ABSTRACT
BACKGROUND: Clinical trials often involve some form of interim monitoring to determine futility before planned trial completion. While many options for interim monitoring exist (e.g., alpha-spending, conditional power), nonparametric based interim monitoring methods are also needed to account for more complex trial designs and analyses. The upstrap is one recently proposed nonparametric method that may be applied for interim monitoring. METHODS: Upstrapping is motivated by the case resampling bootstrap and involves repeatedly sampling with replacement from the interim data to simulate thousands of fully enrolled trials. The p-value is calculated for each upstrapped trial and the proportion of upstrapped trials for which the p-value criteria are met is compared with a pre-specified decision threshold. To evaluate the potential utility for upstrapping as a form of interim futility monitoring, we conducted a simulation study considering different sample sizes with several different proposed calibration strategies for the upstrap. We first compared trial rejection rates across a selection of threshold combinations to validate the upstrapping method. Then, we applied upstrapping methods to simulated clinical trial data, directly comparing their performance with more traditional alpha-spending and conditional power interim monitoring methods for futility. RESULTS: The method validation demonstrated that upstrapping is much more likely to find evidence of futility in the null scenario than the alternative across a variety of simulations settings. Our three proposed approaches for calibration of the upstrap had different strengths depending on the stopping rules used. Compared to O'Brien-Fleming group sequential methods, upstrapped approaches had type I error rates that differed by at most 1.7% and expected sample size was 2-22% lower in the null scenario, while in the alternative scenario power fluctuated between 15.7% lower and 0.2% higher and expected sample size was 0-15% lower. CONCLUSIONS: In this proof-of-concept simulation study, we evaluated the potential for upstrapping as a resampling-based method for futility monitoring in clinical trials. The trade-offs in expected sample size, power, and type I error rate control indicate that the upstrap can be calibrated to implement futility monitoring with varying degrees of aggressiveness and that performance similarities can be identified relative to considered alpha-spending and conditional power futility monitoring methods.
Subject(s)
Clinical Trials as Topic , Computer Simulation , Medical Futility , Research Design , Humans , Clinical Trials as Topic/methods , Sample Size , Data Interpretation, Statistical , Models, Statistical , Treatment OutcomeABSTRACT
OBJECTIVE: To compare the antinociceptive, sedative and cardiovascular effects of dexmedetomidine pharmacopuncture at Governing Vessel 1 (GV 1) with dexmedetomidine intramuscular (IM) administration. STUDY DESIGN: Randomized, masked crossover design. ANIMALS: A group of eight healthy female cats. METHODS: Cats were randomly administered either dexmedetomidine (0.005 mg kg-1; Dex-IM) IM or at acupuncture point GV 1 (Dex-P) separated by 1 week. Prior to and up to 120 minutes posttreatment, skin temperature (ST), thermal threshold (TT), heart rate (HR), respiratory rate (fR), sedation, muscle relaxation and auditory response scores were recorded. Parametric data were analyzed using a two-way repeated measures anova followed by Tukey's test for multiple comparisons. Nonparametric data were analyzed using a Friedman test followed by Dunn's multiple comparisons test, and Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons. Significance was set at p ≤ 0.05. RESULTS: There were no differences within or between treatments for ST, fR and auditory response. TT was significantly higher at 30-90 minutes in Dex-P (p ≤ 0.0285) than baseline. TT was significantly higher at 60-90 minutes for Dex-P than for Dex-IM (p ≤ 0.0252). HR was significantly lower at 10-75 minutes in Dex-P (p ≤ 0.0378) and at 5-75 minutes in Dex-IM (p ≤ 0.0132) than baseline. Compared with baseline, sedation scores were higher at 25 minutes (p = 0.0327) and 30 minutes (p = 0.0327), and muscle relaxation scores were higher at 25 minutes (p = 0.0151) and 35 minutes (p = 0.0151) in Dex-P. There were no differences in HR, sedation and muscle relaxation scores between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Dex-P increased thermal antinociception compared with Dex-IM at the same dose of dexmedetomidine in cats. This antinociceptive effect must be evaluated under clinical situations.
