Curtailed two-stage design for comparing two arms in randomized phase II clinical trials.

In phase II clinical trials, patients are recruited sequentially and consequently the time required to complete the clinical trial will become long if the accrual rate is low. To speed up the drug development process and account for ethical issues, stochastically and non-stochastically curtailed two-stage designs have been proposed in single-arm phase II clinical trials. More recently, randomized phase II clinical trials are being increasingly recommended to avoid biased evaluation of the treatment effect when compared with a historical control. The current patient population and the historical one may be quite heterogeneous. Moreover, it is impossible to randomly assign patients for treatments. Consequently, various two-stage designs have been presented for comparing two arms. Since the sample size required in a randomized phase II trial is usually larger than that required in a single-arm phase II trial, we introduce the concept of curtailed sampling procedure to develop curtailed two-stage design for two-armed, randomized phase II clinical trials. The proposed design does not require pairwise patient response comparison, yet it allows a trial to be stopped early as soon as the difference in therapeutic effect of the experimental therapy and the standard at the end of a trial is foreknown.

Power and sample size calculation for paired recurrent events data based on robust nonparametric tests.

The purpose of this paper is to develop a formula for calculating the required sample size for paired recurrent events data. The developed formula is based on robust non-parametric tests for comparing the marginal mean function of events between paired samples. This calculation can accommodate the associations among a sequence of paired recurrent event times with a specification of correlated gamma frailty variables for a proportional intensity model. We evaluate the performance of the proposed method with comprehensive simulations including the impacts of paired correlations, homogeneous or nonhomogeneous processes, marginal hazard rates, censoring rate, accrual and follow-up times, as well as the sensitivity analysis for the assumption of the frailty distribution. The use of the formula is also demonstrated using a premature infant study from the neonatal intensive care unit of a tertiary center in southern Taiwan. Copyright © 2017 John Wiley & Sons, Ltd.

Confidence intervals for the ratio of two median residual lifetimes with left-truncated and right-censored data.

The confidence intervals for the ratio of two median residual lifetimes are developed for left-truncated and right-censored data. The approach of Su and Wei (1993) is first extended by replacing the Kaplan-Meier survival estimator with the estimator of the conditional survival function (Lynden-Bell, 1971). This procedure does not involve a nonparametric estimation of the probability density function of the failure time. However, the Su and Wei type confidence intervals are very conservative even for larger sample size. Therefore, this article proposes an alternative confidence interval for the ratio of two median residual lifetimes, which is not only without nonparametric estimation of the density function of failure times but is also computationally simpler than the Su and Wei type confidence interval. A simulation study is conducted to examine the accuracy of these confidence intervals and the implementation of these confidence intervals to two real data sets is illustrated.

Marginal regression approach for additive hazards models with clustered current status data.

Current status data arise naturally from tumorigenicity experiments, epidemiology studies, biomedicine, econometrics and demographic and sociology studies. Moreover, clustered current status data may occur with animals from the same litter in tumorigenicity experiments or with subjects from the same family in epidemiology studies. Because the only information extracted from current status data is whether the survival times are before or after the monitoring or censoring times, the nonparametric maximum likelihood estimator of survival function converges at a rate of n(1/3) to a complicated limiting distribution. Hence, semiparametric regression models such as the additive hazards model have been extended for independent current status data to derive the test statistics, whose distributions converge at a rate of n(1/2) , for testing the regression parameters. However, a straightforward application of these statistical methods to clustered current status data is not appropriate because intracluster correlation needs to be taken into account. Therefore, this paper proposes two estimating functions for estimating the parameters in the additive hazards model for clustered current status data. The comparative results from simulation studies are presented, and the application of the proposed estimating functions to one real data set is illustrated.

The association between enterovirus 71 infections and meteorological parameters in Taiwan.

BACKGROUND: Enterovirus 71 (EV71) infections are a significant cause of neurological disorder and death in children worldwide. Seasonal variations in EV71 infections have been recognized, but the mechanisms responsible for this phenomenon remain unknown. The purpose of this study was to examine the relationship between meteorological parameters and EV71 infection. METHODS AND FINDINGS: We analyzed the number of EV71 infections and daily climate data collected in Taiwan between 1998 and 2008 and used Poisson regression analysis and case-crossover methodology to evaluate the association between weather variability and the incidence of EV71 infection. A total of 1,914 EV71-infected patients were reported between 1998 and 2008. The incidence of EV71 infections reflected significant summertime seasonality (for oscillation, p<0.001). The incidence of EV71 infections began to rise at temperatures above 13°C (r(2) = 0.76, p<0.001); at temperatures higher than approximately 26°C (r(2) = 0.94, p<0.05), the incidence began to decline, producing an inverted V-shaped relationship. The increase in the incidence with increasing relative humidity was positive and linear (r(2) = 0.68, p<0.05). EV71 infection was most highly correlated with temperature and relative humidity in the period that likely preceded the infection. CONCLUSION: Our study provides quantitative evidence that the rate of EV71 infection increased significantly with increasing mean temperature and relative humidity in Taiwan.

Curtailed two-stage designs with two dependent binary endpoints.

When phase I clinical trials were found to be unable to precisely estimate the frequency of toxicity, Brayan and Day proposed incorporating toxicity considerations into two-stage designs in phase II clinical trials. Conaway and Petroni further pointed out that it is important to evaluate the clinical activity and safety simultaneously in studying cancer treatments with more toxic chemotherapies in a phase II clinical trial. Therefore, they developed multi-stage designs with two dependent binary endpoints. However, the usual sample sizes in phase II trials make these designs difficult to control the type I error rate at a desired level over the entire null region and still have sufficient power against reasonable alternatives. Therefore, the curtailed sampling procedure summarized by Phatak and Bhatt will be applied to the two-stage designs with two dependent binary endpoints in this paper to reduce sample sizes and speed up the development process for drugs.

Statistical inference for clinical trials with binary responses when there is a shift in patient population.

In clinical research, it is not uncommon to modify a trial procedure and/or statistical methods of ongoing clinical trials through protocol amendments. A major modification to the study protocol could result in a shift in target patient population. In addition, frequent and significant modifications could lead to a totally different study that is unable to address the medical questions that the original study intended to answer. In this article, we propose a logistic regression model for statistical inference based on a binary study endpoint for trials with protocol amendments. Under the proposed method, sample size adjustment is also derived.

Analyzing survival curves at a fixed point in time for paired and clustered right-censored data.

In clinical trials, information about certain time points may be of interest in making decisions about treatment effectiveness. Rather than comparing entire survival curves, researchers can focus on the comparison at fixed time points that may have a clinical utility for patients. For two independent samples of right-censored data, Klein et al. (2007) compared survival probabilities at a fixed time point by studying a number of tests based on some transformations of the Kaplan-Meier estimators of the survival function. However, to compare the survival probabilities at a fixed time point for paired right-censored data or clustered right-censored data, their approach would need to be modified. In this paper, we extend the statistics to accommodate the possible within-paired correlation and within-clustered correlation, respectively. We use simulation studies to present comparative results. Finally, we illustrate the implementation of these methods using two real data sets.

Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.

UNLABELLED: One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores > or =2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (> or =2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a > or =1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. CONCLUSION: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis.

The simultaneous use of weighted logrank and weighted Kaplan-Meier statistics with clustered right-censored data.

Clustered right-censored data often arise from tumorigenicity experiments and clinical trials. For testing the equality of two survival functions, Jung and Jeong extended weighted logrank (WLR) tests to two independent samples of clustered right-censored data, while the weighted Kaplan-Meier (WKM) test can be derived from the work of O'Gorman and Akritas. The weight functions in both classes of tests (WLR and WKM) can be selected to be more sensitive to detect a certain alternative; however, since the exact alternative is unknown, it is difficult to specify the selected weights in advance. Since WLR is rank-based, it is not sensitive to the magnitude of the difference in survival times. Although WKM is constructed to be more sensitive to the magnitude of the difference in survival times, it is not sensitive to late hazard differences. Therefore, in order to combine the advantages of these two classes of tests, this paper developed a class of versatile tests based on simultaneously using WLR and WKM for two independent samples of clustered right-censored data. The comparative results from a simulation study are presented and the implementation of the versatile tests to two real data sets is illustrated.

Sample size estimation based on event data for a two-stage survival adaptive trial with different durations.

In clinical development, an adaptive design combining results from two separate studies (e.g., a seamless adaptive design with a dose finding study phase and a confirmatory study phase) is commonly considered. The purpose of an adaptive design is not only to reduce lead time between the two studies, but also to evaluate the treatment effect in a more efficient way. In this paper, the focus is on the case where the study objectives are the same but the time durations of the study periods are different in the two stages. In particular, event data are collected in both stages. Statistical procedure for combining data observed from the two different stages is discussed. Furthermore, results on hypotheses testing and sample size calculation are derived for the comparison of two treatments.

Curtailed two-stage designs in Phase II clinical trials.

When the accrual rate is low and the treatment period is long, a long observational period is required before information concerning the primary end point, such as binary response, becomes available in the study. Simon's two-stage designs are often employed in Phase II clinical trials to avoid giving patient an ineffective drug. Thus, if the new drug is ineffective then this design would certainly accelerate the process of drug discovery and development. However, for a promising new drug this design may still require a long observational period. Therefore, when drug safety is not a primary concern, this paper proposes curtailed two-stage designs to shorten the drug development process as soon as the treatment either shows lack of efficacy or is very effective. The proposed design is superior to Simon's two-stage designs in terms of savings in expected sample size and is much easier to implement in practice than stochastically curtailed Simon's designs.

Interval estimation of binomial proportion in clinical trials with a two-stage design.

Generally, a two-stage design is employed in Phase II clinical trials to avoid giving patients an ineffective drug. If the number of patients with significant improvement, which is a binomial response, is greater than a pre-specified value at the first stage, then another binomial response at the second stage is also observed. This paper considers interval estimation of the response probability when the second stage is allowed to continue. Two asymptotic interval estimators, Wald and score, as well as two exact interval estimators, Clopper-Pearson and Sterne, are constructed according to the two binomial responses from this two-stage design, where the binomial response at the first stage follows a truncated binomial distribution. The mean actual coverage probability and expected interval width are employed to evaluate the performance of these interval estimators. According to the comparison results, the score interval is recommended for both Simon's optimal and minimax designs.

Testing the equality of two survival functions with right truncated data.

To compare the survival functions based on right-truncated data, Lagakos et al. proposed a weighted logrank test based on a reverse time scale. This is in contrast to Bilker and Wang, who suggested a semi-parametric version of the Mann-Whitney test by assuming that the distribution of truncation times is known or can be estimated parametrically. The approach of Lagakos et al. is simple and elegant, but the weight function in their method depends on the underlying cumulative hazard functions even under proportional hazards models. On the other hand, a semi-parametric test may have better efficiency, but it may be sensitive to misspecification of the distribution of truncation times. Therefore, this paper proposes a non-parametric test statistic based on the integrated weighted difference between two estimated survival functions in forward time. The comparative results from a simulation study are presented and the implementation of these methods to a real data set is demonstrated.

Simultaneous quantification and genotyping of hepatitis B virus for genotypes A to G by real-time PCR and two-step melting curve analysis.

Both the viral titer and the genotype significantly determine clinical outcomes and responses to antiviral treatment in chronic hepatitis B virus (HBV) infection. A method was developed for large-scale A-to-G genotyping with simultaneous viral quantification. The assay was run on a LightCycler instrument using hybridization probes. The genotype was determined from the melting points of the probes in a two-step manner. Set 1 amplicons differentiated genotypes B, E, and F from A, C, D, and G and simultaneously quantified viremia by real-time PCR. Melting curve analysis using the set 2-1 amplicon or the set 2-2 amplicon reaction mixture was then used to differentiate these genotype groups into single genotypes. HBV DNA quantification was consistent with that of the Amplicor assay and linear in a range from 10(2) to 10(13) copies/ml. By comparison with the restriction fragment length polymorphism method, 92.3% of 441 samples were accurately genotyped by the current assay. The method should be useful for genotyping and quantification of HBV DNA in areas where all genotypes exist.

Multiple testing procedures based on weighted Kaplan-Meier statistics for right-censored survival data.

In clinical trials or drug development studies, researchers are often interested in identifying which treatments or dosages are more effective than the standard one. Recently, several multiple testing procedures based on weighted logrank tests have been proposed to compare several treatments with a control in a one-way layout where survival data are subject to random right-censorship. However, weighted logrank tests are based on ranks, and these tests might not be sensitive to the magnitude of the difference in survival times against a specific alternative. Therefore, it is desirable to develop a more robust and powerful multiple testing procedure. This paper proposes multiple testing procedures based on two-sample weighted Kaplan-Meier statistics, each comparing an individual treatment with the control, to determine which treatments are more effective than the control. The comparative results from a simulation study are presented and the implementation of these methods to the prostate cancer clinical trial and the renal carcinoma tumour study are presented.

Effects of educational intervention on changing parental practices for recurrent febrile convulsions in Taiwan.

PURPOSE: To evaluate the effects of educational interventions on parental practices for recurrent febrile convulsions (FC). METHODS: A 2-year follow-up, nonequivalent comparison group design was used to evaluate the intervention effects. Two educational interventions were provided for FC parents in southern Taiwan. The 326 parents voluntarily chose either to receive a mailed pamphlet (n=196) or to attend a 2-h educational program (n=130). Five telephone interviews focused on investigating FC episodes and parental practices for seizures were conducted at months 3, 6, 12, 18, and 24 after the interventions. RESULTS: Of the 326 FC children, 78 (23.9%) had recurrent FCs within the 2-year follow-up. Parents who only received pamphlets did not show significant improvements. Parents who attended the educational program demonstrated significant improvements in the recommended practices, particularly in protecting the convulsing child (8.3 vs. 36.1%; p=0.02 by McNemar) and placing the child on his or her side (19.4 vs. 47.2%; p=0.01). Nonrecommended practices including rushing the convulsing child to the hospital (88.9 vs. 30.6%; p < 0.01) and putting protective devices in the child's mouth (38.9 vs. 8.3%; p < 0.01) significantly decreased. By generalized estimating equation analyses, the types of interventions are the single significant factor influencing parental practice changes from initial to recurrent FCs. CONCLUSIONS: Most parents used inappropriate practices for their child's initial FC. Compared with the mailed pamphlet, the educational program had significant improvements in recommended and nonrecommended practices from initial to recurrent FCs.