseline measurements, including questionnaires, blood samples and MRI assessments, have been collected from these 54 participants. At 6 weeks follow-up, there was no loss of follow-up, of one participant no blood sample was available and one participant started hormone replacement therapy. Therefore, we conclude that the FOCUM study is feasible. The next step will be to investigate differences in cardiometabolic and inflammatory biomarkers, joint complaints and structural OA features between baseline and follow-up measurements.