Title: A feasibility study in female symptomatic hand osteoarthritis for a randomised placebo-controlled trial of estrogen-containing therapy and its efficacy on pain
Funder: Department of Health and Social Care

Abstract: Background:Hand osteoarthritis (OA) affects ~2 million people in the UK. The only current drug treatments are standard analgesia or steroid injections. Painful small joint hand OA often affects use of the hands and is more common in women, often coming on around the menopause when levels of the hormone estrogen fall. In hip/knee OA, there is evidence that estrogen may slow disease progression. In hand OA, which appears more closely related to estrogen deficiency, this effect may be greater and more discernible. However, unopposed estrogen increases risk of womb cancer. Newer selective estrogen receptor modulators (SERMs) can be used in combination with estrogen to protect the womb. SERMS also appear to slow progression and improve pain in animal models of OA. A combination of estrogen and SERM (bazedoxifene) Duavive was approved in 2014 for menopausal symptoms and has good safety data. On available evidence, the use of combination estrogen-SERM in hand OA could be more acceptable and effective than either treatment alone. To date, no prospective, randomised studies of this agent, or any other estrogen-containing therapies have been carried out, and so a feasibility study is proposed. Aims: To evaluate the feasibility of a trial in female symptomatic hand OA testing effectiveness on average hand pain of: Estrogen-SERM combination Duavive Placebo We aim to assess: feasibility of recruitment to this type of study acceptability of randomisation tolerability of the study medication in this population retention within the study other measures of acceptability We will also: confirm/refine outcome measures estimate a treatment effect perform a power calculation for a full study Plan of investigation: We propose a 2 arm feasibility study using a double-blind randomised controlled intervention. Eligible, consenting participants (females; age 40-65; >12 months after last menstrual period and Recruitment will be over 18 months, aiming to randomise 60-90 participants (to allow at least 30 in to each arm). Study visits include screening, baseline, 4 weeks, 3 months and 6 months, and will include face-to-face visits with safety blood monitoring. The study will be conducted at 2 sites (Oxford and Imperial), and managed via Oxford Clinical Trials Research Unit. The primary outcome is average hand pain over the previous 14 days, comparing 6 months to baseline. Secondary outcome measures relate to pain and function, menopause symptoms, joint appearance and joint function. Feasibility outcomes to be analysed include rates of eligible patient identification and subsequent rates of recruitment/randomisation from different sources. Measures of acceptability/tolerability include retention rates and adverse events: information on acceptability will also be gathered by questionnaire and qualitative focus groups at end of study. Summary of potential benefits: There is a pressing clinical unmet need for drug treatments for patients with symptomatic hand osteoarthritis which improve pain, function and quality of life. This study will determine the feasibility of a future full trial and provide valuable preliminary data on the tolerability and acceptability of this drug class in this patient population. Pfizer providing study medication would represent a considerable cost-saving. Pre-defined stop-go criteria will enable a clear decision on proceeding to a fully-powered study, for which further funding would be sought. Using an existing approved therapy extended to a new indication is likely to enable cheaper and faster availability of treatment to NHS clinics and patients, should the drug be shown to be acceptable and effective.

Lay abstract: Hand osteoarthritis (OA) is a debilitating condition affecting over 2 million people in the UK, that for many causes pain and swelling in the hands. The condition can affect people s independence, confidence and ultimately for some the ability to work. Currently there is no cure available. The only available drugs to try to help with the pain of hand OA are standard pain killers and steroid injections. The condition is much more common in women, especially after the menopause, when levels of the hormone estrogen fall. Estrogen-containing therapy (often called Hormone Replacement Therapy (HRT)) has been shown to reduce the progression of knee and hip OA, and there is some evidence that HRT may also improve the symptoms associated with hand OA, but this has never been tested in a clinical trial. The study will investigate if giving HRT to women after the menopause improves their hand OA symptoms. The proposed study wants to test in 2 UK Hospitals over a period of 18 months, whether 60-90 women with painful hand OA who are already menopausal but are not already taking HRT will agree to take part in this study. Those who agree to take part will be asked to take either an HRT tablet once a day for 6 months or a sugar tablet that looks like the HRT tablets but does not contain any hormones. After 6 months of taking the tablets, measurements of hand pain, function, quality of life and menopause symptoms will be collected from patients and the acceptability of taking the drug everyday will be questioned. The study will run for 3 years, managed by doctors and researchers with a strong track record of research of this kind. It is hoped that if this trial is successful that a larger trial could then be undertaken.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL