Mei-Chiung Shih

Effect of Home Testing of International Normalized Ratio on Clinical Events

BACKGROUND Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes. METHODS We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death). RESULTS The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001). CONCLUSIONS As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

Sequential Generalized Likelihood Ratio Tests for Vaccine Safety Evaluation

The evaluation of vaccine safety involves pre-clinical animal studies, pre-licensure randomized clinical trials, and post-licensure safety studies. Sequential design and analysis are of particular interest because they allow early termination of the trial or quick detection that the vaccine exceeds a prescribed bound on the adverse event rate. After a review of the recent developments in this area, we propose a new class of sequential generalized likelihood ratio tests for evaluating adverse event rates in two-armed pre-licensure clinical trials and single-armed post-licensure studies. The proposed approach is illustrated using data from the Rotavirus Efficacy and Safety Trial. Simulation studies of the performance of the proposed approach and other methods are also given.

Sequential Experimentation in Clinical Trials

Features 7 Interdisciplinary approach that Statistics researchers and advanced students will use, in addition to Statisticians working in medical fields 7 Includes recent work that provides a new class of adaptive designs which are both flexible and efficient a new development for adaptive design literature 7 Uses a unique approach to: early phase I and II trials, both information and time-sequential phase III trials, the analysis following a clinical trial, the interactions between each of the stages

Sequential design of phase II-III cancer trials.

Although traditional phase II cancer trials are usually single arm, with tumor response as endpoint, and phase III trials are randomized and incorporate interim analyses with progression-free survival or other failure time as endpoint, this paper proposes a new approach that seamlessly expands a randomized phase II study of response rate into a randomized phase III study of time to failure. This approach is based on advances in group sequential designs and joint modeling of the response rate and time to event. The joint modeling is reflected in the primary and secondary objectives of the trial, and the sequential design allows the trial to adapt to increase in information on response and survival patterns during the course of the trial and to stop early either for conclusive evidence on efficacy of the experimental treatment or for the futility in continuing the trial to demonstrate it, on the basis of the data collected so far.

Effect of the MTHFR C677T and A1298C Polymorphisms on Survival in Patients With Advanced CKD and ESRD: A Prospective Study

BACKGROUND Abnormalities in the gene regulating methylenetetrahydrofolate reductase (MTHFR) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease (CKD) populations. STUDY DESIGN Gene association study. SETTING & PARTICIPANTS This was a substudy of 677 patients from 21 Veterans Affairs medical centers participating in a randomized clinical trial (Homocysteinemia in Kidney and End-Stage Renal Disease [HOST]) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels. Of 677 patients, 213 (31%) were treated by using dialysis (end-stage renal disease [ESRD]) and 464 (69%) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min (advanced CKD). PREDICTOR Polymorphisms C677T (rs1801133) and A1298C (rs1801131) of the MTHFR gene. OUTCOMES Unadjusted and adjusted all-cause mortality. MEASUREMENTS DNA was extracted from blood samples and amplified by means of polymerase chain reaction. RESULTS The adjusted hazard ratio in a recessive model of the relationship between the C677T polymorphism and all-cause mortality in all patients was 1.47 (95% confidence interval, 1.00 to 2.16; P = 0.05). In patients with ESRD with the mutant TT genotype, the adjusted hazard ratio for mortality in all patients was 2.27 (95% confidence interval, 1.07 to 4.84; P = 0.03); patients with advanced CKD showed a similar, although not significant, trend. The risk of myocardial infarction (P = 0.05) and composite risk of myocardial infarction, stroke, lower-extremity amputation, and mortality (P = 0.02) were greater in patients with ESRD with the mutant T allele at nucleotide 677. The overall relationship between the A1298C polymorphism and mortality was not significant (P = 0.6). LIMITATIONS Participants were 98% men; DNA samples were not obtained at enrollment in HOST; linkage disequilibrium with another causal polymorphism is a potential confounding factor; and power was reduced by the limited number of participants. CONCLUSIONS These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD.

Adaptive Trial Designs

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.

Sequential Methods for Vaccine Safety Evaluation and Surveillance in Public Health

In this chapter we describe the applications of sequential testing methodology to the problem of testing the incidence rates of adverse events in vaccine clinical trials and post-marketing safety evaluation. Section 5.1 describes typical design considerations for vaccine safety evaluation and the application of the SPRT and its other sequential tests that have been applied to test vaccine safety.

Sequential Testing Theory and Stochastic Optimization Over Time

The first seven sections of this chapter give an overview of the theory of fully sequential tests, starting with simple hypotheses involving likelihood ratio statistics and then extending the theory to composite hypotheses via generalized likelihood ratio (GLR) statistics. This theory is of particular relevance to Sect. 5.2 on vaccine clinical trials. The theory is modified in Sect. 3.5 for group sequential designs and later for adaptive designs in Sect. 8.2.3. The classic result of Wald and Wolfowitz on the optimality of the sequential probability ratio test is derived in Sect. 3.6 by using dynamic programming that is also introduced in that section for general stochastic optimization over time. Dynamic programming is often difficult to implement directly for nonlinear models and approximate dynamic programming (ADP) methods have been developed to overcome the computational and analytical difficulties.

Nonlinear Regression, Experimental Design, and Phase I Clinical Trials

In typical Phase I studies in the development of relatively benign drugs, the drug is initiated at low doses and subsequently escalated to show safety at a level where some positive response occurs, and healthy volunteers are often used as study subjects. In Sect. 2.2 we describe some basic pharmacologic principles and models underlying dose determination.

Group Sequential Design of Phase II and III Trials

In standard (nonsequential) designs of Phase II or III clinical trials, the sample size is determined by the power at a given alternative. In practice, especially for new treatments about which there is little information concerning the magnitude of the treatment effect before actual data are collected, it is often difficult for investigators to specify a realistic alternative at which sample size determination can be based. On the other hand, economic considerations related to funding and duration for the trial and administrative considerations related to other trials that compete for patients and investigators impose constraints on the sample size.