The finalised guidelines show the European Medicines Agency’s (EMA) expectations of manufacturers involved in the clinical development of new urate-lowering therapies (ULTs) and anti-inflammatory treatments of gout.
Gout is a common inflammatory disorder of joints and tendons, caused by hyperuricemia, which is an excess of uric acid in the blood, leading to the accumulation of uric acid crystals in joints. Renal damage and kidney stones can develop in severe gout. The current standard of treatment consists of analgesics and anti-inflammatory drugs for acute flare-ups, and ULTs to lower the level of uric acid.
However, there are only a few ULTs available in Europe and all have issues regarding safety. For example, allopurinol, the first-line ULT treatment, is known to commonly cause skin hypersensitivity reactions, and the dose must be lowered in renal patients. Furthermore, the many adverse events associated with non-steroidal anti-inflammatory drugs (NSAIDs) can limit their use for acute treatment.
In the guidelines, the EMA outlines recommendations for patient selection, safety, efficacy and clinical trial design, as well as considering studies in elderly, paediatric and renally impaired patients. As co-morbidities such as renal and cardiovascular disorders are frequent in the target populations, safety and optimal dosing in these special populations should be addressed.
There are different potential treatment goals for gout which require different clinical development plans and trial designs, such as the reduction of hyperuricemia and urate crystal load, or the symptomatic treatment of acute gouty arthritis flares.
For ULTs, it is recommended that sponsors conduct parallel, randomised double-blind placebo-controlled trials for at least six months. For first line treatments, at least one study should use allopurinol as an active control. The guidelines then provide different options for study design for second line treatments, depending on whether the drug will be used as a monotherapy, or in combination with a xanthine oxidase inhibitor (XOI) like allopurinol.
For anti-inflammatory drugs, the guidance also recommends parallel, double-blind randomised placebo-controlled trials, although it states that “no placebo-control is needed if the study objective is demonstrating superiority towards an active control.” For non-inferiority studies, a three-arm study with a placebo is generally appropriate.
Read the full guidance here.