Abstract and Introduction
Abstract
Chronic kidney disease is assuming epidemic proportions, and an increasing number of clinical trials are testing treatments developed to improve morbidity and mortality. Surprisingly, however, a large proportion of these trials have had negative or neutral results. When trials unexpectedly demonstrate either no benefit or a detrimental impact of a treatment, especially when that treatment is already used in practice, critics commonly argue that the results were dictated by flawed trial design rather than the intrinsic properties of the treatment. In kidney disease therapeutics, trials commonly rely on observational data and test the hypothesis that these associations may be extrapolated to cause-and-effect. Other key issues in trial design that may affect outcomes include the impact of enrolling relatively healthier subjects, the complexity of recruiting participants with specific characteristics while maintaining generalizability, and the subtleties of event adjudication and quality of life assessments. In this article, general principles of trial design will be discussed and the potential lessons learned from recent trials in nephrology will be critically reviewed.
Introduction
Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are complex, chronic conditions that affect nearly 17% of the US population. Extensive basic and clinical research has been conducted during the past several decades to improve the often dismal outcomes in patients with these conditions. Although results from laboratory investigations, observational studies, and clinical trials in populations other than those with CKD and ESRD have often suggested promising therapeutic approaches, a growing list of randomized controlled trials in nephrology have not rejected their null hypotheses or have had rather counterintuitive and unexpected negative results. For example, the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) and Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trials did not show a benefit of greater anemia correction in a CKD population; the Hemodialysis Study (HEMO) and Adequacy of Peritoneal Dialysis in Mexico trials did not support the aggressive removal of small solutes from ESRD patients; and the German Diabetes and Dialysis Study (Die Deutsche Diabetes Dialyse Studie, 4D) did not demonstrate improved outcomes with atorvastatin in hemodialysis (HD) patients with diabetes mellitus.
Why have there been so many trials in nephrology that have failed to reject their null hypotheses? There are at least two possibilities: first, the null hypothesis is true (that is, the treatment does not result in the anticipated benefit); and second, subtleties in trial design affected comparison of outcomes. Our goal in this review is not to criticize individual trials, but to raise points for discussion about potential methodological 'lessons learned.' This review is organized to follow the natural progress in the design of a clinical trial to include the formulation of the clinical question, the designation of the study population and basic trial design, subject recruitment, detection of end points, and assessment of quality of life (QOL) ( Table 1 ).