Curtailed two-stage matched pairs design in double-arm Phase II clinical trials

Abstract

This article proposes a curtailed two-stage matched pairs design to shorten the drug development process in Phase II clinical trials for which there are two arms, a treatment arm and a control arm, and the primary goal being to test whether the treatment is significantly better than the control. The design presented in this article uses the inverse trinomial distribution to determine appropriate cutoff points for the termination or continuation of the trial at each stage and is best suited for trials in which there is a low success rate and the available sample size is limited, such as is the case for trials involving rare forms of cancer or other uncommon diseases.

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

“…These decision rules are the NSC boundaries used by Chen et al, 12 though we relax their requirement for continuous monitoring. Jung, Carsten and Chen and Chen et al also include an explicit interim analysis, that is, an interim analysis at which point a go/no go decision is made regardless of whether or not the final pre‐specified stopping boundary may be reached 10,11,12 . However, such an approach may result in a no go decision even when there is a high probability of correctly identifying that the null hypothesis is false.…”

“…For existing design approaches that permit early stopping to reject H 0 under NSC only, such as Carsten and Chen and Chen et al, the upper bound for rejecting the null hypothesis in terms of CP is always fixed at θ E = 1 . 11,12 That is, the CP must be equal to one in order to reject the null hypothesis, and this value may not be altered. Further, the designs of Jung, Carsten and Chen and Chen et al include an explicit interim analysis, containing some stopping boundary that does not take into account the probability of reaching the final stopping boundary.…”

“…This can be incorporated as an extension of Jung's design, 10 by additionally allowing the trial to stop immediately if the response rates are such that the final decision to reject or not reject the null is known with certainty, either at the interim (to not reject only) or by the end (to either reject or not reject). This approach was first proposed by Carsten and Chen 11 . Their proposed design allows stopping after every pair of participants, where each pair is allocated evenly to experimental treatment and control, therefore assuming perfect balance.…”

“…The trial stops as soon as the required difference in the number of responses is guaranteed to be reached, or cannot be reached (again, either at the interim or by the end of the trial). Thus the designs of Carsten and Chen and Chen et al require continuous or almost continuous monitoring 11,12 …”

“…We note that other two‐arm approaches have been proposed 17,18,19,20,21,22 . However, it is impractical to compare all randomised two‐arm designs, and so our approach will be compared only to Jung's design, as this is the two‐arm analogue to the popular Simon design, and Carsten and Chen and Chen et al's designs, as these designs use curtailment and as such are similar to our approach 10,11,12 . Table 1 shows the main differences between the designs to be compared.…”