Low patient enrollment sites in multicenter randomized clinical trials of cerebrovascular diseases: associated factors and impact on trial outcomes

Abstract

Wide variability in patient enrollment among participating sites is a common phenomenon in multicenter trials. We examined stroke trial-related factors associated with the proportion of sites with low patient enrollment and the effect of these low-enrollment sites on trial outcome. We identified efficacy clinical trials enrolling patients with cerebrovascular diseases between 1980 and 2008 using an electronic database. The trials included in our analyses were multicenter randomized controlled trials (RCTs) comparing efficacy endpoints between two or more treatment groups and having >5 sites. Sites enrolling <10 patients or <2% of total trial patients were defined as low- enrollment sites. Trials were classified into tertiles based on the proportion of low-enrollment sites. Factors associated with trials that could be ascertained through a systematic review of published data were identified and examined. The association between low enrollment and a conclusive trial designation (defined by the ability to reject the primary null hypothesis either at or before target enrollment or demonstrate equivalence/noninferiority with adequate statistical power, depending on the initial design) was assessed using a multivariate logistic regression model. We identified 51 trials that met the inclusion criteria and provided information regarding patients enrolled per center. A total of 3059 participating centers enrolled a total of 53,742 trial participants; 78% of the participating sites enrolled <2% of trial participants. Trials enrolling acute stroke patients (within 24 hours of symptom onset) or those evaluating endovascular/surgical intervention had a higher proportion of low-enrollment sites (<10 patients per site). Studies with a higher proportion of low-enrollment sites were more likely to target acute stroke patients and less likely to randomize ≥1000 patients, use general efficacy endpoints, and stratify by site. There was no association between the studies with a higher proportion of low-enrollment sites and designation as a conclusive trial. A better understanding of factors associated with low-enrollment sites in clinical trials and the impact on a trial's ability to demonstrate conclusive outcomes may lead to strategies to make trial enrollments more efficient and cost-effective.