trial sequential analysis
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Statistics in practice
2nd rev.ed xii, 314 s.
- MeSH
- klinické zkoušky jako téma MeSH
- Publikační typ
- klinické zkoušky MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- diagnostika
1st ed. xviii, 390 s.
- MeSH
- klinické zkoušky jako téma MeSH
- Publikační typ
- klinické zkoušky MeSH
- Konspekt
- Veřejné zdraví a hygiena
- NLK Obory
- management, organizace a řízení zdravotnictví
A unique, unifying treatment for statistics and science in clinical trials What sets this volume apart from the many books dealing with clinical trials is its integration of statistical and clinical disciplines. Stressing communication between biostatisticians and clinical scientists, this work clearly relates statistical interpretation to clinical issues arising in different stages of pharmaceutical research and development. Plus, the principles presented here are universal enough to be easily adapted in non-biopharmaceutical settings. Design and Analysis of Clinical Trials tackles concepts and methodologies. It not only covers statistical basics such as uncertainty and bias, design considerations such as patient selection, randomization, and the different types of clinical trials but also deals with various methods of data analysis, group sequential procedures for interim analysis, efficacy data evaluation, analysis of safety data, and more. Throughout, the book: * Surveys current and emerging clinical issues and newly developed statistical methods * Presents a critical review of statistical methodologies in various therapeutic areas * Features case studies from actual clinical trials * Minimizes the mathematics involved, making the material widely accessible * Offers each chapter as a self-contained entity * Includes illustrations to highlight the text This monumental reference on all facets of clinical trials is important reading for physicians, clinical and medical researchers, pharmaceutical scientists, clinical programmers, biostatisticians, and anyone involved in this burgeoning area of clinical research. It can also be used as a textbook in graduate-level courses in the field.
- MeSH
- klinické zkoušky jako téma MeSH
- Publikační typ
- klinické zkoušky MeSH
Summary: High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is superior than conventional therapy in response rates as well as in prolongation of event-free survival (EFS) and overall survival (OS) in multiple myeloma (MM). Optimal maintenance therapy after ASCT is unclear. In order to assess the role of interferon alfa (IFN) and IFN plus dexamethasone (IFN/DEX) as the maintenance therapy after ASCT, 212 previously untreated patients with multiple myeloma (MM) were enrolled to trial 4W from 1996 to 2002. Patients received primary therapy with four cycles of VAD regimen (vincristine, doxorubicin, dexamethasone) followed by mobilization with cyclophosphamide 5g/m2 and G-CSF 10 μg/kg. A conditioning regimen with melphalan 200mg/m2 was used for first and second transplantation. The later was indicated only in patients who did not achieve a good remission (>75% reduction of M-component). After transplantation patients were randomized to two arms of maintenance therapy: IFN 3 x 106 units three times weekly s.c. or the same dose of IFN in alternating cycles with dexamethasone 40 mg in days 1-4, 10-13, 20-23. Data of 151 randomized patients to 31st August 2001 were evaluated in this analysis. One month after transplantation 6 % of patients achieved complete remission (M-component 0% and negative immunofixation), 58 % remission (<75 % reduction of starting level of M-component), 24 % partial remission (<50 % reduction of M-component). Transplant related mortality at day +100 was 2.35 %. All 151 randomized patients received the maintenance therapy, 77 patients in the IFN arm and 74 patients in the IFN/DEX arm. Median of EFS for all 151 patients was 36 months and median of OS was not yet achieved. In this interim analysis, the OS and EFS curves have shown no significant differences between the IFN and IFN/DEX groups (p = 0.593 for EFS; p = 0.316 for OS). Longer follow-up is required to receive final results comparing efficacy of the two types of maintenance therapy after autologous transplantation.
- MeSH
- analýza přežití MeSH
- autologní transplantace metody trendy využití MeSH
- dexamethason analogy a deriváty terapeutické užití MeSH
- indukce remise MeSH
- interferon alfa terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- klinický obraz nemoci MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie terapie MeSH
- progrese nemoci MeSH
- protokoly protinádorové kombinované chemoterapie normy terapeutické užití MeSH
- recidiva MeSH
- statistika jako téma MeSH
- transplantace periferních kmenových buněk metody trendy využití MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) MeSH
- Check Tag
- lidé MeSH
During production of γ-hexachlorocyclohexane (γ-HCH), thousands of tons of other isomers were synthesized as byproducts, and after dumping represent sources of contamination for the environment. Several microbes have the potential for aerobic and anaerobic degradation of HCHs, and zero-valent iron is an effective remediation agent for abiotic dechlorination of HCHs, whereas the combination of the processes has not yet been explored. In this study, a sequence of anoxic/oxic chemico-biological treatments for the degradation of HCHs in a real extremely contaminated soil (10-30 g/kg) was applied. Approximately 1500 kg of the soil was employed, and various combinations of reducing and oxygen-releasing chemicals were used for setting up the aerobic and anaerobic phases. The best results were obtained with mZVI/nZVI, grass cuttings, and oxygen-releasing compounds. In this case, 80 % removal of HCHs was achieved in 129 days, and 98 % degradation was achieved after 1106 days. The analysis of HCHs and their transformation products proved active degradation when slight accumulation of the transformation product during the anaerobic phase was followed by aerobic degradation. The results document that switching between aerobic and anaerobic phases, together with the addition of grass, also created suitable conditions for the biodegradation of HCHs and monochlorobenzene/benzene by microbes.
BACKGROUND: This systematic review and meta-analysis aimed to assess the prognostic value of sequential of abiraterone (ABI) and enzalutamide (ENZ) therapy in patients with castration-resistant prostate cancer (CRPC). METHODS: PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched for articles published prior to December 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared overall survival (OS), combined progression-free survival (PFS), combined prostate specific antigen (PSA)-PFS, and PSA response rates in CRPC patients receiving sequential ABI/ENZ or vice versa. PSA response to both the first and second agents was defined as a >50% decrease in PSA achieved with each of these agents. Formal meta-analyses were performed for these outcomes. RESULTS: Ten studies with 1096 patients were eligible for the systematic review and eight studies with 643 patients for the meta-analysis. The ABI-to-ENZ sequence was significantly associated with better PFS (pooled hazard ratio (HR): 0.62, 95% confidential interval (CI): 0.49-0.78, P < 0.001), and PSA-PFS (pooled HR: 0.48, 95% CI: 0.38-0.61, P < 0.001) than the ENZ-to-ABI sequence. PSA response rates of both agents were significantly better with the ABI-to-ENZ sequence (risk ratio: 0.21, 95% CI: 0.09-0.47, P < 0.001). In contrast, treatment sequence was not significantly associated with OS (pooled HR: 0.77, 95% CI: 0.59-1.01, P = 0.055). CONCLUSIONS: ABI-to-ENZ sequential therapy in patients with CRPC was associated with better PFS, PSA-PFS, and PSA response rates. Regardless of sequencing, response to drug therapy was transient for both ABI and ENZ when either agent was used as a secondary therapy. Despite this, treatment sequencing is important to achieve the maximum possible benefit from available drugs in CRPC.
- MeSH
- androsteny aplikace a dávkování MeSH
- antagonisté androgenů aplikace a dávkování MeSH
- benzamidy aplikace a dávkování MeSH
- fenylthiohydantoin aplikace a dávkování MeSH
- kalikreiny krev MeSH
- klinické zkoušky, fáze II jako téma MeSH
- lidé MeSH
- míra přežití MeSH
- nádory prostaty rezistentní na kastraci krev farmakoterapie patologie MeSH
- nitrily aplikace a dávkování MeSH
- progrese nemoci MeSH
- prostatický specifický antigen krev MeSH
- randomizované kontrolované studie jako téma MeSH
- rozvrh dávkování léků MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
Od roku 2013 jsou předkládány poznatky ze studií hledajících optimální léčbu nemocných s metastazujícím kolorektálním karcinomem (mCRC). Dosavadní výsledky léčby, přes vynaložené prostředky, nejsou uspokojivé a pětiletého přežití dosahuje jen 11,7 % pacientů. Stále více se ukazuje význam přítomnosti mutací RAS, která se v průběhu onemocnění mění. Hypoxie, jež přirozeně vzniká v rostoucím nádoru nebo vlivem antiangiogenní léčby, vyvolává negativní selekční tlak na buňky s mutací KRAS a vede ke vzniku nových mutovaných klonů v nádoru. Transformuje nemutovaný (divoký) typ RAS (wt RAS), který se aktivuje nezávisle na EGFR. Změněné mikroprostředí nádoru mění jeho chování. Anti-EGFR léčba metastazujícího kolorektálního karcinomu s wt RAS v 1. linii vytváří změny v nádoru, které po vzniku rezistence významně zvyšují účinnost antiangiogenní léčby ve 2. linii. Naopak antiangiogenní léčba mCRC s wt RAS v 1. linii vyvolává změny, které snižují úspěšnost anti-EGFR léčby ve 2. linii. Pochopení tohoto biologického chování nádoru usnadňuje správnou volbu sekvenční léčby mCRC s wt RAS. Preklinické poznatky jsou potvrzovány v klinických studiích. Přesto existují rozporné výsledky studií porovnávajících léčbu s cetuximabem/panitumumab a bevacizumabem v 1. linii léčby mCRC s wt RAS. Postupnou analýzou studií FIRE-3, PEAK a CALGB/SWOG 80405 se daří najít správnou sekvenční léčbu.
Since 2013 new insights continue to be published obtained in studies looking for optimum therapies of patients with metastatic colorectal cancer (mCRC). Treatment results observed so far, in spite of the resources spent, fall short of being satisfactory, with only 11.7% patients attaining five-year survival. The presence of RAS mutations is becoming increasingly important as it has been observed to change over the course of the disease. Hypoxia known to develop naturally in a growing tumour or as a result of antiangiogenic therapy leads to selection pressure for cells harbouring mutated KRAS and results in the development of new mutated clones in the tumour. Transformation occurs of the non-mutated (wild-type) RAS (wt RAS) that becomes active independently of EGFRrelated mutation. Changed microenvironment influences the behaviour of the tumour. Anti-EGFR first-line therapy of mCRC harbouring wt RAS results in changes in the tumour that, once resistance has developed, significantly increase the efficacy of second-line antiangiogenic treatment. Antiangiogenic therapy of wt RAS mCRC as first-line, on the contrary, produces changes that reduce the successes obtained with second-line anti-EGFR therapy. Understanding this biological behaviour of tumours facilitates correct selection of sequential therapy of wt RAS mCRC. Preclinical data are being confirmed in clinical studies. Even so, contradictory results are obtained in clinical studies comparing therapy with cetuximab/panitumumab with that using bevacizumab as first-line therapies of wt RAS mCRC. Applying gradual analysis to FIRE3, PEAK and CALGB/SWOG 80405 trials it is possible to succeed in finding correct sequential treatment.
- MeSH
- biologické markery MeSH
- erbB receptory * antagonisté a inhibitory farmakokinetika terapeutické užití MeSH
- geny ras MeSH
- hypoxie MeSH
- kolorektální nádory * farmakoterapie genetika MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- metastázy nádorů farmakoterapie genetika MeSH
- mutace genetika MeSH
- nádorové cirkulující buňky účinky léků MeSH
- protoonkogeny MeSH
- randomizované kontrolované studie jako téma MeSH
- ras proteiny fyziologie MeSH
- vaskulární endoteliální růstové faktory * antagonisté a inhibitory farmakokinetika terapeutické užití MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The simple scoring systems for predicting the outcome of sepsis in intensive care units (ICUs) are few, especially for limited-resource settings. Therefore, this study aimed to evaluate the accuracy of the quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score in predicting the mortality of ICU patients with sepsis in Vietnam. METHODS: We did a multicenter cross-sectional study of patients with sepsis (≥18 years old) presenting to 15 adult ICUs throughout Vietnam on the specified days (i.e., 9th January, 3rd April, 3rd July, and 9th October) representing the different seasons of 2019. The primary and secondary outcomes were the hospital and ICU all-cause mortalities, respectively. The area under the receiver operating characteristic curve (AUROC) was calculated to determine the discriminatory ability of the qSOFA score for deaths in the hospital and ICU. The cut-off value of the qSOFA scores was determined by the receiver operating characteristic curve analysis. Upon ICU admission, factors associated with the hospital and ICU mortalities were assessed in univariable and multivariable logistic models. RESULTS: Of 252 patients, 40.1% died in the hospital, and 33.3% died in the ICU. The qSOFA score had a poor discriminatory ability for both the hospital (AUROC: 0.610 [95% CI: 0.538 to 0.681]; cut-off value: ≥2.5; sensitivity: 34.7%; specificity: 84.1%; PAUROC = 0.003) and ICU (AUROC: 0.619 [95% CI: 0.544 to 0.694]; cutoff value: ≥2.5; sensitivity: 36.9%; specificity: 83.3%; PAUROC = 0.002) mortalities. However, multivariable logistic regression analyses show that the qSOFA score of 3 was independently associated with the increased risk of deaths in both the hospital (adjusted odds ratio, AOR: 3.358; 95% confidence interval, CI: 1.756 to 6.422) and the ICU (AOR: 3.060; 95% CI: 1.651 to 5.671). CONCLUSION: In our study, despite having a poor discriminatory value, the qSOFA score seems worthwhile in predicting mortality in ICU patients with sepsis in limited-resource settings. CLINICAL TRIAL REGISTRATION: Clinical trials registry-India: CTRI/2019/01/016898.
- MeSH
- Asijci MeSH
- dospělí MeSH
- jednotky intenzivní péče MeSH
- lidé MeSH
- mladiství MeSH
- mortalita v nemocnicích MeSH
- prognóza MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- ROC křivka MeSH
- sepse * diagnóza MeSH
- vyhodnocení orgánové dysfunkce * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Vietnam MeSH
OBJECTIVES: To compare the accuracy of the Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) Scores in predicting mortality among intensive care unit (ICU) patients with sepsis in a low-income and middle-income country. DESIGN: A multicentre, cross-sectional study. SETTING: A total of 15 adult ICUs throughout Vietnam. PARTICIPANTS: We included all patients aged ≥18 years who were admitted to ICUs for sepsis and who were still in ICUs from 00:00 to 23:59 of the specified study days (ie, 9 January, 3 April, 3 July and 9 October of the year 2019). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was hospital all-cause mortality (hospital mortality). We also defined the secondary outcome as all-cause deaths in the ICU (ICU mortality). RESULTS: Of 252 patients, 40.1% died in hospitals, and 33.3% died in ICUs. SOFA Score (areas under the receiver operating characteristic curve (AUROC): 0.688 (95% CI 0.618 to 0.758); cut-off value≥7.5; PAUROC<0.001) and APACHE II Score (AUROC: 0.689 (95% CI 0.622 to 0.756); cut-off value ≥20.5; PAUROC<0.001) both had a poor discriminatory ability for predicting hospital mortality. However, the discriminatory ability for predicting ICU mortality of SOFA (AUROC: 0.713 (95% CI 0.643 to 0.783); cut-off value≥9.5; PAUROC<0.001) was fair and was better than that of APACHE II Score (AUROC: 0.672 (95% CI 0.603 to 0.742); cut-off value≥18.5; PAUROC<0.001). A SOFA Score≥8 (adjusted OR (AOR): 2.717; 95% CI 1.371 to 5.382) and an APACHE II Score≥21 (AOR: 2.668; 95% CI 1.338 to 5.321) were independently associated with an increased risk of hospital mortality. Additionally, a SOFA Score≥10 (AOR: 2.194; 95% CI 1.017 to 4.735) was an independent predictor of ICU mortality, in contrast to an APACHE II Score≥19, for which this role did not. CONCLUSIONS: In this study, SOFA and APACHE II Scores were worthwhile in predicting mortality among ICU patients with sepsis. However, due to better discrimination for predicting ICU mortality, the SOFA Score was preferable to the APACHE II Score in predicting mortality.Clinical trials registry - India: CTRI/2019/01/016898.
- MeSH
- dospělí MeSH
- jednotky intenzivní péče MeSH
- lidé MeSH
- obyvatelé jihovýchodní Asie MeSH
- prognóza MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- ROC křivka MeSH
- sepse * MeSH
- vyhodnocení orgánové dysfunkce * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Geografické názvy
- Vietnam MeSH
BACKGROUND: We provide an overview of Bayesian estimation, hypothesis testing, and model-averaging and illustrate how they benefit parametric survival analysis. We contrast the Bayesian framework to the currently dominant frequentist approach and highlight advantages, such as seamless incorporation of historical data, continuous monitoring of evidence, and incorporating uncertainty about the true data generating process. METHODS: We illustrate the application of the outlined Bayesian approaches on an example data set, retrospective re-analyzing a colon cancer trial. We assess the performance of Bayesian parametric survival analysis and maximum likelihood survival models with AIC/BIC model selection in fixed-n and sequential designs with a simulation study. RESULTS: In the retrospective re-analysis of the example data set, the Bayesian framework provided evidence for the absence of a positive treatment effect of adding Cetuximab to FOLFOX6 regimen on disease-free survival in patients with resected stage III colon cancer. Furthermore, the Bayesian sequential analysis would have terminated the trial 10.3 months earlier than the standard frequentist analysis. In a simulation study with sequential designs, the Bayesian framework on average reached a decision in almost half the time required by the frequentist counterparts, while maintaining the same power, and an appropriate false-positive rate. Under model misspecification, the Bayesian framework resulted in higher false-negative rate compared to the frequentist counterparts, which resulted in a higher proportion of undecided trials. In fixed-n designs, the Bayesian framework showed slightly higher power, slightly elevated error rates, and lower bias and RMSE when estimating treatment effects in small samples. We found no noticeable differences for survival predictions. We have made the analytic approach readily available to other researchers in the RoBSA R package. CONCLUSIONS: The outlined Bayesian framework provides several benefits when applied to parametric survival analyses. It uses data more efficiently, is capable of considerably shortening the length of clinical trials, and provides a richer set of inferences.
