Keeping phase III tuberculosis trials relevant: Adapting to a rapidly changing landscape.
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ABSTRACT:
SUBMITTER: Phillips PPJ
PROVIDER: S-EPMC6430373 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Well-designed clinical trials are of great importance in validating novel treatments and ensuring an evidence-based approach for sarcoma. This study aimed to provide a comprehensive landscape of the characteristics of metastatic or advanced sarcoma clinical trials using the substantial resource of the ClincialTrials.gov database. METHODS:We identified 260,755 trials registered with ClinicalTrials.gov in the last 20?years, and 277 of them were eligible for inclusion. The baseline characteristics were ascertained for each trial. The trials were systematically reviewed to validate their classification into 96 trials registered before 2008 and 181 trials registered between 2008 and 2017. RESULTS:We found that in the last decade, metastatic and advanced sarcoma trials were predominantly phase II-III studies (p?=?0.048), were more likely to be ?2 arms (17.7% vs 35.3%, respectively; p?=?0.007), and were more likely to use randomized (13.5% vs 30.4%; p?=?0.002) and double-blinded (2.1% vs 9.4%; p?=?0.024) assignment than trials registered before 2008. Furthermore, in the last 10-year period, metastatic sarcoma trials were more likely to be conducted in Asia. Treatment involving target therapy and immunotherapy were more common (71.8% vs 37.5%; p?<?0.001) than in previous years. CONCLUSIONS:Our data showed provocative changes in the sarcoma landscape and demonstrated that the incidence of clinical trials with target therapy and immunotherapy is increasing. These findings emphasize the desperate need for novel strategies, including target therapy and immunotherapy, to improve the outcomes for patients with advanced sarcoma.
| S-EPMC6293634 | biostudies-literature
Project description: Not available
| S-EPMC6881185 | biostudies-literature
Project description:Despite significant progress, metastatic urothelial cancer remains an incurable condition with a limited life expectancy. Platinum-based chemotherapy is still the mainstay of treatment for metastatic disease, but immunotherapy, antibody drug conjugates, and targeted agents have shown encouraging results in several recent practice changing trials. In this review, we discuss the standard of care, recent therapeutic advances, ongoing clinical trials, and future perspectives in metastatic urothelial carcinoma.
| S-EPMC8488509 | biostudies-literature
Project description:BackgroundClinical trials, conducted efficiently and with the utmost integrity, are a key component in identifying effective vaccines, therapies, and other interventions urgently needed to solve the COVID-19 crisis. Yet launching and implementing trials with the rigor necessary to produce convincing results is a complicated and time-consuming process. Balancing rigor and efficiency involves relying on designs that employ flexible features to respond to a fast-changing landscape, measuring valid endpoints that result in translational actions and disseminating findings in a timely manner. We describe the challenges involved in creating infrastructure with potential utility for shared learning.MethodsWe have established a shared infrastructure that borrows strength across multiple trials. The infrastructure includes an endpoint registry to aid in selecting appropriate endpoints, a registry to facilitate establishing a Data & Safety Monitoring Board, common data collection instruments, a COVID-19 dedicated design and analysis team, and a pragmatic platform protocol, among other elements.ResultsThe authors have relied on the shared infrastructure for six clinical trials for which they serve as the Data Coordinating Center and have a design and analysis team comprising 15 members who are dedicated to COVID-19. The authors established a pragmatic platform to simultaneously investigate multiple treatments for the outpatient with adaptive features to add or drop treatment arms.ConclusionThe shared infrastructure provides appealing opportunities to evaluate disease in a more robust manner with fewer resources and is especially valued during a pandemic where efficiency in time and resources is crucial. The most important element of the shared infrastructure is the pragmatic platform. While it may be the most challenging of the elements to establish, it may provide the greatest benefit to both patients and researchers.
| S-EPMC8172421 | biostudies-literature
Project description:Quantitative evidence for the risk of zoonoses and the spread of antimicrobial resistance remains lacking. Here, as part of the UrbanZoo project, we sampled Escherichia coli from humans, livestock and peri-domestic wildlife in 99 households across Nairobi, Kenya, to investigate its distribution among host species in this rapidly developing urban landscape. We performed whole-genome sequencing of 1,338 E. coli isolates and found that the diversity and sharing patterns of E. coli were heavily structured by household and strongly shaped by host type. We also found evidence for inter-household and inter-host sharing and, importantly, between humans and animals, although this occurs much less frequently. Resistome similarity was differently distributed across host and household, consistent with being driven by shared exposure to antimicrobials. Our results indicate that a large, epidemiologically structured sampling framework combined with WGS is needed to uncover strain-sharing events among different host populations in complex environments and the major contributing pathways that could ultimately drive the emergence of zoonoses and the spread of antimicrobial resistance.
| S-EPMC8975746 | biostudies-literature
Project description: Not available
| S-EPMC10952960 | biostudies-literature
Project description:BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
| S-EPMC9390817 | biostudies-literature
Project description:The genetic diversity of a species is shaped by its recent evolutionary history and can be used to infer demographic events or selective sweeps. Most inference methods are based on the null hypothesis that natural selection is a weak or infrequent evolutionary force. However, many species, particularly pathogens, are under continuous pressure to adapt in response to changing environments. A statistical framework for inference from diversity data of such populations is currently lacking. Towards this goal, we explore the properties of genealogies in a model of continual adaptation in asexual populations. We show that lineages trace back to a small pool of highly fit ancestors, in which almost simultaneous coalescence of more than two lineages frequently occurs. Whereas such multiple mergers are unlikely under the neutral coalescent, they create a unique genetic footprint in adapting populations. The site frequency spectrum of derived neutral alleles, for example, is nonmonotonic and has a peak at high frequencies, whereas Tajima's D becomes more and more negative with increasing sample size. Because multiple merger coalescents emerge in many models of rapid adaptation, we argue that they should be considered as a null model for adapting populations.
| S-EPMC3545819 | biostudies-literature
Project description:Purpose of reviewInnovative clinical trial designs for glioblastoma (GBM) are needed to expedite drug discovery. Phase 0, window of opportunity, and adaptive designs have been proposed, but their advanced methodologies and underlying biostatistics are not widely known. This review summarizes phase 0, window of opportunity, and adaptive phase I-III clinical trial designs in GBM tailored to physicians.Recent findingsPhase 0, window of opportunity, and adaptive trials are now being implemented for GBM. These trials can remove ineffective therapies earlier during drug development and improve trial efficiency. There are two ongoing adaptive platform trials: GBM Adaptive Global Innovative Learning Environment (GBM AGILE) and the INdividualized Screening trial of Innovative GBM Therapy (INSIGhT). The future clinical trials landscape in GBM will increasingly involve phase 0, window of opportunity, and adaptive phase I-III studies. Continued collaboration between physicians and biostatisticians will be critical for implementing these trial designs.
| S-EPMC10474988 | biostudies-literature
Project description:Movement plays a key role in allowing animal species to adapt to sudden environmental shifts. Anthropogenic climate and land use change have accelerated the frequency of some of these extreme disturbances, including megafire. These megafires dramatically alter ecosystems and challenge the capacity of several species to adjust to a rapidly changing landscape. Ungulates and their movement behaviors play a central role in the ecosystem functions of fire-prone ecosystems around the world. Previous work has shown behavioral plasticity is an important mechanism underlying whether large ungulates are able to adjust to recent changes in their environments effectively. Ungulates may respond to the immediate effects of megafire by adjusting their movement and behavior, but how these responses persist or change over time following disturbance is poorly understood. We examined how an ecologically dominant ungulate with strong site fidelity, Columbian black-tailed deer (Odocoileus hemionus columbianus), adjusted its movement and behavior in response to an altered landscape following a megafire. To do so, we collected GPS data from 21 individual female deer over the course of a year to compare changes in home range size over time and used resource selection functions (RSFs) and hidden Markov movement models (HMMs) to assess changes in behavior and habitat selection. We found compelling evidence of adaptive capacity across individual deer in response to megafire. Deer avoided exposed and severely burned areas that lack forage and could be riskier for predation immediately following megafire, but they later altered these behaviors to select areas that burned at higher severities, potentially to take advantage of enhanced forage. These results suggest that despite their high site fidelity, deer can navigate altered landscapes to track rapid shifts in encounter risk with predators and resource availability. This successful adjustment of movement and behavior following extreme disturbance could help facilitate resilience at broader ecological scales.
| S-EPMC11293098 | biostudies-literature