Title: Anti-TNF (Adalimumab) injection for the treatment of adults with frozen shoulder during the pain-predominant phase: a multi-centre, randomised, double blind, parallel group, feasibility study
Funder: Department of Health and Social Care

Abstract: RESEARCH QUESTION: What is the feasibility of conducting a large randomised controlled trial to test whether intra-articular injection of adalimumab can reduce pain and improve function in people with early stage frozen shoulder? BACKGROUND: Frozen shoulder (adhesive capsulitis) is extremely painful and debilitating, affecting the ability to perform daily tasks and sleep. The capsule surrounding the shoulder joint becomes inflamed, thickened and tight. It is commoner in people with diabetes or Dupuytren's disease and presents in three overlapping phases: i) early painful inflammatory stage (3-9 months), ii) increased stiffness and impaired function (4-12 months), iii) final thawing phase (12-48 months). Current early stage treatments provide little or no long-term benefit. Adalimumab is used very successfully to treat other inflammatory diseases such as rheumatoid arthritis and downregulates the cells causing Dupuytren s disease; the underlying biological processes for frozen shoulder are similar to Dupuytren s disease. AIMS: Assess the feasibility of a RCT to test whether intra-articular injection of adalimumab can reduce pain and improve function in people with early stage frozen shoulder. FEASIBILITY OBJECTIVES: Assess: i) our ability to screen and identify participants with early stage frozen shoulder; ii) willingness of participants to consent and randomisation; iii) practicalities of delivering the intervention; iv) standard deviation of SPADI and range of motion at 3 months to inform sample size for definitive trial. DESIGN: A multi-centre, randomised, double blind, parallel group, feasibility study, with an embedded qualitative sub-study. SETTING: 84 participants from five NHS primary-care-based musculoskeletal services and their related physiotherapy services. TARGET POPULATION: Men and women &ge;18 years with a new episode of shoulder pain attributable to early stage pain-predominant frozen shoulder who have not received injection or physiotherapy for shoulder pain in the last 3 months, nor being considered for surgery INTERVENTIONS: Participants randomised to receive either i) intra-articular injection of anti-TNF (adalimumab 80mg; 0.8ml) or 2) placebo injection (saline [0.9% sodium chloride] 0.8ml), both under ultrasound guidance by a medically qualified practitioner experienced in treating frozen shoulder by injection. A second injection administered at 2-3 weeks if there is no significant improvement one week after first injection. All participants will receive a single face-to-face session with a physiotherapist. MEASUREMENT OF OUTCOMES: Assess success of feasibility objectives using data from screening and treatment logs from sites. Data will also be collected at baseline and 3 months after randomisation via face to face clinic assessment to assess follow up rates and viability of patient outcome measures to inform a future definitive trial, including generation of potential efficacy data An embedded qualitative sub-study will explore what factors help or hinder recruitment to the trial interventions. TIMELINES FOR DELIVERY: Prior to grant: protocol development and approvals; Months 1-5: finalise approvals and initial site set up; Months 6-17: recruitment; Months 9-20: follow up; Months 21-24: analysis and publication; Months 22-24: proposal for full trial. ANTICIPATED IMPACT AND DISSEMINATION: The results will provide critical information for the design of a definitive NIHR-funded trial. With our PPI representatives and wider stakeholders, we will develop a broad dissemination strategy.

Lay abstract: Frozen shoulder is a common condition affecting approximately 9% of people aged 25-64 years. During the early phase the pain is usually unbearable and the later restriction in movement is severely limiting. It occurs when the flexible tissue (capsule) that surrounds the shoulder joint becomes inflamed, thickened and tight. It's not fully understood why this happens but it's more common in people with diabetes or Dupuytren's disease, which causes the fingers to curl. It can also occur following shoulder injury or surgery. The pain can be very severe and lasts 3-9 months, followed by a 4-12 month period of increasing stiffness, after which the condition usually improves. Frozen shoulder often affects a person s ability to sleep, carry out everyday activities, and work. Current treatments include rest, painkillers, anti-inflammatories, physiotherapy and steroid injections. If stiffness persists, surgery is sometimes recommended. However, there is no evidence that any of these treatments lead to significant benefit in the long term, with many being ineffective. Steroid injections only help in the short term. The aim of this study is to find out if it is possible to run a larger study to test whether an injection of adalimumab can reduce pain and prevent the disease from getting worse if given during the early painful phase of frozen shoulder. We need to conduct this smaller study first to be sure it s possible to identify and treat people with early stage frozen shoulder within the current NHS system, before we conduct a much larger study to find out if this treatment works. In this study we will include 84 adults with painful early stage frozen shoulder who have not yet received treatment. People will be randomised to receive either an injection of the drug adalimumab or a dummy injection of saline directly into the shoulder joint guided by ultrasound. All participants will also see a physiotherapist to help them manage their shoulder condition. We will assess participants before treatment and three months later. Adalimumab has been used very successfully and safely to treat other inflammatory diseases such as rheumatoid arthritis. This drug has been chosen as the biological processes underlying frozen shoulder are similar to those in Dupuytren s disease, where we found it helps to stop the cells causing the disease. The views of patients with frozen shoulder are important to us and have been incorporated into this study. We have worked with a group of patients who have experienced frozen shoulder. All were supportive of our study aims and design. They provided useful feedback that has been incorporated into the study. A patient representative is part of the team for this application. Patient representatives will also be part of the committee that oversees the study.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL