Researchers at the Massachusetts General Hospital and University of North Carolina (UNC) Kidney Center recently published in the journal Arthritis Research & Therapy a review on important aspects concerning the design of clinical trials for lupus nephritis. The study is entitled “Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials.”
Systemic lupus erythematosus (SLE) is a severe autoimmune disease in which the body’s own immune system is abnormally activated, leading to an attack to healthy joints and organs, resulting in inflammation, swelling, pain, disability and often in tissue destruction and multi-organ damage. When the immune system attacks the kidney it becomes inflamed, a process known as lupus nephritis, one of the most severe complications in SLE patients that can lead to long-term damage, kidney failure and death. Lupus nephritis treatment is based on immunosuppressant medication. However, it has been reported that up to 70% of the patients might be resistant to such therapies.
Diverse clinical SLE manifestations can lead to challenges in clinical trial design, and well-designed trials with precise inclusion and exclusion criteria, guidelines, and carefully chosen endpoints are required to advance the treatment and management of lupus nephritis. In this study, researchers conducted a review focusing on the proper design and endpoints for lupus nephritis clinical trials.
Given the fact that SLE is a systemic disease that can affect several organs, the U.S. Food and Drug Administration (FDA) has recommended that a primary endpoint in trials should be the patient’s overall disease activity, as a specific therapy may benefit one organ system while it may worsen the symptoms in another organ.
Lupus nephritis therapies mainly have two goals: induction or maintenance of remission. However, there is no established definition of ‘complete remission’ despite the fact that it is a common endpoint in clinical trials.
As treating nephrologists and rheumatologists, the authors of the review suggest that clinical trials in lupus nephritis should have endpoints that include the assessment of kidney disease activity by the measurement of glomerular filtration rate (GFR) and proteinuria (the excess of serum proteins in the urine), and an analysis of urine sediment only in conjunction with the previous two measures. Complete remission or response should be considered when proteinuria levels are less than 0.3 g/day, while the GFR measure should account for a substantial change instead of a static arbitrary value. In addition, a kidney biopsy can provide decisive evidence of histologic responses such as remission.
In trials testing therapies for remission maintenance, the primary endpoint is usually “treatment failure.” According to the authors, this should be defined by the patient’s death, a need for renal replacement therapy or transplant, GFR decrease by at least 50%, persistent doubling of serum creatinine, or a renal flare requiring treatment.
It is unethical to refuse effective treatment to study participants; therefore, all clinical trials need to have a steroid dosing strategy in its design although there are no standard guidelines that define the dose and type of steroid that should be used. The authors emphasize that an essential component in the design of lupus nephritis trials is to provide participants with a detailed guidance regarding steroid use and dosing.
The authors concluded that clinical trials for lupus nephritis should assess the overall disease activity, including renal assessment through parameters such as GFR and proteinuria. Researchers also suggest that clinical trials should have a follow-up period of at least 12 months, ideally 24 months, and should have proper inclusion/exclusion criteria, pre-specified dosing parameters for steroids and endpoints that are clinically meaningful. In addition, the authors also suggest that an important endpoint to be considered is the reduction in steroid dose in patients due to its associated side effects.