Title: A randomised controlled trial of Anakinra vs. Steroids for Gout Attacks in patients with Renal Disease (ASGARD): a feasibility study
Funder: Department of Health and Social Care

Abstract: Introduction Acute gout attacks affect 1-2% of the adult population and are common in patients with chronic kidney disease(CKD). Acute attacks are associated with considerable morbidity, hospital admissions, and prolonging of hospital stays. The prevalence of CKD is 5% and increasing primarily due to the large numbers of older people with chronic diseases such as diabetes, heart failure and hypertension. There is inadequate evidence for the treatment of acute gout attacks in patients with CKD and many patients are treated with courses of non-steroidal anti-inflammatory drugs(NSAID) or colchicine which has been shown to cause acute kidney injury and serious side effects. Episodes of acute kidney injury in these patients worsen underlying kidney disease and risk precipitating end stage kidney disease, with an increased risk of mortality and considerable costs of starting dialysis earlier. Steroid therapy is the only safe treatment option currently available but it has limited evidence base for patients with kidney disease. Short courses of steroids can exacerbate co-existing conditions such diabetes and patients with CKD are susceptible to worsening hypertension and heart failure from increased salt and water retention. Interleukin-1 has been shown to play a critical role in the initiation of an inflammatory response in acute gout arthritis. Targeted therapy with inhibitors of interleukin-1 has opened a novel specific treatment opportunity in patients with kidney disease. Anakinra, an interleukin-1 receptor antagonist is the safest and most efficacious agent that has been used in patients with CKD, and is increasingly being utilised for patients with multiple co-morbidities. Aim The aim of this study is to determine the feasibility of running a phase III double-blind, double-dummy randomised controlled trial comparing Depo-Medrone 120mg intramuscular injection vs. Anakinra 100mg subcutaneous injection for 5 days for the treatment of acute gout attacks in patients with chronic kidney disease as defined by a egfr2 and >30mls/min/1.73m2. A significant component of the larger study will be a preliminary health economic evaluation to compare the two treatment arms. Method The feasibility study will be a multi-centre, double-blind, and double-dummy randomised control trial. We will aim to recruit 32 patients with acute gout and chronic kidney disease (16 in each arm). We will recruit from patients in secondary care, including in-patients or those referred to acute medical take or clinics. The study will test recruitment rates, retention rates and patient s willingness to be randomised. Practically, we would examine aspects of capacity and scalability to go to a definitive multi-centre trial and collect economic information to inform a future economic evaluation. Further work Following this study, we hope to undertake a well-designed and adequately powered study to be the first to establish an evidence base for therapies for acute gout in patients with kidney disease. We hope providing a definitive study will enable national and international guidelines to give clear guidance on treatment for patients with chronic kidney disease. This will avoid confusion and prevent the use of potentially nephrotoxic agents like NSAIDS and colchicine, which can cause fatal side-effects. We feel that treatment with a specific agent like Anakinra would be an economically better treatment option even with its higher treatment costs as we expect a faster resolution of symptoms and improved patient quality of life. We also expect lesser side effects than from steroid treatment such as increasing the chronic burden of hypertension, diabetes and heart failure in frail and vulnerable patients.

Lay abstract: Gout is a common condition that affects 1.3 million people in the UK. It causes very painful attacks" of joint swelling, redness and tenderness. It can affect joints of the foot, ankle, knee, hand and wrist. It is very common in people with kidney disease, who also tend to be older people with other medical conditions such as high blood pressure, heart disease and diabetes. We do not know which is the safest and best way to treat an attack of gout in these patients. A lot of people are given treatment that can worsen their kidney disease, along with their other medical conditions. We want to compare the safest treatment currently available, steroids, with a new treatment that is being increasingly used called Anakinra. This treatment stops the action of a chemical called interleukin-1 which has been discovered to play an important role in the acute gout attack. This treatment has already been used in a handful of patients with kidney disease. We feel it may be a better alternative to steroid treatment which can worsen diabetes, and blood pressure if used for a long time. We would like to perform a scientific study comparing these two treatments. This would involve a big expensive study requiring large numbers of patients and large amounts of information to be collected. Before we do a big study like this, we want to perform a small study using smaller numbers of patients. This will then give us information to plan a larger study to answer the question of which treatment may be better, safer and provides the most value for money for the NHS."

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