Planning and monitoring of placebo‐controlled survival trials: comparison of the triangular test with usual interim analyses methods

Abstract

Aims For ethical and economic reasons, interim analysis of phase III clinical trials is essential. This study was conducted to compare the efficiency of two interim analysis procedures, which could be used to allow early termination of a clinical trial. Methods We made a post hoc application of two interim analysis methods (Lan & DeMets with O’Brien–Flemming modification, and the triangular test according to Whitehead) by using individual patient data from four published placebo‐controlled survival trials. We determined the date the trial would have been stopped had each method been used, and we estimated consequent results in terms of events and patient numbers included in the trial, the duration of the trial, and on treatment effect. Results The triangular test provided the lowest number of events required to reach a conclusion of the trials while providing an accurate estimate of experimental treatment effects. The triangular test thus indicated the smallest number of patients that would have been enrolled, and the shortest trial duration. The difference between the methods was most important with a detrimental effect of experimental treatment: the number of required events was reduced by 75% and the trial duration was shortened by 48% with the triangular test compared to the Lan & DeMets method. Conclusions Stopping a trial early must depend on the clinical context. It is most important to stop a placebo‐controlled trial as soon as possible when the experimental treatment can be shown deleterious. In such a situation the triangular test is more appropriate than the Lan & DeMets method. When a treatment effect is no different from, or better than, placebo the triangular test is also superior but the importance of premature termination of the trial in such cases has to be balanced against the inevitable reduction of information that the trial can provide.

Improving the rate of negative margins after surgery for oral cavity squamous cell carcinoma: A prospective randomized controlled study

“…Because of ethical concerns and the uncertainties around the actual treatment benefit, interim analyses based on the triangular test were scheduled after inclusion of approximately every 20 patients, with computation of Z and V statistics from the accumulated data. 18,19 Positive values of Z indicate superiority of the experimental treatment; zero values indicate equivalence, and negative values indicate inferiority, whereas V is a measure of information in the trial. Once Z and V were computed, they were plotted against one another and the resulting point was compared with the stopping boundaries.…”

“…Assuming a positive or close margin status as the sole indication for an adjuvant treatment rate of 20% in the control group, and controlling for a 5% type I error and a power of 80%, a sample size of 244 patients was needed to detect a difference with specimen‐derived margin assessment of at least 15%. Because of ethical concerns and the uncertainties around the actual treatment benefit, interim analyses based on the triangular test were scheduled after inclusion of approximately every 20 patients, with computation of Z and V statistics from the accumulated data . Positive values of Z indicate superiority of the experimental treatment; zero values indicate equivalence, and negative values indicate inferiority, whereas V is a measure of information in the trial.…”

Intravenous dexamethasone to prevent the recurrence of benign headache after discharge from the emergency department: a randomized, double-blind, placebo-controlled clinical trial

“…There are potential issues with terminating the study early after interim analysis; however, this decision is supported even when scrutinized retrospectively by the most conservative theoretical statistical models. Both Peto's rule of a fixed minimized α' and 0.001 for efficacy for interim analysis, 33,34 and an O'Brien and Fleming p value of 0.05 for first interim analysis between 2 treatment groups 34 support the early termination since the p value for our primary outcome was so overwhelmingly statistically significant (p < 0.001).…”