An adaptive clinical trial design to identify the target dose of tenecteplase for treatment of acute pulmonary embolism

Abstract

Background/aims: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy.

Methods: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios.

Results: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis.

Conclusion: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Keywords: Bayes theorem; Pulmonary embolism; adaptive clinical trial; dose selection; statistical methods; thrombolysis.

Figure 1.

Study Design. Success criteria are based on sequential evaluation of the endpoint with a continuous analysis strategy, followed by evaluation with a dichotomized analysis strategy, if and only if superiority has been established with the continuous analysis. If the success criteria with both the continuous and the dichotomized analysis strategies have been met, the trial will terminate and conclude that superiority has been established with both analysis approaches. If superiority with the dichotomized analysis is not established, the decision to continue to enroll subjects in an effort to demonstrate superiority is based on the posterior probability of a clinically significant benefit with the dichotomized analysis. If the likelihood of a clinically significant benefit with the dichotomized analysis is small, the trial will terminate and conclude that superiority has been established with the continuous analysis alone.

Figure 2.

Operating Characteristics

Figure 3.

A Simulated Trial Demonstrating Superiority with Both Analysis Strategies. Each row represents an analysis point, beginning with the first interim analysis at 200 subjects and ending with trial termination. The left panel shows the estimated dose-response curve, with the continuous analysis (solid line) on the left vertical axis and the dichotomized analysis (dashed line) on the right vertical axis; the inset shows the decision quantities used to inform the next stage. The right panel shows the quantities relevant to allocation. The gray bar shows the number of currently enrolled subjects allocated to each arm, with corresponding left vertical axis labeled “Number of Subjects.” The open circle represents the probability that a given arm is the , and the asterisk represents the allocation probability for a given arm for the next allocation period, each with the corresponding right vertical axis labeled “Probability.”

Figure 4.

A Simulated Trial Demonstrating Superiority with Only the Continuous Analysis. Each row represents an analysis point, beginning with the first interim analysis at 200 subjects and ending with trial termination. The left panel shows the estimated dose-response curve, with the continuous analysis strategy (solid line) on the left vertical axis and the dichotomized analysis strategy (dashed line) on the right vertical axis; the inset shows the decision quantities used to inform the next stage. The right panel shows the quantities relevant to allocation. The gray bar shows the number of currently enrolled subjects allocated to each arm. The open circle represents the probability that a given arm is the , and the asterisk represents the allocation probability for a given arm for the next allocation period.