scholarly journals A simple solution to the inadequacy of asymptotic likelihood-based inference for response-adaptive clinical trials

2021 ◽  
Author(s):  
Alessandro Baldi Antognini ◽  
Marco Novelli ◽  
Maroussa Zagoraiou
Keyword(s):  
Clinical Trials ◽  
Primary Outcome ◽  
Wald Test ◽  
Simple Solution ◽  
Nuisance Parameters ◽  
Simulation Studies ◽  
Fundamental Properties ◽  
Adaptive Clinical Trials ◽  
Treatment Comparisons ◽  
Practical Recommendations

AbstractThe present paper discusses drawbacks and limitations of likelihood-based inference in sequential clinical trials for treatment comparisons managed via Response-Adaptive Randomization. Taking into account the most common statistical models for the primary outcome—namely binary, Poisson, exponential and normal data—we derive the conditions under which (i) the classical confidence intervals degenerate and (ii) the Wald test becomes inconsistent and strongly affected by the nuisance parameters, also displaying a non monotonic power. To overcome these drawbacks, we provide a very simple solution that could preserve the fundamental properties of likelihood-based inference. Several illustrative examples and simulation studies are presented in order to confirm the relevance of our results and provide some practical recommendations.

scholarly journals A new inferential approach for response-adaptive clinical trials: the variance-stabilized bootstrap

Test ◽  
2021 ◽  
Author(s):  
Alessandro Baldi Antognini ◽  
Marco Novelli ◽  
Maroussa Zagoraiou
Keyword(s):  
Clinical Trials ◽  
Adaptive Designs ◽  
Simulation Studies ◽  
Adaptive Randomization ◽  
Allocation Procedure ◽  
Adaptive Clinical Trials ◽  
Response Adaptive Designs ◽  
Treatment Comparisons

AbstractThis paper discusses disadvantages and limitations of the available inferential approaches in sequential clinical trials for treatment comparisons managed via response-adaptive randomization. Then, we propose an inferential methodology for response-adaptive designs which, by exploiting a variance stabilizing transformation into a bootstrap framework, is able to overcome the above-mentioned drawbacks, regardless of the chosen allocation procedure as well as the desired target. We derive the theoretical properties of the suggested proposal, showing its superiority with respect to likelihood, randomization and design-based inferential approaches. Several illustrative examples and simulation studies are provided in order to confirm the relevance of our results.

scholarly journals Prior National Drug Abuse Treatment Clinical Trials Network (CTN) opioid use disorder trials as background and rationale for NIDA CTN-0100 “optimizing retention, duration and discontinuation strategies for opioid use disorder pharmacotherapy (RDD)”

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Matisyahu Shulman ◽  
Roger Weiss ◽  
John Rotrosen ◽  
Patricia Novo ◽  
Elizabeth Costello ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Extended Release ◽  
Primary Outcome ◽  
Opioid Use Disorder ◽  
Drug Abuse Treatment ◽  
Opioid Use ◽  
National Drug ◽  
Retention In Treatment ◽  
Abuse Treatment

AbstractOpioid use disorder continues to be a significant problem in the United States and worldwide. Three medications—methadone, buprenorphine, and extended-release injectable naltrexone,— are efficacious for treating opioid use disorder (OUD). However, the utility of these medications is limited, in part due to poor rates of retention in treatment. In addition, minimum recovery milestones and other factors that influence when and whether individuals can safely discontinue medications are unknown. The National Drug Abuse Treatment Clinical Trials Network (CTN) study “Optimizing Retention, Duration, and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy” (RDD; CTN-0100) will be among the largest clinical trials on treatment of OUD yet conducted, consisting of two phases, the Retention phase, and the Duration-Discontinuation phase. The Retention phase, open to patients initiating treatment, will test different doses and formulations of buprenorphine (standard dose sublingual, high dose sublingual, or extended-release injection), and a digital therapeutic app delivering contingency management and cognitive behavioral counseling on the primary outcome of retention in treatment. The Discontinuation phase, open to patients in stable remission from OUD and choosing to discontinue medication (including participants from the Retention phase or from the population of patients treated at the clinical site, referred by an outside prescriber or self-referred) will study different tapering strategies for buprenorphine (sublingual taper vs taper with injection buprenorphine), and a digital therapeutic app which provides resources to promote recovery, on the primary outcome of relapse-free discontinuation of medication. This paper describes how the RDD trial derives from two decades of research in the CTN. Initial trials (CTN-0001; CTN-0002; CTN-0003) focused on opioid detoxification, showing buprenorphine-naloxone was effective for detoxification, but that acute detoxification did not appear to be an effective treatment strategy. Trials on comparative effectiveness of medications for opioid use disorder (MOUD) (CTN-0027; CTN-0030; and CTN-0051) highlighted the problem of dropout from treatment and few trials defined retention on MOUD as the primary outcome. Long-term follow-up studies on those patient samples demonstrated the importance of long-term continuation of medication for many patients to sustain remission. Overall, these trials highlight the potential of a stable research infrastructure such as CTN to advance treatment effectiveness through a programmatic succession of large clinical trials.

scholarly journals Impact of timing of randomization after an acute coronary syndrome and subsequent events in patients with type 2 diabetes mellitus: an analysis of the EXAMINE trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Elharram ◽  
A Sharma ◽  
W White ◽  
G Bakris ◽  
P Rossignol ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Type 2 Diabetes Mellitus ◽  
Acute Coronary Syndrome ◽  
Primary Outcome ◽  
Funding Source ◽  
Coronary Syndrome ◽  
The Impact

Abstract Background The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes. Methods EXAMINE was a randomized trial of alogliptin versus placebo in 5380 patients with T2DM and a recent ACS. The primary outcome was a composite of CV death, non-fatal myocardial infarction [MI], or non-fatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8–34, 35–56, and 57–141 days. Results Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs. 33.0%), prior coronary artery bypass graft (9.6% vs. 15.9%), or atrial fibrillation (5.9% vs. 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio [aHR] 1.47; 95% CI 1.21–1.74) (Figure 1). Similarly, patients randomized early had an increased risk of recurrent MI (aHR 1.51; 95% CI 1.17–1.96) and HF hospitalization (1.49; 95% CI 1.05–2.10). Conclusion In a contemporary cohort of T2DM with a recent ACS, early randomization following the ACS increases the risk of CV events including recurrent MI and HF hospitalization. This should be taken into account when designing future clinical trials. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Takeda Pharmaceutical

scholarly journals Critical concepts in adaptive clinical trials

2018 ◽  
Vol Volume 10 ◽  
pp. 343-351 ◽  
Author(s):  
Jay JH Park ◽  
Kristian Thorlund ◽  
Edward J Mills
Keyword(s):  
Clinical Trials ◽  
Adaptive Clinical Trials

scholarly journals Movement-Evoked Pain Versus Pain at Rest in Postsurgical Clinical Trials and Meta-Analyses: Protocol for a Follow-Up Systematic Review

10.2196/15309 ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. e15309
Author(s):  
Daenis Camiré ◽  
Jason Erb ◽  
Henrik Kehlet ◽  
Timothy Brennan ◽  
Ian Gilron
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Postoperative Pain ◽  
Primary Outcome ◽  
Outcome Measure ◽  
Pain Treatment ◽  
Pain Outcome ◽  
Meta Analyses ◽  
Pain At Rest

Background Postoperative pain is one of the most prevalent and disabling complications of surgery that is associated with personal suffering, delayed functional recovery, prolonged hospital stay, perioperative complications, and chronic postsurgical pain. Accumulating evidence has pointed to the important distinction between pain at rest (PAR) and movement-evoked pain (MEP) after surgery. In most studies including both measures, MEP has been shown to be substantially more severe than PAR. Furthermore, as MEP is commonly experienced during normal activities (eg, breathing, coughing, and walking), it has a greater adverse functional impact than PAR. In a previous systematic review conducted in 2011, only 39% of reviewed trials included MEP as a trial outcome and 52% failed to identify the pain outcome as either PAR or MEP. Given the recent observations of postsurgical pain trials that continue to neglect the distinction between PAR and MEP, this updated review seeks to evaluate the degree of progress in this area. Objective This updated review will include postsurgical clinical trials and meta-analyses in which the primary outcome was early postoperative pain intensity. The primary outcome for this review is the reporting of MEP (vs PAR) as an outcome measure for each trial and meta-analysis. Secondary outcomes include whether trials and meta-analyses distinguished between PAR and MEP. Methods To be consistent with the 2011 review that we are updating, this review will again focus on randomized controlled trials and meta-analyses, from Medical Literature Analysis and Retrieval System Online and EMBASE databases, focusing on pain treatment after thoracotomy, knee arthroplasty, and hysterectomy in humans. Trials and meta-analyses will be characterized as to whether or not they assessed PAR and MEP; whether their pain outcome acknowledged the distinction between PAR and MEP; and, for trials assessing MEP, which pain-evoking maneuver(s) were used. Results Scoping review and pilot data extraction are under way, and the results are expected by March 2020. Conclusions It is our belief that every postsurgical analgesic trial should include MEP as an outcome measure. The previous 2011 review was expected to have an impact on more widespread assessment of MEP in subsequent postoperative pain treatment trials. Thus, the purpose of this follow-up review is to reevaluate the frequency of use of MEP as a trial outcome, compared with PAR, in more recently published postoperative pain trials. Trial Registration PROSPERO CRD42019125855; https://tinyurl.com/qw9dty8 International Registered Report Identifier (IRRID) DERR1-10.2196/15309

Time to first relapse as an endpoint in multiple sclerosis clinical trials

2012 ◽  
Vol 19 (4) ◽  
pp. 466-474 ◽  
Author(s):  
MP Sormani ◽  
A Signori ◽  
P Siri ◽  
N De Stefano
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Primary Outcome ◽  
Model Fitting ◽  
Clinical Trial Design ◽  
Fixed Time ◽  
Sound Design ◽  
Sample Sizes ◽  
Design Strategies ◽  
First Relapse

Background: The increasing number of effective therapies to treat multiple sclerosis (MS) raises ethical concerns for the use of placebo in clinical trials, suggesting that new clinical trial design strategies are needed. Objectives: To evaluate time to first relapse as an endpoint for MS clinical trials. Methods: A recently-developed model fitting the distribution of time to first relapse in MS was used for simulations estimating the sample sizes of trials using this as an outcome, and for comparison with the size of trials using the annualized relapse rate (ARR) as the primary outcome. Results: Trials based on time to first relapse were feasible, requiring sample sizes that were similar or even smaller than if the study was based on ARR instead. In the case of low ARR (0.4 relapses/year), as is expected in future trials, the 1-year trials designed to detect a treatment effect of 30%, with 90% power, require fewer patients when based on time to first relapse (470 patients/arm) than if based on ARR (540 patients/arm). Conclusions: Our simulations show that time to first relapse is not less powerful than ARR in MS trials; thus, this measure would be a potentially useful primary outcome offering the advantage of an ethically sound design, as the patients randomized to placebo can then switch to the active drug, once they relapse. A potential drawback is the loss of information for other endpoints collected at fixed time points.

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