Simulation of various randomization strategies for a clinical trial in sickle cell disease

Abstract

Objective: To use numerical simulation to evaluate various randomization strategies for a clinical trial in sickle cell disease (SCD).

Methods: The Inhaled Mometasone to Promote Reduction in Vaso-occlusive Events trial* is a randomized, controlled, feasibility study of inhaled mometasone for individuals with SCD who do not have asthma. The target sample size is 45 patients and one goal is to limit imbalance with respect to two important covariates (1) hydroxyurea use and (2) historical emergency department (ED) utilization. We compared three methods of patient allocation (simple randomization, block randomization, and biased-coin adaptive randomization) using numerical simulation (10 000 trials). The primary outcome measure was the proportion of simulated trials with numerically apparent differences in the two covariates: hydroxyurea use (binary) and ED utilization (three-level ordinal).

Results: Overall, only 1.6% of simulated trials had any covariate comparison with P < 0.3 across groups for simple randomization, and 0% for both the block and adaptive randomization. In trials where the total sample size was 45 patients, the block randomization strategy achieved the greatest balance because participants were deterministically assigned to the treatment arm that balanced covariates. The adaptive strategy achieved similar results without deterministic treatment assignments even when trials included only 45 patients.

Discussion: Adaptive clinical trial designs have potential to mitigate some of the challenges that have hampered SCD trials. In small exploratory trials, even non-statistically significant differences in important covariates can threaten interpretability and external validity.

Conclusion: Adaptive randomization performed similarly to block randomization and offers advantages including better allocation concealment and less ability for investigators to predict the next assignment.

Keywords: Adaptive clinical trials; Bayesian statistics; Clinical trials; Sickle cell disease.

Figure 1. Performance of the three methods

Histograms depict the final imbalance states of simulated trials of 45 participants. A total of 10,000 sets of virtual patients were generated, and each of the three trial algorithms were applied to each set. For the top four rows, the positive portion of the histogram represents trials with imbalances (and their magnitude) with a higher proportion of that covariate for the placebo group. The bottom row depicts the distribution of final placebo proportion from the various methods.