Trends in Adaptive Design Methods in Dialysis Clinical Trials: A Systematic Review

Abstract Rationale & Objective Adaptive design methods are intended to improve efficiency of clinical trials and are relevant to evaluating interventions in dialysis populations. We sought to determine the use of adaptive designs in dialysis clinical trials and quantify trends in their use over time. Study Design We completed a novel full text systematic review which utilised a machine learning classifier (RobotSearch) for filtering randomized control trials and adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Setting & Study Populations We searched MEDLINE (Pubmed) and Clinicaltrials.gov using sensitive dialysis search terms. Selection Criteria for Studies We included all randomized clinical trials with patients on dialysis or clinical trials with dialysis as a primary or secondary outcome. There was no restriction of disease type or intervention type. Data Extraction and Analytical Approach We performed a detailed data extraction of trial characteristics and a completed a narrative synthesis of the data. Results 57 studies, available as 68 articles and 7 clinicaltrials.gov summaries, were included after full text review (initial search 209,033 Pubmed abstracts and 6,002 clinicaltrials.gov summaries). 31 studies were conducted in a dialysis population and 26 studies included dialysis as a primary or secondary outcome. While the absolute number of adaptive design methods is increasing over time, the relative use of adaptive design methods in dialysis trials is decreasing over time (6.12% in 2009 to 0.43% in 2019 with a mean of 1.82%). Group sequential designs were the most common type of adaptive design method used. Adaptive design methods impacted the conduct of 50.9% of trials, most commonly resulting in stopping early for futility (41.2%), and early stopping for safety (23.5%). Acute Kidney Injury (AKI) was studied in 32 trials (56.1%), kidney failure requiring dialysis was studied in 24 trials (42.1%) and Chronic Kidney Disease (CKD) was studied in 1 trial (1.75%). 27 studies (47.4%) were supported by public funding. 44 studies (77.2%) did not report their adaptive design method in the title or abstract and would not be detected by a standard systematic review. Limitations We limited our search to two databases (Pubmed and Clinicaltrials.gov) due to the scale of studies sourced (209,033 and 6,002 results, respectively). Conclusions Adaptive design methods are employed in dialysis trials, but there has been a decline in their relative use over time.