Background: Improving informed consent to participate in randomized clinical trials (RCTs) is a key challenge in cancer communication. The current study examines strategies for enhancing randomization comprehension among patients with diverse levels of health literacy and identifies cognitive and affective predictors of intentions to participate in cancer RCTs.

Methods: Using a post-test-only experimental design, cancer patients (n = 500) were randomly assigned to receive one of three message conditions for explaining randomization (ie, plain language condition, gambling metaphor, benign metaphor) or a control message. All statistical tests were two-sided.

Results: Health literacy was a statistically significant moderator of randomization comprehension (P = .03). Among participants with the lowest levels of health literacy, the benign metaphor resulted in greater comprehension of randomization as compared with plain language (P = .04) and control (P = .004) messages. Among participants with the highest levels of health literacy, the gambling metaphor resulted in greater randomization comprehension as compared with the benign metaphor (P = .04). A serial mediation model showed a statistically significant negative indirect effect of comprehension on behavioral intention through personal relevance of RCTs and anxiety associated with participation in RCTs (P < .001).

Conclusions: The effectiveness of metaphors for explaining randomization depends on health literacy, with a benign metaphor being particularly effective for patients at the lower end of the health literacy spectrum. The theoretical model demonstrates the cognitive and affective predictors of behavioral intention to participate in cancer RCTs and offers guidance on how future research should employ communication strategies to improve the informed consent processes.