Challenges in conducting clinical trials in nephrology: conclusions from a Kidney Disease—Improving Global Outcomes (KDIGO) Controversies Conference

Abstract

Despite the high costs of treatment of people with kidney disease and associated comorbid conditions, the amount of reliable information available to guide the care of such patients is very limited. Some treatments have been assessed in randomized trials, but most such trials have been too small to detect treatment effects of a magnitude that would be realistic to achieve with a single intervention. Therefore, KDIGO convened an international, multidisciplinary controversies conference titled "Challenges in the Conduct of Clinical Trials in Nephrology" to identify the key barriers to conducting trials in patients with kidney disease. The conference began with plenary talks focusing on the key areas of discussion that included appropriate trial design (covering identification and evaluation of kidney and nonkidney disease outcomes) and sensible trial execution (with particular emphasis on streamlining both design and conduct). Break out group discussions followed in which the key areas of agreement and remaining controversy were identified. Here we summarize the main findings from the conference and set out a range of potential solutions. If followed, these solutions could ensure future trials among people with kidney disease are sufficiently robust to provide reliable answers and are not constrained by inappropriate complexities in design or conduct.

Znanost temeljena na dokazima u nefrologiji, dijalizi i transplantaciji bubrega

“…Na konferenciji se dogovorila strategija istraživanja i postavili su se jasni ciljevi i zadatci. Nakon početnog sagledavanja stanja u kojemu se između ostaloga uočilo kako nedostaje kvalitetnih randomiziranih studija s dovoljnim brojem uključenih pacijenata, nastala je publikacija sa smjernicama kako osmisliti randomiziranu kontroliranu studiju u specifič-noj grupi nefroloških pacijenata, publicirana u kolovozu 2017. godine 15 . Na sastanku su se jasno i nedvosmisleno dale smjernice za buduća istraži-vanja, dosadašnja literatura očistila se od velikog nepotrebnog otpada koji nije dao tražene rezultate, a potrošio velike financijske resurse.…”

“…Na sastanku su se jasno i nedvosmisleno dale smjernice za buduća istraži-vanja, dosadašnja literatura očistila se od velikog nepotrebnog otpada koji nije dao tražene rezultate, a potrošio velike financijske resurse. Ako se navedene preporuke budu uvažavale, buduće studije trebale bi biti dovoljno velike i kvalitetne da nam daju prijeko potrebne znanstveno utemeljene dokaze za sigurno i učinkovito liječenje nefroloških pacijenata 15 . Navedene akcije u uskoj su suradnji i s nefrološkom Cochrane grupom.…”

Guidelines for clinical evaluation of chronic kidney disease

“…Regarding setting mortality as an outcome, given that sensitivity and generalization feasibility are both low, it is rarely possible to appropriately use mortality as an endpoint of CKD clinical trials [5]. Since deaths are caused by various reasons, it is hard to associate direct reasons with CKD studied in clinical trials.…”

“…Even for the evaluation of outcomes specific to renal disease using surrogate endpoints, the appropriate endpoints are expected to vary according to the speed of progress and clinical stage of the disease. KDIGO proposed the endpoints shown in Table 1 based on the results of the controversy conference held in 2016 [5].…”

Should We Increase GFR with Bardoxolone in Alport Syndrome?

“…9 Because the drug target of bardoxolone is likely to be present in many primary renal diseases with a higher prevalence (including diabetes, the original target disease in the BEAM Study and the BEACON Trial), efficacy and safety would be most reliably assessed in long-term trials that include a wider range of patients. Given its known hazards, the theoretical potential for adverse long-term effects on renal function, and a target population that is young and relatively healthy, we believe that the model of accelerated drug development of bardoxolone in patients with Alport syndrome is inappropriate.…”