Estimation on conditional restricted mean survival time with counting process.

In a comparative longitudinal clinical study, multiple clinical events of interest are typically collected in timing and occurrence during the follow-up period. These clinical events are often indicative of disease burden over the study period and provide overall evidence of benefit/risk of one treatment relative to another. While these clinical events are usually used to form a composite endpoint, only the first occurrence of the composite endpoint event is considered in primary efficacy analysis. This type of analysis is commonly performed but it may not be ideal. Most of the existing methods for analyzing multiple event-time data were developed, relying on certain model assumptions. However, the assumptions may greatly affect the inferences for treatment effect. In this paper, we propose a simple, non-parametric estimator of conditional mean survival time for multiple events to quantify treatment effect which has clinically meaningful interpretation. We use simulation studies to evaluate the performance of the new method. Further, we apply this method to analyze the data from a cardiovascular clinical trial as an illustration.

Design and monitoring of survival trials in complex scenarios.

This paper proposes an approach to design and monitor survival trials accounting for complex scenarios such as delayed treatment effect, treatment dilution, and treatment crossover. These scenarios often lead to non-proportional hazards, making study design and monitoring more difficult. We demonstrate that, with event times following piecewise exponential distributions, the log-rank statistic as well as its variance-covariance structure can be easily computed, which greatly simplifies study design and monitoring. As the number of pieces in the exponential distributions can be arbitrary, this approach can handle a wide range of scenarios. Three hypothetical examples are used to demonstrate its potential use.

Estimation on conditional restricted mean survival time with counting process.

In traditional survival analyses, hazard ratio (HR) is commonly used to evaluate treatment effects. However, HR may not be easy to interpret. Restricted mean survival time is a viable alternative to HR, particularly when the proportional hazards assumption is not satisfied. We developed a conditional restricted mean survival time (CRMST) estimator for a time interval of interest using counting process. The variance of CRMST was estimated using a perturbation re-sampling method for asymptotic normality. The utility of our CRMST seems promising based on comprehensive simulation studies and a real data case study.

Weighted win loss approach for analyzing prioritized outcomes.

To analyze prioritized outcomes, Buyse (2010) and Pocock et al. (2012) proposed the win loss approach. In this paper, we first study the relationship between the win loss approach and the traditional survival analysis on the time to the first event. We then propose the weighted win loss statistics to improve the efficiency of the unweighted methods. A closed-form variance estimator of the weighted win loss statistics is derived to facilitate hypothesis testing and study design. We also calculated the contribution index to better interpret the results of the weighted win loss approach. Simulation studies and real data analysis demonstrated the characteristics of the proposed statistics. Copyright © 2017 John Wiley & Sons, Ltd.

Statistical power considerations in the use of win ratio in cardiovascular outcome trials.

BACKGROUND: In cardiovascular outcome trials, the win ratio (WR) method models the composite endpoint under a hierarchical structure to account for clinical priorities. It also can be applied to both survival and nonsurvival outcomes. METHODS: In this article, we assess the performance of the WR method via extensive simulation studies and real data analyses and discuss power considerations of the method with respect to hierarchical order, variable type, magnitude of treatment effect, and event rates when applied to clinical studies. RESULTS AND CONCLUSION: In the hierarchy of the WR method, the first-ordered component (e.g., death) plays a dominant role in statistical power, especially when that component has a large treatment effect and a high event rate. This is in contrast with the score test of the Cox proportional hazards model in which the power is more likely affected by the nonfatal events that are usually observed earlier. Furthermore, when adding an additional component to the composite endpoint, the performance of the WR method varies depending on the treatment effect, event rate, and hierarchical position of the component. If the additional component has a relatively smaller or no treatment effect, the statistical power will decrease; if the additional component has a relatively larger treatment effect and higher event rate, the statistical power will increase. When adding a nonsurvival continuous outcome (e.g., 6-min walk distance) with even a tiny treatment effect, the statistical power could dramatically increase.

Structure-activity relationship and pharmacokinetic profile of 5-ketopyrazole factor Xa inhibitors.

Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.

Design, structure-activity relationship, and pharmacokinetic profile of pyrazole-based indoline factor Xa inhibitors.

A new series of pyrazole-based factor Xa inhibitors have been identified as part of our ongoing efforts to optimize previously reported clinical candidate razaxaban. Concern over the possible formation of primary aniline metabolites via amide hydrolysis led to the replacement of the primary amide linker between the pyrazole and phenyl moieties with secondary amides. This was accomplished by replacing the aniline with a variety of heterobicycles, of which indolines were the most potent. The indoline series demonstrated subnanomolar factor Xa binding K(i)s, modest to high selectivity versus other serine proteases, and good in vitro clotting activity. A small number of indoline fXa inhibitors were profiled in a dog pharmacokinetic model, one of which demonstrated pharmacokinetic parameters similar to that of clinical candidate razaxaban.

Discovery of 1-(2-aminomethylphenyl)-3-trifluoromethyl-N- [3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-4-yl]-1H-pyrazole-5-carboxyamide (DPC602), a potent, selective, and orally bioavailable factor Xa inhibitor(1).

Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.

Synthesis and structure-activity relationships of 8-(pyrid-3-yl)pyrazolo[1,5-a]-1,3,5-triazines: potent, orally bioavailable corticotropin releasing factor receptor-1 (CRF1) antagonists.

This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.

1-[3-Aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.

Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5'-yl]-3-trifluoromethyl-6-[2'-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1']-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki=30 pM) with a rapid onset of inhibition (2.7x10(7) M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.