Title: Steroid-Reducing Options for ReLapsING PMR (STERLING-PMR): a pragmatic, randomised trial to compare the clinical and cost-effectiveness of adding immunosuppression to steroid-tapering treatment for patients with relapsing PMR, versus steroid-tapering alone
Funder: Department of Health and Social Care

Abstract: This study aims to find out whether adding disease modifying antirheumatic drugs (DMARDs) to steroid treatment is beneficial for people with relapsing polymyalgia rheumatica (PMR). _x000D_ _x000D_ Background: _x000D_ _x000D_ Polymyalgia rheumatica (PMR) is an inflammatory disease affecting older people. PMR causes pain and stiffness, and restricts mobility. It is treated with prednisolone (“steroid”). As the steroid dose reduces, symptoms may return or worsen (relapse), needing an increase in steroid dose. Treatment often lasts over 2 years and may carry serious health risks. The best indicator of these risks is the total steroid dose given throughout the illness._x000D_ _x000D_ Management of relapsing PMR, and referral to rheumatology, are inconsistent. Patients who see rheumatologists are often given tablet drugs called DMARDs (methotrexate (MTX), leflunomide (LEF)), to control inflammation and reduce the need for steroids. With blood monitoring, DMARDs are very safe and do not have the long-term toxicity of steroids. However, we do not know the added benefit of DMARDs in relapsing PMR. Only 6% of NHS patients with PMR take MTX; far fewer take LEF._x000D_ _x000D_ Design and methods:_x000D_ _x000D_ GP practices will contact people with PMR who take steroids, inviting them to contact us if they have relapsed, “flared” or had difficulty reducing steroid dose due to PMR symptoms. We will recruit 200 people: everyone will continue gradual steroid reduction, guided by their GP, aiming for the smallest dose that controls PMR symptoms. 100 of them, chosen at random, will start MTX. This will be switched to LEF if there are side-effects, or if PMR symptoms persist or return despite three months of MTX._x000D_ _x000D_ We will follow up patients for 18 months. Every month, we will ask participants to record their current steroid dose and rate their health-related quality of life using a questionnaire. We will calculate the total amount of steroid taken over 18-months and compare those allocated a DMARD to those not allocated DMARD. We will also see whether adding DMARD controls PMR better and improves the chances of stopping steroids. Health economic analysis will help us understand whether everything involved in prescribing DMARD for relapsing PMR would be a cost-effective and viable approach for the NHS._x000D_ _x000D_ Patient and public involvement (PPI): _x000D_ _x000D_ This trial has been designed together with patients and the public to ensure that it is feasible and relevant to the patient experience. Our PPI group identified key public/patient misperceptions about PMR and its treatments that must be addressed in patient information. They helped us select the target effect size: total prednisolone dose would need to be reduced by at least 30% to justify the burden of adding a DMARD. They advised us that many GPs are yet to fully implement current PMR guidelines on steroid tapering, relapse management and referral. Clear guidance for participants and GPs on these will therefore be provided._x000D_ _x000D_ Dissemination: _x000D_ _x000D_ Regular updates and newsletters throughout the trial will keep people engaged. Our trial website and training packages will promote a consistent, symptom-directed approach for GPs and rheumatologists in steroid prescribing for relapsing PMR; our PPI group confirms this is a key unmet need. We will talk to GP and pharmacist leads locally and nationally about how we all can work together to improve care for patients with PMR.

Lay abstract: Research question:_x000D_ In patients with relapsing polymyalgia rheumatica (PMR) receiving steroid taper, what is the clinical and cost-effectiveness of adding disease modifying antirheumatic drugs (DMARDs) to steroid tapering therapy?_x000D_ _x000D_ Background:_x000D_ 278,000 people in the UK have PMR; symptoms include pain, stiffness and restricted mobility. PMR is the commonest reason for long-term prednisolone therapy. The prednisolone dose is tapered over 12-18 months. 50% of patients relapse requiring dose escalations, prolonging therapy often far beyond 2 years. Cumulative prednisolone toxicity includes diabetes and fracture. Prednisolone dose may be reduced by adding the DMARD, methotrexate (MTX). Case series suggest a similar benefit from another DMARD, leflunomide (LEF)._x000D_ _x000D_ Aim:_x000D_ To determine clinical and cost-effectiveness of adding a DMARD to prednisolone-tapering treatment in people with PMR who have relapsed._x000D_ _x000D_ Primary objective:_x000D_ To conduct a pragmatic, multicentre RCT to test whether adding DMARD to usual-care prednisolone-tapering reduces patient-reported cumulative steroid dose requirements over 18 months, compared with usual-care prednisolone tapering alone._x000D_ _x000D_ Secondary objectives:_x000D_ To assess the impacts over 18 months of adding DMARD to steroids: PMR symptom severity and PMR disease activity; time to stopping steroids and to steroid-free remission; cumulative prescribed steroid dose; adverse events; health-related quality of life; work participation; diagnosis of adrenal insufficiency or of GCA; cost-effectiveness; and impact of increased referrals on capacity of rheumatology services._x000D_ _x000D_ Methods:_x000D_ Multi-centre, Phase III, parallel-group, open-label, randomised controlled trial with internal pilot._x000D_ Patients with PMR will be identified primarily from the community. Eligibility, including PMR diagnosis and history of relapse, will be confirmed in secondary care. 200 patients will be randomised and treated in 20 secondary care sites, providing 90% power to detect a 30% reduction in cumulative prednisolone dose at 18 months, assuming 20% attrition._x000D_ 20 GP practices per secondary care study site will work with the NIHR Clinical Research Network to identify patients with PMR diagnostic Read codes. We will invite potential patients to contact their study site. Patients may also self-refer with GP assent or be recruited from rheumatology clinics._x000D_ Central randomisation will be conducted on a 1:1 patient allocation basis between DMARD plus usual care or usual care alone. The primary DMARD prescribed will be MTX, starting at 15mg weekly, increasing to 20mg weekly at 4 weeks if tolerated. Folic acid will be co-prescribed with MTX to reduce toxicity. If MTX is not tolerated, contra-indicated, or fails to prevent further relapse despite 3 months therapy, MTX may be switched to LEF, starting at 10mg daily, increasing to 20mg daily if tolerated. All patients will continue a standardised prednisolone taper, based on current guidelines, under the care of their GP. Thus, care will be shared between GP and hospital._x000D_ _x000D_ Timelines:_x000D_ 12 month set up; 24 month recruitment; 18 month follow-up; 6 month analysis._x000D_ _x000D_ Anticipated impact and dissemination:_x000D_ This trial will quantify benefits and costs of adding DMARD to standard steroid treatment for patients with relapsing PMR. It will also standardise management of PMR across primary and secondary care. This will improve quality of care for PMR and build UK research capacity for further PMR clinical trials.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM