Hypothetical Trial Research Articles

Patients’ views on paying to participate in clinical trials.

e13614 Background: Clinical trials are critical to development of drugs for cancers and other conditions. Sometimes investigational drugs are not covered by insurance or sponsors and trial participants are asked to bear costs. Review boards must decide whether to approve these trials and how costs should be presented. We evaluated patients’ views about being asked to pay for investigational drugs. Methods: Thirty patients were interviewed: 15 cancer patients approached at an infusion center, and 15 cardiology patients approached in clinic or selected among patients who had authorized research contact. Interviews contained two hypothetical scenarios of clinical trials; one randomized trial comparing two standard of care drugs at $5 or $100/month, and another trial of a novel drug at $1000/month. Participants were asked whether they thought trials like these should be allowed to occur, how they would want to be approached, what should happen if removed due to safety concerns, and what other concerns they had. Results: For the hypothetical trial comparing two drugs, 11 participants (37%) stated they would be willing to enroll and pay the cost of the drug. Motivations by those willing to enroll were the opportunity for another treatment option (2/11), hoping to receive a life-saving medication for a severe condition (4/11), and having the financial ability to pay costs associated with the trial (4/11). Regardless of willingness to enroll in this trial, 17 (57%) participants explicitly stated concerns about costs, 25 (83%) mentioned a concern about side effects or efficacy of the medications, and 11 (37%) felt that trial participants would bear a greater burden and receive less benefit than the trial sponsors. For the $1000/month trial, six participants (20%) were willing to enroll and pay the costs. Participants cited motivations for enrolling as exposure to new treatment options (2/6), hoping to receive a life-saving treatment for a severe condition (4/6), and being financially stable enough to afford the costs (2/6). Concerns among respondents included the cost of the medication (25, 83%), the efficacy or side effects of this new drug (15, 50%), and unequal benefits to participants compared to trial sponsors (6, 20%). Although not all participants were willing to enroll in these trials, 24 (80%) stated that they should still be allowed to happen, because there are people willing to pay the costs; only one participant explicitly stated that these types of trials should not happen at all. Conclusions: Patients were not offended by being asked to pay to participate in clinical trials, despite having concerns about costs and the medications. Regardless of personal willingness to enroll, most respondents thought participants should have the freedom to choose whether to participate. There is a need for continued understanding of patient views of research involving direct costs, but these data suggest that patients would not support outright prohibition of cost-sharing.

Lowering serum urate with urate-lowering therapy to target and incident fracture among people with gout.

Gout is associated with a higher risk of fracture; however, the associations of hyperuricemia and urate-lowering therapy (ULT) with the risk of fracture have been inconsistent. We examined whether lowering serum urate (SU) levels with ULT to a target level (i.e., <360 μmol/L) reduces risk of fracture among people with gout. We emulated analyses of a hypothetical target trial using a "cloning, censoring, and weighting" approach to examine the association between lowering SU with ULT to the target levels and the risk of fracture using data from The Health Improvement Network, a United Kingdom primary care database. Individuals with gout who were 40 years or older and initiated ULT were included in the study. Among 28,554 people with gout, the 5-year risk of hip fracture was 0.5% for the "achieving the target SU level" arm and 0.8% for "not achieving the target SU level" arm, respectively. The risk difference and hazard ratio for "achieving the target SU level" arm was -0.3% (95% confidence interval [CI]: -0.5% to -0.1%) and 0.66 (95% CI: 0.46 to 0.93), respectively, compared with "not achieving the target SU level". Similar results were observed when the associations of lowering SU level with ULT to the target levels with the risk of composite fracture, major osteoporotic fracture, vertebral fracture, and non-vertebral fracture were assessed. In this population-based study, lowering the SU level with ULT to the guideline-based target level is associated with a lower risk of incident fracture in people with gout.

Is it worth it? Greater risk aversion with lower life satisfaction among depressed individuals

ABSTRACT Decisions of individuals with depression are often risk-averse. Risk-aversion may also extend to decisions regarding treatment, which may cause individuals to forgo or delay treatment. It is also well established that depression is associated with lower satisfaction with life. However, whether life satisfaction is associated with risk aversion for individuals with depression is not yet known. Three groups of participants (Depressed: n = 61; Chronic pain: n = 61; Comorbid depression and pain: n = 58) completed a clinical interview and several self-report questionnaires, including the Satisfaction with Life Scale (SWLS). Participants also completed two utility elicitation tasks: time trade-off (TTO), which measures utilities of health states without implied risks, and standard gamble (SG), which measures utilities of health states in the presence of risk (presented in this study as a hypothetical clinical trial described as having both potential harms and benefits). Risk aversion is defined as the difference in the utility ratings generated via SG and via TTO. For both TTO and SG, individuals evaluated their own depression or pain. When perfect health was used as a hypothetical benefit in TTO and SG tasks, satisfaction with life was not associated with risk preferences, for either depressed participants or participants with chronic pain (all ps ns). However, for participants with depression, when the hypothetical benefit was a more ecologically valid ‘mild’ depression in TTO and SG tasks, lower satisfaction with life was associated with greater risk aversion (p < .005; p < .03). For depressed individuals, therefore, lower satisfaction with life may be associated with risk aversion regarding treatments when benefits are seen as minor, which may result in treatment avoidance and, consequently, further worsening of both symptoms and life satisfaction.

A Multi-Modal AI-Driven Cohort Selection Tool to Predict Suboptimal Non-Responders to Aflibercept Loading-Phase for Neovascular Age-Related Macular Degeneration: PRECISE Study Report 1.

Patients diagnosed with exudative neovascular age-related macular degeneration are commonly treated with anti-vascular endothelial growth factor (anti-VEGF) agents. However, response to treatment is heterogeneous, without a clinical explanation. Predicting suboptimal response at baseline will enable more efficient clinical trial designs for novel, future interventions and facilitate individualised therapies. In this multicentre study, we trained a multi-modal artificial intelligence (AI) system to identify suboptimal responders to the loading-phase of the anti-VEGF agent aflibercept from baseline characteristics. We collected clinical features and optical coherence tomography scans from 1720 eyes of 1612 patients between 2019 and 2021. We evaluated our AI system as a patient selection method by emulating hypothetical clinical trials of different sizes based on our test set. Our method detected up to 57.6% more suboptimal responders than random selection, and up to 24.2% more than any alternative selection criteria tested. Applying this method to the entry process of candidates into randomised controlled trials may contribute to the success of such trials and further inform personalised care.

A Structured Process to Identify Fit-for-Purpose Study Design and Data to Generate Valid and Transparent Real-World Evidence for Regulatory Uses.

Generating evidence from real-world data requires fit-for-purpose study design and data. In addition to validity, decision makers require transparency in the reasoning that underlies study design and data source decisions. The 2019 Structured Preapproval and Postapproval Comparative Study Design Framework to Generate Valid and Transparent Real-World Evidence (SPACE) and the 2021 Structured Process to Identify Fit-For-Purpose Data (SPIFD)-intended to be used together-provide a step-by-step guide to identify decision grade, fit-for-purpose study design and data. In this update (referred to as "SPIFD2" to encompass both the design and data aspects) we provide an update to these frameworks that combines the templates into one, more explicitly calls for articulation of the hypothetical target trial and sources of bias that may arise in the real-world emulation, and provides explicit references to the Structured Template and Reporting Tool for Real-World Evidence (STaRT-RWE) tables that we suggest using immediately after invoking the SPIFD2 framework. Following the steps recommended in the SPIFD2 process requires due diligence on the part of the researcher to ensure that every aspect of study design and data selection is rationalized and supported by evidence. The resulting stepwise documentation enables reproducibility and clear communication with decision makers, and it increases the likelihood that the evidence generated is valid, fit-for-purpose, and sufficient to support healthcare and regulatory decisions.

Comparative Safety of Gout Treatment Strategies on Cardiovascular Outcomes Using Observational Data: Clone-censor-weight Target Trial Emulation Approach.

We sought to examine the cardiovascular safety of intensive treat-to-target serum urate strategies for gout using Medicare claims data linked to electronic health record laboratory data. We selected patients with gout who initiated urate-lowering therapy. We emulated a hypothetical trial comparing the rate of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) among seven different strategies over 24 months. Three aspects were considered in defining increasingly intensive strategies: (1) continuation of urate-lowering therapy, (2) serum urate monitoring, and (3) modification of urate-lowering therapy when serum urate >6 mg/dl. We applied the "clone-censor-weight" method to account for baseline and time-varying confounding. We identified 4402 patients with gout who initiated urate-lowering therapy (mean age 77; male 60%). During a total of 6611 person-years (PY) of follow-up under usual care, the rate of major cardiovascular events (first and recurrent) was 4.5/100 PY (95% CI = 4.0, 5.1). The rate ratios (RRs) suggested reductions (RR point estimates 0.88-0.84) compared with usual care. All 95% CIs were imprecise, but their upper bounds excluded substantial increase in RRs. RRs were closer to 1.0 for the analysis focusing on the first major adverse cardiovascular event during follow-up and on comparison to the strategy requiring continuation of urate-lowering therapy (but not necessarily titration). Our treatment strategy trial emulation did not find increased risk of major adverse cardiovascular events with intensive urate-lowering strategies. Results may provide reassurance of the cardiovascular safety of intensive treat-to-target serum urate strategies recommended by rheumatology societies.

Dietary Temperature's Influence on Energy Balance in Humans: Protocol for a Randomized Controlled Trial and Crossover Design.

According to the first law of thermodynamics, energy cannot be created or destroyed in an isolated system. Water has a characteristically high heat capacity, indicating that the temperature of ingested fluids and meals could contribute to energy homeostasis. Citing the underlying molecular mechanisms, we present a novel hypothesis that states that the temperature of one's food and drink contributes to energy balance and plays a role in the development of obesity. We provide strong associations with certain molecular mechanisms that are activated by heat and correlate them with obesity and a hypothetical trial that could test this hypothesis. We conclude that if meal or drink temperature proves to contribute to energy homeostasis, then depending on its contribution and scale, future clinical trials should attempt to adjust this effect when analyzing data. In addition, previous research and established relationships of disease states with dietary patterns, energy intake, and food component intakes should be revisited. We understand the common assumption that thermal energy in food is absorbed by the body during digestion and dissipated as heat into the environment, not contributing to the energy balance. We challenge this assumption herein, including a proposed study design that would test our hypothesis. This paper hypothesizes that the temperature of ingested foods or fluids influences energy homeostasis through the expression of heat shock proteins (HSPs), especially HSP-70 and HSP-90, which are expressed to a greater extent in obesity and are known to cause deficits in glucose metabolism. We provide preliminary evidence supporting our hypothesis that greater dietary temperatures disproportionally induce activation of both intracellular and extracellular HSPs and that these HSPs influence energy balance and contribute to obesity. This trial protocol has not been initiated and funding has not been sought at the time of this publication. To date, no clinical trials are available regarding the potential effects of meal and fluid temperature on weight status or its confounding effects in data analysis. A potential mechanism is proposed as a basis by which higher temperatures of foods and beverages might influence energy balance via HSP expression. On the basis of the evidence supporting our hypothesis, we propose a clinical trial that will further elucidate these mechanisms. PRR1-10.2196/42846.

Abstract OT2-13-01: Willingness to Participate in a Trial Comparing Standard Genetic Counseling versus Genetic Counseling with Personalized Cancer Risks Estimates in Patients with Li-Fraumeni Syndrome

Abstract Background: Individuals with Li-Fraumeni Syndrome (LFS) have increased risk of developing breast cancer, sarcomas, brain tumors, leukemia, and other cancers throughout their lifetime. LFS is primarily caused by autosomal dominant germline mutations in the TP53 tumor suppressor gene. Due to the large number of cancers caused by LFS, and their variable age of presentation, each LFS family often presents very differently. Currently, standard genetic counseling for patients with LFS often involves general lifetime risk predictions for developing several primary cancers. At present, there are no standard tools available to help genetics providers obtain a personalized risk assessment for a patient with LFS based on their unique personal and family history data. To address this, the LFSPRO risk model was developed to estimate the likelihood of a proband having LFS, to provide cancer-specific risks of a first primary cancer, and to estimate risk of time to second primary cancer diagnosis by utilizing detailed personal and family history information. Specific Aims: This study aims to understand patients’ willingness to participate in a randomized trial comparing standard genetic counseling practice to personalized genetic counseling via LFSPRO risk estimates. Trial Design: Eligible patients or parents/guardians are invited via email to complete a survey assessing interest in a hypothetical clinical trial scenario where patients are randomized to receive one of two types of post-disclosure genetic counseling approaches: standard genetic counseling for TP53 results, involving generic risk predictions for developing cancers, or personalized risk information provided from LFSPRO. Following the hypothetical scenario, participants are asked about their perceived benefits and barriers to this research scenario and interest in receiving personalized risk results. Demographic information is also collected. Eligibility Criteria: Individuals who receive genetic counseling through MD Anderson Cancer Center genetics clinics specifically for TP53 genetic testing and who consent to undergo TP53 genetic testing or individuals who genetic testing already indicates a TP53 germline mutation are offered this survey. Patients must be 13 years or older to complete the survey, otherwise a parent/guardian may complete the survey on their behalf. Patients must have English fluency. Statistical methods: Descriptive statistics will be used to analyze the data and summarize the opinion of the participants. Accrual: Enrollment is set to open in July 2022. Currently, 157 patients have been identified to be invited to participate in the study. Funding: This research is supported by the Cancer Research and Prevention Institute of Texas. Contact: Jacynda Woodman-Ross, MS, CGC, The University of Texas MD Anderson Cancer Center, jawoodman@mdanderson.org Citation Format: Jacynda Woodman-Ross, Sierra O. Green, Jessica Corredor, Elissa Dodd-Eaton, Nathaniel Hernandez, Susan K. Peterson, Wenyi Wang, Banu K. Arun. Willingness to Participate in a Trial Comparing Standard Genetic Counseling versus Genetic Counseling with Personalized Cancer Risks Estimates in Patients with Li-Fraumeni Syndrome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-13-01.

Forecasting individual progression trajectories in Alzheimer’s disease

The anticipation of progression of Alzheimer’s disease (AD) is crucial for evaluations of secondary prevention measures thought to modify the disease trajectory. However, it is difficult to forecast the natural progression of AD, notably because several functions decline at different ages and different rates in different patients. We evaluate here AD Course Map, a statistical model predicting the progression of neuropsychological assessments and imaging biomarkers for a patient from current medical and radiological data at early disease stages. We tested the method on more than 96,000 cases, with a pool of more than 4,600 patients from four continents. We measured the accuracy of the method for selecting participants displaying a progression of clinical endpoints during a hypothetical trial. We show that enriching the population with the predicted progressors decreases the required sample size by 38% to 50%, depending on trial duration, outcome, and targeted disease stage, from asymptomatic individuals at risk of AD to subjects with early and mild AD. We show that the method introduces no biases regarding sex or geographic locations and is robust to missing data. It performs best at the earliest stages of disease and is therefore highly suitable for use in prevention trials.

Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers

Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals. This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses. Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

On optimal timing of antenatal corticosteroids: time to reformulate the question.

Administration of antenatal corticosteroids (ACS) for accelerating foetal lung maturation in threatened preterm birth is one of the cornerstones of prevention of neonatal mortality and morbidity. To identify the optimal timing of ACS administration, most studies have compared subgroups based on treatment-to-delivery intervals. Such subgroup analysis of the first placebo-controlled randomised controlled trial indicated that a one to seven day interval between ACS administration and birth resulted in the lowest rates of neonatal respiratory distress syndrome. This efficacy window was largely confirmed by a series of subgroup analyses of subsequent trials and observational studies and strongly influenced obstetric management. However, these subgroup analyses suffer from a methodological flaw that often seems to be overlooked and potentially has important consequences for drawing valid conclusions. In this commentary, we point out that studies comparing treatment outcomes between subgroups that are retrospectively identified at birth (i.e. after randomisation) may not only be plagued by post-randomisation confounding bias but, more importantly, may not adequately inform decision making before birth, when the projected duration of the interval is still unknown. We suggest two more formal interpretations of these subgroup analyses, using a counterfactual framework for causal inference, and demonstrate that each of these interpretations can be linked to a different hypothetical trial. However, given the infeasibility of these trials, we argue that none of these rescue interpretations are helpful for clinical decision making. As a result, guidelines based on these subgroup analyses may have led to suboptimal clinical practice. As an alternative to these flawed subgroup analyses, we suggest a more principled approach that clearly formulates the question about optimal timing of ACS treatment in terms of the protocol of a future randomised study. Even if this 'target trial' would never be conducted, its protocol may still provide important guidance to avoid repeating common design flaws when conducting observational 'real world' studies using statistical methods for causal inference.

Juror interpretations of metadata and content information: implications for the going dark debate

AbstractThe rise of consumer encryption has led to a fierce debate over whether the loss of potential evidence due to encryption will be offset by the increase in evidence available from electronic metadata. One major question raised by this debate is how jurors will interpret and value metadata as opposed to content information. Though there are plausible arguments in favor of the persuasive power of each type of evidence, to date no empirical study has examined how ordinary people, potential jurors, view each of these sorts of evidence.We address this issue through a series of survey experiments that present respondents with hypothetical criminal trials, randomly assigning them to descriptions featuring either metadata or content information. These studies show that the relative power of content and metadata information is highly contextual. Content information and metadata can be equally useful when conveying logically equivalent information. However, content information may be more persuasive where the defendant’s state of mind is critical, while metadata can more convincingly establish a pattern of behavior. This suggests that the rise of encryption will have a heterogeneous effect on criminal cases, with the direction of the effect depending on the facts that the prosecution must prove.

Head-to-head comparison of FOLFIRINOX versus gemcitabine plus nab-paclitaxel in advanced pancreatic cancer: a target trial emulation using real-world data

To emulate a hypothetical target trial assessing the effect of initiating 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) versus gemcitabine plus nab-paclitaxel (GN) within 8 weeks of diagnosis on overall survival. An observational cohort study was conducted using population-level data from Alberta, Canada. Individuals diagnosed with advanced pancreatic cancer between April 2015 and December 2019 were identified through the provincial cancer registry and followed until March 2021. Records were linked to other administrative databases containing information on relevant variables. Individuals were excluded if they did not have adequate hemoglobin, platelet, white blood cell, and serum creatinine measures or if they received prior therapy. The observational analog of the per-protocol effect was estimated using inverse probability weighted Kaplan-Meier curves with bootstrapped 95% confidence intervals. Four hundred seven individuals were eligible. The weighted median overall survival was 8.3 months (95% CI, 5.7-11.9) for FOLFIRINOX and 5.1 months (95% CI: 4.3 to 5.8) for GN. The adjusted difference in median overall survival was 3.2 months (95% CI, 1.1-7.4) and the mortality hazard ratio was 0.78 (95% CI, 0.61-0.97). Our estimates favored the initiation of FOLFIRINOX over GN with respect to overall survival.

57: INTENSIVIST PHYSICIANS’ KNOWLEDGE AND ATTITUDES ABOUT BAYESIAN ADAPTIVE CLINICAL TRIALS

Introduction: Randomized clinical trials are critical to evidence-based medicine but have drawbacks including time and cost. Bayesian adaptive designs attempt to address some of these limitations and are increasingly common in critical care. However, the complexity of such trials raises concerns that clinicians may not adequately understand their methods or act on their results. There has been no systematic investigation of clinician understanding or acceptance of Bayesian trials. We sought to determine intensivist physicians’ understanding and acceptance of Bayesian trials compared to more traditional frequentist trials. Methods: We surveyed US intensivists as part of a longitudinal survey of how physicians develop and update treatment preferences in response to new evidence. We randomized participants to review an abstract reporting a hypothetical new drug trial that used a) Bayesian adaptive methods (“Bayesian group”) or b) traditional frequentist methods (“frequentist group”). The same simulated trial data were used for each abstract. Participants were asked eight Likert style questions to evaluate acceptance, self-perceived understanding, and measured understanding of the trial. Groups were compared using proportional odds logistic regression with an odds ratio >1 indicating lower Bayesian group acceptance or understanding. Results: The response rate was 273 of 592 surveys sent (46.1%). For the two questions related to general acceptance there were no significant differences between groups (OR=1.19 p=0.464 and OR=1.46 p=0.099). However, for the two questions related to self-perceived understanding the frequentist group scored significantly higher (OR=2.6 p< 0.001 and OR=3.21 p< 0.001). For the four questions related to measured understanding, the frequentist group scored significantly higher on three of four (OR=2.06 p=0.001, OR=1.49 p=0.077, OR=2.94 p< 0.001, and OR=1.60 p=0.041). Conclusions: We found no difference in Bayesian adaptive and frequentist trial acceptance among intensivists, but they had lower understanding of Bayesian trials. While efforts are needed to promote understanding of complex Bayesian trial designs, researchers and sponsors should confidently utilize these methods as clinicians are similarly accepting of results compared to traditional trials.

Adjuvant Chemotherapy Plus Radiotherapy versus Chemotherapy Alone for Locally Advanced Bladder Cancer after Radical Cystectomy.

Survival with locally advanced bladder cancer (LABC) following radical cystectomy (RC) remains poor. Although adjuvant chemotherapy (AC) is standard of care, one small, randomized trial has suggested a potential survival benefit when combined with post-operative radiotherapy (PORT). We examined the association of AC + PORT with overall survival (OS) in patients with LABC after RC. Using a prior phase 2 trial to inform design, we conducted observational analyses to emulate a hypothetical target trial of patients aged 18-79 years with pT3-4 Nany M0 or pTany N1-3 M0 urothelial bladder carcinoma following RC who were treated with AC (multiagent chemotherapy within 3 months of RC) with or without PORT (≥45 Gy to the pelvis) from 2006-2015 in the NCDB. Patients who received preoperative chemotherapy or radiotherapy were excluded. The associations of treatment with OS were evaluated using multivariable Cox regression. 1,684 patients were included, with 66 receiving AC + PORT and 1,618 AC alone. Compared to patients treated with AC alone, those treated with AC + PORT were more likely to have pT4 disease (52% vs 26%; p < 0.01), positive surgical margins (44% vs 17%; p < 0.01), and be treated at a non-academic facility (75% vs 53%; p < 0.01). Crude 5-year OS was 19% for AC + PORT versus 36% for AC alone (p = 0.01). Adjusted 5-year OS was 33% for AC + PORT versus 36% for AC alone (p = 0.49). After adjusting for baseline characteristics including pathologic features, AC + PORT was not associated with improved OS compared to AC alone (HR 1.11; 95% CI 0.82-1.51). Although infrequently utilized, the addition of radiotherapy to AC is not associated with improved OS in LABC. These results highlight the need for prospective trials to better define the potential benefits from PORT with regard to symptomatic progression and oncologic outcomes.

Composite SUVR: a new method for boosting Alzheimer’s disease monitoring and diagnostic performance, applied to tau PET

AbstractBackgroundAbnormal brain tau protein accumulation is strongly linked to multiple neurodegenerative disorders. Currently, brain tau pathology is quantified in vivo using tau PET by calculating the Standardized Uptake Value Ratio (SUVR) of target and reference regions of interest (ROIs).Recent work (Schwarz et al., 2021) in Alzheimer’s Disease (AD) explored various target and reference ROIs to report performance of SUVR as a biomarker for diagnosis, disease monitoring, and clinical trial efficacy/eligibility (sample size estimate, SSE). Here we introduce a new method and biomarker: Composite SUVR (CUVR).MethodsWe analyzed longitudinal SUV data from ADNI in the available 103 participants having three or more tau PET scans ([18F]AV‐1451): 58 cognitively normal (CN); 21 mild cognitive impairment; 24 probable AD. In the spirit of SUVR and statistical ROIs (Chen, et al., NeuroImage 2010), we calculate CUVR as the SUV ratio of two composite regions. Our novel method is that the composite regions are determined by a genetic algorithm that searches the possible 3^96 combinations of regions from FreeSurfer’s default atlas. We compare performance of SUVR with CUVR.Performance metrics follow Schwarz et al.: a linear mixed‐effects model quantifies longitudinal group separation by tau accumulation rate (t statistic between fixed effects for CN and AD) and longitudinal precision (model residuals’ standard deviation). CUVR and SUVR values were log‐transformed before model fitting.We calculated SSE for a hypothetical clinical trial designed for 80% power to reduce tau PET accumulation by 20% (vs. placebo) in non‐CN individuals.ResultsOur method identified a CUVR biomarker involving 60 regions. Figure‐1 shows the vast performance improvement of CUVR versus the best‐performing SUVR (inferior‐temporal target; eroded subcortical white matter reference). Group separation improved by 2.9x (t = 9.57 vs 3.32); longitudinal precision by 6.5x (residual std = 0.331% vs 2.14%); and CUVR required a smaller sample size by 3.9x (83 vs 318).ConclusionsOur simple data‐driven approach discovered a new tau PET biomarker called CUVR. Experimental results show state‐of‐the‐art longitudinal group separation, longitudinal precision, and clinical trial enrichment. The remarkable performance improvements provide compelling evidence for using CUVR for both eligibility and efficacy in Alzheimer’s disease clinical trials, particularly of anti‐tau therapies.

PCR279 Value-Based Assessment of Clinical Trial Outcomes: A Hypothetical Example Using the Childhood Autism Rating Scale in Autism Spectrum Disorder

This research explores the application of patient preferences, as estimated by a discrete choice experiment (DCE), to hypothetical clinical trial results in childhood autism spectrum disorder (ASD), as measured by (between-group) changes from baseline. In childhood ASD, the Childhood Autism Rating Scale–2nd edition (CARS2) instrument is used to assess severity and change.

Influence of Cost-Related Considerations on Clinical Trial Participation: Results from the 2020 Health Information National Trends Survey (HINTS).

People experiencing financial burden are underrepresented in clinical trials. Describe the prevalence of cost-related considerations influential to trial participation and their associations with person-level characteristics. This cross-sectional study used and assessed how three cost-related considerations would influence the decision to participate in a hypothetical clinical trial. A total of 3682 US adult respondents to the Health Information National Trends Survey MAIN MEASURES: Survey-weighted multivariable logistic regression estimated associations between respondent characteristics and odds of reporting cost-related considerations as very influential to participation. Among 3682 respondents, median age was 48 (IQR 33-61). Most were non-Hispanic White (60%), living comfortably or getting by on their income (74%), with ≥ 1 medical condition (61%). Over half (55%) of respondents reported at least one cost-related consideration as very influential to trial participation, including if usual care was not covered by insurance (reported by 42%), payment for participation (24%), or support for participation (24%). Respondents who were younger (18-34 vs. ≥ 75, adjusted odds ratio [aOR] 4.3, 95% CI 2.3-8.1), more educated (high school vs. <high school, aOR 2.1, 95% CI 1.1-4.1), or with lower perceived income (having difficulty vs. living comfortably, aOR 2.1, 95% CI 1.1-3.8) had higher odds of reporting any cost-related consideration as very influential to trial participation. Non-Hispanic Black vs. non-Hispanic White respondents had 29% lower odds (95% CI 0.5-0.9) of reporting any cost-related consideration as very influential to trial participation. Cost-related considerations would influence many individuals' decisions to participate in a clinical trial, though prevalence of these concerns differed by respondent characteristics. Reducing financial barriers to trial participation may promote equitable trial access and greater trial enrollment diversity.

Immediate radiotherapy versus observation in patients with node-positive prostate cancer after radical prostatectomy.

The optimal management of node-positive (pN1) prostate cancer following radical prostatectomy (RP) remains uncertain. Despite randomized evidence, utilization of immediate, life-long androgen deprivation therapy (ADT) remains poor, and recent trials of early salvage radiotherapy included only a minority of pN1 patients. We therefore emulated a hypothetical pragmatic trial of adjuvant radiotherapy versus observation in men with pN1 prostate cancer. Using the RADICALS-RT trial to inform the design of a hypothetical trial, we identified men aged 50-69 years with pT2-3 Rany pN1 M0, pre-treatment PSA < 50 ng/mL prostate cancer in the NCDB from 2006 to 2015 treated with 60-72 Gy of adjuvant RT (aRT) ±ADT within 26 weeks of RP or observation. After estimating a propensity score for receipt of aRT, we estimated absolute and relative treatment effects using stabilized inverse probability of treatment (sIPW) re-weighting. In total, 3510 patients were included in the study, of whom 587 (17%) received aRT (73% with concurrent ADT). Median follow-up was40.0 -months, during which 333 deaths occurred. After sIPW re-weighting, baseline characteristics were well-balanced. Adjusted overall survival (OS) was 93% versus 89% at 5-years and 82% versus 79% at 7-years for aRT versus observation (p = 0.11). In IPW-reweighted Cox regression, aRT was associated with a lower risk of all-cause mortality (ACM) than observation, but this did not reach statistical significance (HR 0.70 p = 0.06). In analyses examining heterogeneity of treatment effects, aRT was associated with improved ACM only for men with Gleason 8-10 disease (HR 0.59, p = 0.01), ≥2 positive LNs (HR 0.49, p = 0.04 for 2 positive LNs; HR 0.42, p = 0.01 for ≥3 positive LNs), or negative surgical margins (HR 0.50, p = 0.02). In observational analyses designed to emulate a hypothetical target trial of aRT versus observation in pN1 prostate cancer, aRT was associated with improved OS only for men with Gleason 8-10 disease, ≥2 positive LNs, or negative surgical margins.

Evaluation of the Effectiveness of Buprenorphine-Naloxone on Opioid Overdose and Death among Insured Patients with Opioid Use Disorder in the United States.

Opioid use disorder (OUD) is a chronic disease requiring long-term treatment and is associated with opioid overdose and increased risk of mortality. However, existing randomized clinical trials focused on short-term treatment engagement and detoxification rather than overdose or mortality risk due to limited follow-up time and ethical considerations. We used a hypothetical trial framework to conduct a retrospective cohort study to assess the effectiveness of time-varying buprenorphine-naloxone on opioid overdose and death. We identified 58,835 insured adult patients with OUD diagnosis in the US, 2010-2017. We fit a marginal structural model using inverse probability weighting methods to account for measured baseline and time-varying confounders, as well as selection bias due to possibly differential loss-to-follow-up. We found that receipt of buprenorphine-naloxone was associated with reduced risk of opioid overdose (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.91), death (HR = 0.24, 95% CI: 0.08, 0.75), and overdose or death (HR = 0.58, 95% CI: 0.40, 0.84). The E-value for death was 7.8, which was larger than the upper 95% CI of the association between each measured baseline variable and all-cause death, which implies that the unmeasured confounding itself may not explain away the estimated effect of treatment on the endpoint of all-cause mortality.