Power and sample size considerations in clinical trials with competing risk endpoints

In clinical trials with a time-to-event endpoint, subjects are often at risk for events other than the one of interest. When the occurrence of one type of event precludes observation of any later events or alters the probably of subsequent events, the situation is one of competing risks. During the planning stage of a clinical trial with competing risks, it is important to take all possible events into account. This paper gives expressions for the power and sample size for competing risks based on a flexible parametric Weibull model. Nonuniform accrual to the study is considered and an allocation ratio other than one may be used. Results are also provided for the case where two or more of the competing risks are of primary interest.     

Impact of dependent left truncation in semiparametric competing risks methods: A simulation study

In this study, we investigated the robustness of the methods that account for independent left truncation when applied to competing risks settings with dependent left truncation. We specifically focused on the methods for the proportional cause-specific hazards model and the Fine–Gray model. Simulation experiments showed that these methods are not in general robust against dependent left truncation. The magnitude of the bias was analogous to the strength of the association between left truncation and failure times, the effect of the covariate on the competing cause of failure, and the baseline hazard of left truncation time.     

Estimation of the marginal survival time in the presence of dependent competing risks using inverse probability of censoring weighted (IPCW) methods

In medical studies, there is interest in inferring the marginal distribution of a survival time subject to competing risks. The Kyushu Lipid Intervention Study (KLIS) was a clinical study for hypercholesterolemia, where pravastatin treatment was compared with conventional treatment. The primary endpoint was time to events of coronary heart disease (CHD). In this study, however, some subjects died from causes other than CHD or were censored due to loss to follow-up. Because the treatments were targeted to reduce CHD events, the investigators were interested in the effect of the treatment on CHD events in the absence of causes of death or events other than CHD. In this paper, we present a method for estimating treatment group-specific marginal survival curves of time-to-event data in the presence of dependent competing risks. The proposed method is a straightforward extension of the Inverse Probability of Censoring Weighted (IPCW) method to settings with more than one reason for censoring. The results of our analysis showed that the IPCW marginal incidence for CHD was almost the same as the lower bound for which subjects with competing events were assumed to be censored at the end of all follow-up. This result provided reassurance that the results in KLIS were robust to competing risks.     

Hazards regression for freemium products and services: a competing risks approach

We propose a competing risks approach to analyse customer behaviours in freemium products and services. The event of interest is when a customer starts to pay for additional features or functionalities. The observation of such an event may be preempted by an event where the customer quits using the product before paying and consuming the additional features or functionalities. One such freemium service is the online game category. The Fine-Gray regression model was implemented for an online game player activity data to study how covariates affect the paying hazard. Some covariates are hypothesized to have different discrete effects at multiple change points. We extend the model to allow for possible change points in the analysis.     

Flexible parametric estimation technique for a competing risks model with unobserved heterogeneity: a Monte Carlo study

We analyse a flexible parametric estimation technique for a competing risks (CR) model with unobserved heterogeneity, by extending a local mixed proportional hazard single risk model for continuous duration time to a local mixture CR (LMCR) model for discrete duration time. The state-specific local hazard function for the LMCR model is per definition a valid density function if we have either one or two destination states. We conduct Monte Carlo experiments to compare the estimated parameters of the LMCR model, and to compare the estimated parameters of a CR model based on a Heckman–Singer-type (HS-type) technique, with the data-generating process parameters. The Monte Carlo results show that the LMCR model performs better or at least as good as the HS-type model with respect to the estimated structure parameters in most of the cases, but relatively poorer with respect to the estimated duration-dependence parameters.     

Weighted log‐rank test for time‐to‐event data in immunotherapy trials with random delayed treatment effect and cure rate

A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece‐wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log‐rank test to detect the treatment effect of an immunotherapy over a chemotherapy control. We showed that the proposed weight was nearly optimal under mild conditions. Our simulation study showed a substantial gain of power in the proposed test over the existing tests and robustness of the test with misspecified weight. We also introduced a sample size calculation formula to design the immunotherapy clinical trials using the proposed weighted log‐rank test.