scholarly journals Adaptive treatment allocation and selection in multi-arm clinical trials: a Bayesian perspective

2021 ◽  
Author(s):  
Elja Arjas ◽  
Dario Gasbarra
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Adaptive Designs ◽  
Critical Threshold ◽  
Attractive Alternative ◽  
Posterior Probabilities ◽  
Statistical Significance Testing ◽  
Treatment Allocation ◽  
Frequentist Paradigm

Abstract Background: Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power. Results: The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during Phase II and III. This approach is based on comparing the performance of the different treatment arm in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm (Rule 1), and treatment selection, removing an arm from the trial permanently (Rule 2). The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package. Conclusion: The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.

scholarly journals Systematic Review and Meta-Analysis of Linezolid and Daptomycin for Treatment of Vancomycin-Resistant Enterococcal Bloodstream Infections

2013 ◽  
Vol 57 (10) ◽  
pp. 5013-5018 ◽  
Author(s):  
Donald W. Whang ◽  
Loren G. Miller ◽  
Neil M. Partain ◽  
James A. McKinnell
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Fixed Effects ◽  
Randomized Clinical Trials ◽  
Small Sample Size ◽  
Statistical Significance ◽  
Bloodstream Infections ◽  
Small Sample ◽  
Antibiotic Selection ◽  
Vancomycin Resistant

ABSTRACTBloodstream infections due to vancomycin-resistant enterococci (VRE-BSI) result in substantial patient mortality and cost. Daptomycin and linezolid are commonly prescribed for VRE-BSI, but there are no clinical trials to determine optimal antibiotic selection. We conducted a systematic review for investigations that compared daptomycin and linezolid for VRE-BSI. We searched Medline from 1966 through 2012 for comparisons of linezolid and daptomycin for VRE-BSI. We included searches of EMBASE, clinicaltrials.gov, and national meetings. Data were extracted using a standardized instrument. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using a fixed-effects model. Our search yielded 4,243 publications, of which 482 contained data on VRE treatment. Most studies (452/482) did not present data on BSI or did not provide information on linezolid or daptomycin. Among the remaining 30 studies, 9 offered comparative data between the two agents. None were randomized clinical trials. There was no difference in microbiologic (n= 5 studies, 517 patients; OR, 1.0; 95% CI, 0.4 to 1.7;P= 0.95) and clinical (n= 3 studies, 357 patients; OR, 1.2; 95% CI, 0.7 to 2.0;P= 0.7) cures between the two antibiotics. There was a trend toward increased survival with linezolid compared to daptomycin treatment (n= 9 studies, 1,074 patients; OR, 1.3; 95% CI, 1.1 to 1.8;I2= 0 [whereI2is a measure of inconsistency]), but this did not reach statistical significance (P= 0.054). There are limited data to inform clinicians on optimal antibiotic selection for VRE-BSI. Available studies are limited by small sample size, lack of patient-level data, and inconsistent outcome definitions. Additional research, including randomized clinical trials, is needed before conclusions can be drawn about treatment options for VRE therapy.

scholarly journals Fidaxomicin versus Vancomycin in the Treatment ofClostridium difficileInfection: Canadian Outcomes

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Christine Lee ◽  
Thomas J. Louie ◽  
Karl Weiss ◽  
Louis Valiquette ◽  
Marvin Gerson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clostridium Difficile ◽  
Clinical Response ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Response Rates ◽  
Antibiotic Use ◽  
Recurrence Rates ◽  
Increased Risk ◽  
Subgroup Analyses

Background. This analysis examined the efficacy of fidaxomicin versus vancomycin in 406 Canadian patients withClostridium difficileinfection (CDI), based on data from 2 randomized, clinical trials.Methods. Patients received fidaxomicin or vancomycin 1. Patients were assessed for clinical response recurrence of infection and sustained clinical response for 28 days after treatment completion. Patients at increased risk of recurrence were subjected to subgroup analyses.Results. Clinical response rates for fidaxomicin (90.0%) were noninferior to those with vancomycin (92.2%; 95% confidence interval for difference: −7.7, 3.5). However, fidaxomicin-treated patients had lower recurrence (14.4% versus 28.0%,p=0.001) and higher sustained clinical response (77.1% versus 66.3%,p=0.016). Compared with vancomycin, fidaxomicin was associated with lower recurrence rates in all subgroups, reaching statistical significance in patients with age ≥ 65 years (16.0% versus 30.9%,p=0.026), concomitant antibiotic use (16.2% versus 38.7%,p=0.036), and non-BI strains (11.8% versus 28.3%,p=0.004). Higher sustained clinical response rates were observed for fidaxomicin compared with vancomycin in all subgroups; this was statistically significant in the non-BI subgroup (82.8% versus 69.1%,p=0.021).Conclusions. In Canadian patients, fidaxomicin was superior to vancomycin in sustaining clinical response and reducing CDI recurrence.

Abiraterone acetate (AA) or docetaxel (D) in metastatic castration-sensitive prostate cancer (mCSPC): A systematic review and network meta-analysis of randomized clinical trials (RCTs).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 243-243
Author(s):  
Irbaz Bin Riaz ◽  
Abdulaali Almutairi ◽  
Zeeshan Ali ◽  
Abdullah Alhifany ◽  
Sandipan Bhattacharjee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Random Effect ◽  
Indirect Comparison ◽  
Cochrane Library ◽  
Cochrane Central Register

243 Background: AA and D have been shown in separate trials to increase overall survival in patients with mCSPC compared to Androgen Derivation Therapy (ADT). In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison of AA and D using network meta-analysis. Methods: We performed a search of MEDLINE, EMBASE, Cochrane Library, and Cochrane Central Register of Controlled Trials to identify relevant clinical trials. Collected data included hazard ratio and confidence interval (CI) for Overall Survival (OS) and number of adverse events in each study arm. Risk for bias was assessed using the Cochrane Collaboration’s tool. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparison of D and AA. Results: Five clinical trials were included in this analysis. Two trials (LATITUDE, STAMPEDE) compared AA to ADT and three trials (CHAARTED,STAMPEDE, GETUG-AFU 15 study) compared D to ADT. Results from both fixed effect and random effect network meta-analyses for the primary outcome (OS) revealed no statistical significance between AA and D (HR 0.81,95%CI 0.65-1.01; HR 0.81, 95%CI 0.40-1.82) respectively. Comparatively, abiraterone had statistically significant fewer events of anemia (OR 0.14,95%CI 0.08-0.23), neutropenia (OR 0.06,95%CI 0.03-0.12), peripheral edema (OR 0.21,95%CI 0.09-0.44), dyspnea (OR 0.22,95%CI 0.08-0.51), nausea (OR 0.09,95%CI 0.02-0.24), diarrhea (OR 0.06,95%CI 0.02-0.15), constipation (OR 0.25,95%CI 0.11-0.53), and fatigue (OR 0.12,95%CI 0.07-0.20). AA had statistically significant more events of hot flashes (OR 3.85, 95% CI2.33-6.25). For other adverse events, both drugs were statistically similar. Conclusions: There is no difference in OS using AA for longer periods in CSPC than a regimen of a limited number of cycles of D. There are significant differences in side effect profile of these drugs. Further analyses are needed to determine cost effectiveness of AA vs D under consideration of comparative efficacy and safety.

scholarly journals A novel complete-case analysis to determine statistical significance between treatments in an intention-to-treat population of randomized clinical trials involving missing data

2016 ◽  
Vol 27 (4) ◽  
pp. 1067-1075 ◽  
Author(s):  
Wei Liu ◽  
Jinhui Ding
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Outcome Data ◽  
Complete Case ◽  
Significant Treatment ◽  
Significance Level ◽  
Intention To Treat ◽  
The Impact

The application of the principle of the intention-to-treat (ITT) to the analysis of clinical trials is challenged in the presence of missing outcome data. The consequences of stopping an assigned treatment in a withdrawn subject are unknown. It is difficult to make a single assumption about missing mechanisms for all clinical trials because there are complicated reactions in the human body to drugs due to the presence of complex biological networks, leading to data missing randomly or non-randomly. Currently there is no statistical method that can tell whether a difference between two treatments in the ITT population of a randomized clinical trial with missing data is significant at a pre-specified level. Making no assumptions about the missing mechanisms, we propose a generalized complete-case (GCC) analysis based on the data of completers. An evaluation of the impact of missing data on the ITT analysis reveals that a statistically significant GCC result implies a significant treatment effect in the ITT population at a pre-specified significance level unless, relative to the comparator, the test drug is poisonous to the non-completers as documented in their medical records. Applications of the GCC analysis are illustrated using literature data, and its properties and limits are discussed.

scholarly journals Use of systematic reviews to justify the conduct of urology clinical trials

2020 ◽  
Author(s):  
Samuel Shepard ◽  
Audrey Wise ◽  
Bradley S. Johnson ◽  
Matt Vassar
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Systematic Reviews ◽  
Randomized Clinical Trials ◽  
Data Extraction ◽  
Statistical Significance ◽  
Extraction Process ◽  
Current Data ◽  
Research Waste ◽  
Pubmed Search

Abstract Background Given the increased amount of research being funded in the field of urology, reducing the amount of research waste is vital. Systematic reviews are an essential tool in aiding in reducing waste in research; they are a comprehensive summary of the current data on a clinical question. The aim of this study is to evaluate the use of systematic reviews as justification in conducting randomized clinical trials (RCT) in high impact urology journals. Methods On December 13, 2019, one of us (BJ) conducted a PubMed search for randomized controlled trials published in the top four urology journals according to their Google Scholar h5-index. Using a masked data extraction process each RCT was searched for systematic reviews. Then each review was evaluated for if it was justification for conducting the trial based on the context the systematic review was used.Results Of the 566 articles retrieved 281 were included. Overall 60.5% (170/281) trials cited a systematic review. We found only 47.6% (134/281) studies cited a systematic review as “verbatim” justification for conducting the trial. Regression analysis yielded a finding of statistical significance in showing a correlation of studies over medical devices were more likely to cite a systematic review than other study topics ( adjusted odds ratio 2.01, 95% CI, 1.08 - 3.73) A total of 409 different systematic review citations were recorded in the 281 trials.Conclusion Less than half of clinical trials cited a systematic review as justification for conducting the trial. If clinical trials were required to support their studies with systematic reviews we believe this would greatly reduce the amount of research waste within clinical research.

scholarly journals Impact of surface decontamination and systemic antimicrobials for surgical treatment of peri-implantitis: A systematic review and meta-analysis of randomized clinical trials

2021 ◽  
Author(s):  
Giacomo Baima ◽  
Filippo Citterio ◽  
Federica Romano ◽  
Giulia Maria Mariani ◽  
Fabrizio Picollo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Surgical Treatment ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Pairwise Comparisons ◽  
Test Procedures ◽  
Implant Surface ◽  
Surface Decontamination ◽  
Meta Analyses ◽  
The Impact

Background: Efficient control of infection is essential to achieve desired outcomes in the surgical treatment of peri-implantitis lesions, although methods employed are largely heterogeneous. Purpose: To compare the impact of different decontamination protocols and adjunctive systemic antimicrobials on the outcomes of surgical treatment of peri-implantitis. Materials and methods: Randomized clinical trials (RCTs) on surgical treatment of peri-implantitis were selected through an electronic search on Medline, Embase, Scopus, and Central databases. Only studies comparing two or more anti-infective strategies were included. Following data extraction, two different sets of meta-analyses were performed. Firstly, overall impact of different implant surface decontamination methods was assessed by comparing baseline values with outcomes at 6-12 months. Secondly, pairwise comparisons evaluated the potential benefit of adjunctive systemic antimicrobials over placebo. Results were expressed as weighted mean effect (WME), weighed mean difference (WMD) or risk ratio (RR). Results: Sixteen RCTs were included. No pairwise comparisons were available for different surface decontamination methods. Use of curettes resulted in improved probing depth (PD) (WME = 2.13 mm), but the results in terms of marginal bone levels (MBL) and percentage of disease resolution were unsatisfactory. Moreover, the adjunctive benefit of systemic antimicrobials over placebo was evaluated in two studies, representing a total of 178 implants. The meta-analyses identified a higher disease resolution (RR = 1.50) for test procedures which approached statistical significance. In terms of overall outcome, systemic antimicrobials with open flap debridement resulted in improved MBL (WME = 0.44 mm), reduced PD (WME = 2.46 mm) and 51.4% of disease resolution. Conclusions: There is not enough evidence to support adjunctive usage of systemic antimicrobials together with the surgical treatment of peri-implantitis. Moreover, higher consistency is required to support the superiority of a surface decontamination protocol over another (PROSPERO CRD42020182303).

scholarly journals APPLICABILITY OF RANDOMIZED TRIALS IN HAND SURGERY: SURVEY STUDY

2018 ◽  
Vol 26 (3) ◽  
pp. 154-157
Author(s):  
VINÍCIUS YNOE DE MORAES ◽  
PRISCILA FRANTZ RUFF ◽  
CARLOS HENRIQUE FERNANDES ◽  
JOÃO BAPTISTA GOMES DOS SANTOS ◽  
JOÃO CARLOS BELLOTI ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Impact Factor ◽  
Journal Impact Factor ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Hand Surgery ◽  
Survey Study ◽  
P Value ◽  
Surgeon Experience ◽  
Journal Impact

ABSTRACT Objective To assess the applicability of randomized clinical trials and whether certain factors (surgeon experience/journal impact factor) influence their applicability. Methods In this survey study we used the Pubmed/Medline database to select 32 consecutive randomized clinical trials published between 2013 and 2015, involving hand surgery (high/low impact). These studies were independently assessed by 20 hand surgeons (with more or less than 10 years of practice) who answered 4 questions regarding their applicability. Agreement was assessed using Cohen’s kappa and comparison of proportions via chi-square statistics. P-value <5% constituted statistical significance. Results A total of 640 evaluations were produced, generating 2560 responses. A weak correlation was observed between less and more experienced respondents (kappa <0.2; range 0.119–0.179). Applicability between the least and most experienced respondents was similar (p = 0.424 and p = 0.70). Stratification by journal impact factor showed no greater propensity of applicability (p = 0.29) for any of the groups. Conclusions Low agreement was found between the respondents for the applicability of the randomized studies. Surgeon experience and journal impact do not seem to influence this decision. Level of Evidence II, Prospective comparative study.

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