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Reassessing the nuremberg military tribunals
For decades the history of the US Military Tribunals at Nuremberg (NMT) has been eclipsed by the first Nuremberg trial-the International Military Tribunal or IMT. The dominant interpretation-neatly summarized in the ubiquitous formula of \"Subsequent Trials\"-ignores the unique historical and legal character of the NMT trials, which differed significantly from that of their predecessor. The NMT trials marked a decisive shift both in terms of analysis of the Third Reich and conceptualization of international criminal law. This volume is the first comprehensive examination of the NMT and brings together diverse perspectives from the fields of law, history, and political science, exploring the genesis, impact, and legacy of the twelve Military Tribunals held at Nuremberg between 1946 and 1949.
eBook
An adaptive trial design to optimize dose-schedule regimes with delayed outcomes
This paper proposes a two-stage phase I-II clinical trial design to optimize doseschedule regimes of an experimental agent within ordered disease subgroups in terms of the toxicity-efficacy trade-off. The design is motivated by settings where prior biological information indicates it is certain that efficacy will improve with ordinal subgroup level. We formulate a flexible Bayesian hierarchical model to account for associations among subgroups and regimes, and to characterize ordered subgroup effects. Sequentially adaptive decisionmaking is complicated by the problem, arising from the motivating application, that efficacy is scored on day 90 and toxicity is evaluated within 30 days from the start of therapy, while the patient accrual rate is fast relative to these outcome evaluation intervals. To deal with this in a practical manner, we take a likelihood-based approach that treats unobserved toxicity and efficacy outcomes as missing values, and use elicited utilities that quantify the efficacy-toxicity trade-off as a decision criterion. Adaptive randomization is used to assign patients to regimes while accounting for subgroups, with randomization probabilities depending on the posterior predictive distributions of utilities. A simulation study is presented to evaluate the design’s performance under a variety of scenarios, and to assess its sensitivity to the amount of missing data, the prior, and model misspecification.
Journal Article
Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data
Background
Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS).
Methods
The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab.
Results
A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively),
Candida
infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs.
Conclusions
Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.
Journal Article
Three randomized controlled trials evaluating the impact of “spin” in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit
Background
News stories represent an important source of information. We aimed to evaluate the impact of “spin” (i.e., misrepresentation of study results) in health news stories reporting studies of pharmacologic treatments on patients’/caregivers’ interpretation of treatment benefit.
Methods
We conducted three two-arm, parallel-group, Internet-based randomized trials (RCTs) comparing the interpretation of news stories reported with or without spin. Each RCT considered news stories reporting a different type of study: (1) pre-clinical study, (2) phase I/II non-RCT, and (3) phase III/IV RCT. For each type of study, we identified news stories reported with spin that had earned mention in the press. Two versions of the news stories were used: the version with spin and a version rewritten without spin. Participants were patients/caregivers involved in Inspire, a large online community of more than one million patients/caregivers. The primary outcome was participants’ interpretation assessed by one specific question “What do you think is the probability that ‘treatment X’ would be beneficial to patients?” (scale, 0 [very unlikely] to 10 [very likely]).
Results
For each RCT, 300 participants were randomly assigned to assess a news story with spin (
n
= 150) or without spin (
n
= 150), and 900 participants assessed a news story. Participants were more likely to consider that the treatment would be beneficial to patients when the news story was reported with spin. The mean (SD) score for the primary outcome for abstracts reported with and without spin for pre-clinical studies was 7.5 (2.2) versus 5.8 (2.8) (mean difference [95% CI] 1.7 [1.0–2.3],
p
< 0.001); for phase I/II non-randomized trials, 7.6 (2.2) versus 5.8 (2.7) (mean difference 1.8 [1.0–2.5],
p
< 0.001); and for phase III/IV RCTs, 7.2 (2.3) versus 4.9 (2.8) (mean difference 2.3 [1.4–3.2],
p
< 0.001).
Conclusions
Spin in health news stories reporting studies of pharmacologic treatments affects patients’/caregivers’ interpretation.
Trial registration
ClinicalTrials.gov,
NCT03094078
,
NCT03094104
,
NCT03095586
Journal Article
The body in question : a novel
\"The place: central Florida. The situation: a sensational murder trial, set in a courthouse more Soviet than Le Corbusier; a rich, white teenage girl--a twin--on trial for murdering her toddler brother. Two of the jurors: Hannah, a married fifty-two-year-old former Rolling Stone and Interview Magazine photographer of rock stars and socialites (she began to photograph animals when she realized she saw people 'as a species'), and Graham, a forty-one-year-old anatomy professor. Both are sequestered (she, juror C-2; he, F-17) along with the other jurors at the Econo Lodge off I-75. As the shocking and numbing details of the crime are revealed during a string of days and courtroom hours, and the nights play out in a series of court-financed meals at Outback Steak House (the state isn't paying for their drinks) and Red Lobster, Hannah and Graham fall into a furtive affair, keeping their oath as jurors never to discuss the trial. During deliberations the lovers learn that they are on opposing sides of the case. Suddenly they look at one another through an altogether different lens, as things become more complicated\"-- Provided by publisher.
Book
Common Sense Oncology principles for the design, analysis, and reporting of phase 3 randomised clinical trials
Common Sense Oncology (CSO) prioritises treatments providing meaningful benefits for people with cancer. Here, we describe CSO principles aimed at improving the design, analysis, and reporting of randomised, controlled, phase 3 clinical trials evaluating cancer treatments. These principles include: (1) control treatment should be the best current standard of care; (2) the preferred primary endpoint is overall survival or a validated surrogate; (3) an absolute measure of benefit should be provided, such as the difference between groups in median overall survival times or the proportion of surviving patients at a prespecified time; (4) health-related quality of life should be at least a secondary endpoint; (5) toxicity should be described objectively without subjective language diminishing its importance; (6) trials should be designed to show or rule out clinically meaningful differences in outcomes, rather than a statistically significant difference alone; (7) censoring should be detailed, and sensitivity analyses done to determine its possible effects; (8) experimental treatments known to improve overall survival at later disease stages should be offered and funded for patients progressing in the control group; and (9) reports of trials should include a lay-language summary. We include checklists to guide compliance with these principles. By encouraging adherence, CSO aims to ensure that clinical trials yield results that are scientifically robust and meaningful to patients.
Journal Article