A Bayesian platform trial design with hybrid control based on multisource exchangeability modelling.

Enrolling patients to the standard of care (SOC) arm in randomized clinical trials, especially for rare diseases, can be very challenging due to the lack of resources, restricted patient population availability, and ethical considerations. As the therapeutic effect for the SOC is often well documented in historical trials, we propose a Bayesian platform trial design with hybrid control based on the multisource exchangeability modelling (MEM) framework to harness historical control data. The MEM approach provides a computationally efficient method to formally evaluate the exchangeability of study outcomes between different data sources and allows us to make better informed data borrowing decisions based on the exchangeability between historical and concurrent data. We conduct extensive simulation studies to evaluate the proposed hybrid design. We demonstrate the proposed design leads to significant sample size reduction for the internal control arm and borrows more information compared to competing Bayesian approaches when historical and internal data are compatible.

Design and analysis of cluster randomized trials with time-to-event outcomes under the additive hazards mixed model.

A primary focus of current methods for cluster randomized trials (CRTs) has been for continuous, binary, and count outcomes, with relatively less attention given to right-censored, time-to-event outcomes. In this article, we detail considerations for sample size requirement and statistical inference in CRTs with time-to-event outcomes when the intervention effect parameter is specified through the additive hazards mixed model (AHMM), which includes a frailty term to explicitly account for the dependency between the failure times. First, we discuss improved inference for the treatment effect parameter via bias-corrected sandwich variance estimators and randomization-based test under AHMM, addressing potential small-sample biases in CRTs. Next, we derive a new sample size formula for AHMM analysis of CRTs accommodating both equal and unequal cluster sizes. When the cluster sizes vary, our sample size formula depends on the mean and coefficient of variation of cluster sizes, based on which we articulate the impact of cluster size variation in CRTs with time-to-event outcomes. Furthermore, we obtain the insight that the classical variance inflation factor for CRTs with a non-censored outcome can in fact apply to CRTs with a time-to-event outcome, providing that an appropriate definition of the intraclass correlation coefficient is considered under AHMM. Simulation studies are carried out to illustrate key design and analysis considerations in CRTs with a small to moderate number of clusters. The proposed sample size procedure and analytical methods are further illustrated using the context of the STrategies to Reduce Injuries and Develop Confidence in Elders CRT.

Bayesian local exchangeability design for phase II basket trials.

We propose an information borrowing strategy for the design and monitoring of phase II basket trials based on the local multisource exchangeability assumption between baskets (disease types). In our proposed local-MEM framework, information borrowing is only allowed to occur locally, that is, among baskets with similar response rate and the amount of information borrowing is determined by the level of similarity in response rate, whereas baskets not considered similar are not allowed to share information. We construct a two-stage design for phase II basket trials using the proposed strategy. The proposed method is compared to competing Bayesian methods and Simon's two-stage design in a variety of simulation scenarios. We demonstrate the proposed method is able to maintain the family-wise type I error rate at a reasonable level and has desirable basket-wise power compared to Simon's two-stage design. In addition, our method is computationally efficient compared to existing Bayesian methods in that the posterior profiles of interest can be derived explicitly without the need for sampling algorithms. R scripts to implement the proposed method are available at https://github.com/yilinyl/Bayesian-localMEM.

Sample size calculation in hierarchical 2×2 factorial trials with unequal cluster sizes.

Motivated by a suicide prevention trial with hierarchical treatment allocation (cluster-level and individual-level treatments), we address the sample size requirements for testing the treatment effects as well as their interaction. We assume a linear mixed model, within which two types of treatment effect estimands (controlled effect and marginal effect) are defined. For each null hypothesis corresponding to an estimand, we derive sample size formulas based on large-sample z-approximation, and provide finite-sample modifications based on a t-approximation. We relax the equal cluster size assumption and express the sample size formulas as functions of the mean and coefficient of variation of cluster sizes. We show that the sample size requirement for testing the controlled effect of the cluster-level treatment is more sensitive to cluster size variability than that for testing the controlled effect of the individual-level treatment; the same observation holds for testing the marginal effects. In addition, we show that the sample size for testing the interaction effect is proportional to that for testing the controlled or the marginal effect of the individual-level treatment. We conduct extensive simulations to validate the proposed sample size formulas, and find the empirical power agrees well with the predicted power for each test. Furthermore, the t-approximations often provide better control of type I error rate with a small number of clusters. Finally, we illustrate our sample size formulas to design the motivating suicide prevention factorial trial. The proposed methods are implemented in the R package H2x2Factorial.

Analyzing determinants of premature trial discontinuation in leukemia clinical trials.

Clinical trials are crucial for improving patient outcomes. Although a significant number of trials are discontinued prematurely, our understanding of factors influencing early termination is limited. We conducted a comprehensive search of ClinicalTrials.gov to identify leukemia trials from 2000 to 2020, followed by data abstraction performed by two independent reviewers. Among 3522 leukemia clinical trials identified, 28.4% were terminated prematurely. Slow accrual was the leading cause of termination 38.2%. The termination rate increased significantly from 17.0% between 2000 and 2005 to 30.9% between 2010 and 2015 (p < .001). Large trials had a lower termination rate than small trials (p < .001). Academic-sponsored trials had the highest termination rates compared to other sponsors' trials (p < .001). Early-phase trials showed higher termination rates compared to late-phase (p < .001). Other significant factors included a sequential assignment, single-center, and non-randomized trials (p < .001). Much of leukemia trials are terminated prematurely, with slow accrual being the most common reason for early termination.

Perioperative Modified FOLFIRINOX for Resectable Pancreatic Cancer: A Nonrandomized Controlled Trial.

Importance: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. Objective: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. Design, Setting, and Participants: This open-label, single-arm, phase 2 nonrandomized controlled trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. Interventions: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. Results: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). Conclusions and Relevance: This nonrandomized controlled trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. Trial Registration: ClinicalTrials.gov Identifier: NCT02047474.

Taking a chance: How likely am I to receive my preferred treatment in a clinical trial?

Researchers should ideally conduct clinical trials under a presumption of clinical equipoise, but in fact trial patients will often prefer one or other of the treatments being compared. Receiving an unblinded preferred treatment may affect the study outcome, possibly beneficially, but receiving a non-preferred treatment may induce 'reluctant acquiescence', and poorer outcomes. Even in blinded trials, patients' primary motivation to enrol may be the chance of potentially receiving a desirable experimental treatment, which is otherwise unavailable. Study designs with a higher probability of receiving a preferred treatment (denoted as 'concordance') will be attractive to potential participants, and investigators, because they may improve recruitment and hence enhance study efficiency. Therefore, it is useful to consider the concordance rates associated with various study designs. We consider this question with a focus on comparing the standard, randomised, two-arm, parallel group design with the two-stage randomised patient preference design and Zelen designs; we also mention the fully randomised and partially randomised patient preference designs. For each of these designs, we evaluate the concordance rate as a function of the proportions randomised to the alternative treatments, the distribution of preferences over treatments, and (for the Zelen designs) the proportion of patients who consent to receive their assigned treatment. We also examine the equity of each design, which we define as the similarity between the concordance rates for participants with different treatment preferences. Finally, we contrast each of the alternative designs with the standard design in terms of gain in concordance and change in equity.

Simulating time-to-event data subject to competing risks and clustering: A review and synthesis.

Simulation studies play an important role in evaluating the performance of statistical models developed for analyzing complex survival data such as those with competing risks and clustering. This article aims to provide researchers with a basic understanding of competing risks data generation, techniques for inducing cluster-level correlation, and ways to combine them together in simulation studies, in the context of randomized clinical trials with a binary exposure or treatment. We review data generation with competing and semi-competing risks and three approaches of inducing cluster-level correlation for time-to-event data: the frailty model framework, the probability transform, and Moran's algorithm. Using exponentially distributed event times as an example, we discuss how to introduce cluster-level correlation into generating complex survival outcomes, and illustrate multiple ways of combining these methods to simulate clustered, competing and semi-competing risks data with pre-specified correlation values or degree of clustering.

ImmunoPET Imaging Identifies the Optimal Timepoint for Combination Therapy in Xenograft Models of Triple-Negative Breast Cancer.

(1) Purpose: The glycoprotein non-metastatic melanoma B (gpNMB) is a type 1 transmembrane protein that is overexpressed in numerous cancers, including triple-negative breast cancer (TNBC). Its overexpression is associated with lower overall survival of patients with TNBC. Tyrosine kinase inhibitors such as dasatinib can upregulate gpNMB expression, which has the potential to enhance therapeutic targeting with anti-gpNMB antibody drug conjugates such as glembatumumab vedotin (CDX-011). Our primary aim is to quantify the degree and identify the timeframe of gpNMB upregulation in xenograft models of TNBC after treatment with the Src tyrosine kinase inhibitor, dasatinib, by longitudinal positron emission tomography (PET) imaging with the 89Zr-labeled anti-gpNMB antibody ([89Zr]Zr-DFO-CR011). The goal is to identify the timepoint at which to administer CDX-011 after treatment with dasatinib to enhance therapeutic efficacy using noninvasive imaging. (2) Methods: First, TNBC cell lines that either express gpNMB (MDA-MB-468) or do not express gpNMB (MDA-MB-231) were treated with 2 µM of dasatinib in vitro for 48 h, followed by Western blot analysis of cell lysates to determine differences in gpNMB expression. MDA-MB-468 xenografted mice were also treated with 10 mg/kg of dasatinib every other day for 21 days. Subgroups of mice were euthanized at 0-, 7-, 14-, and 21-days post treatment, and tumors were harvested for Western blot analysis of tumor cell lysates for gpNMB expression. In a different cohort of MDA-MB-468 xenograft models, longitudinal PET imaging with [89Zr]Zr-DFO-CR011 was performed before treatment at 0 (baseline) and at 14 and 28 days after treatment with (1) dasatinib alone (2) CDX-011 (10 mg/kg) alone, or (3) sequential treatment of dasatinib for 14 days then CDX-011 to determine changes in gpNMB expression in vivo relative to baseline. As a gpNMB-negative control, MDA-MB-231 xenograft models were imaged 21 days after treatment with dasatinib, combination of CDX-011 and dasatinib, and vehicle control. (3) Results: Western blot analysis of MDA-MB-468 cell and tumor lysates showed that dasatinib increased expression of gpNMB in vitro and in vivo at 14 days post treatment initiation. In PET imaging studies of different cohorts of MDA-MB-468 xenografted mice, [89Zr]Zr-DFO-CR011 uptake in tumors (SUVmean = 3.2 ± 0.3) was greatest at 14 days after treatment initiation with dasatinib (SUVmean = 4.9 ± 0.6) or combination of dasatinib and CDX-011 (SUVmean= 4.6 ± 0.2) compared with that at baseline (SUVmean = 3.2 ± 0.3). The highest tumor regression after treatment was observed in the combination-treated group with a percent change in tumor volume relative to baseline (%CTV) of -54 ± 13 compared with the vehicle control-treated group (%CTV = +102 ± 27), CDX-011 group (%CTV = -25 ± 9.8), and dasatinib group (%CTV = -23 ± 11). In contrast, the PET imaging of MDA-MB-231 xenografted mice indicated no significant difference in the tumor uptake of [89Zr]Zr-DFO-CR011 between treated (dasatinib alone or in combination with CDX-011) and vehicle-control groups. (4) Conclusions: Dasatinib upregulated gpNMB expression in gpNMB-positive MDA-MB-468 xenografted tumors at 14 days post treatment initiation, which can be quantified by PET imaging with [89Zr]Zr-DFO-CR011. Furthermore, combination therapy with dasatinib and CDX-011 appears to be a promising therapeutic strategy for TNBC and warrants further investigation.

Effects of hypnosis versus enhanced standard of care on postoperative opioid use after total knee arthroplasty: the HYPNO-TKA randomized clinical trial.

BACKGROUND: Hypnosis decreases perioperative pain and has opioid-sparing potential but has not been rigorously studied in knee arthroplasty. This trial investigates the impact of perioperative hypnosis on inpatient opioid use following total knee arthroplasty. METHODS: This prospective randomized controlled trial was conducted at a single academic medical center. The hypnosis arm underwent a scripted 10 min hypnosis session prior to surgery and had access to the recorded script. The control arm received hypnosis education only. The primary outcome was opioid use in milligram oral morphine equivalents per 24 hours during hospital admission. A secondary analysis was performed for patients taking opioids preoperatively. RESULTS: 64 primary knee arthroplasty patients were randomized 1:1 to hypnosis (n=31) versus control (n=33) and included in the intent-to-treat analysis. The mean (SD) postoperative opioid use in oral morphine equivalents per 24 hours was 70.5 (48.4) in the hypnosis versus 90.7 (74.4) in the control arm, a difference that was not statistically significant (difference -20.1; 95% CI -51.8 to 11.4; p=0.20). In the subgroup analysis of the opioid-experienced patients, there was a 54% daily reduction in opioid use in the hypnosis group (82.4 (56.2) vs 179.1 (74.5) difference of -96.7; 95% CI -164.4 to -29.0; p=<0.01), equivalent to sparing 65 mg of oxycodone per day. CONCLUSION: Perioperative hypnosis significantly reduced inpatient opioid use among opioid-experienced patients only. A larger study examining these findings is warranted. TRIAL REGISTRATION NUMBER: NCT03308071.

Design and analysis of partially randomized preference trials with propensity score stratification.

While the two-stage randomized design allows us to unbiasedly evaluate the impact of patients' treatment preference on the outcome of interest, it may not always be practical to implement in clinical practice; patients with a strong preference may not be willing to be randomized. The more pragmatic, partially randomized preference design (PRPD) allows patients who are unwilling to be randomized, but willing to state their preference, to receive their preferred treatment in lieu of the first-stage randomization in the two-stage design, at the cost of potentially introducing bias in estimating the effects of interest. In this article, we consider the application of propensity score stratification (PSS) in a PRPD to recreate a conditional first-stage randomization based on observed covariates, enabling the estimation and inference of the overall treatment, selection and preference effects with minimum bias. We additionally derive a set of closed-form sample size formulas for detecting all three effects of interest in a PSS-PRPD. Simulation studies demonstrate the bias reduction properties of the PSS-PRPD, and validate the accuracy of the proposed sample size formulas. Our results show that 5 to 10 propensity score strata may be needed to correct for biases in effect estimates, and the exact number of strata needed to achieve the best match between the empirical power and formula prediction may depend on the degree of effect heterogeneity. Finally, we demonstrate our proposed formulas by estimating the required sample sizes to detect treatment, selection and preference effects in the context of the Harapan Study.

Predictive accuracy of elevated mitotic rate on lymph node positivity and recurrence in thin melanomas.

Background: Mitotic rate (MR) is considered an important prognostic factor for melanoma but is not currently used for staging because its nuanced effect is not yet well-delineated. We sought to determine if T category-specific MR is predictive of sentinel lymph node (SLN) positivity, recurrence, and melanoma-specific mortality (MSM). Methods: A retrospective review of patients with primary cutaneous melanoma from 1994 to 2020 at a single academic center was performed. Patient demographics and tumor characteristics were recorded. MR was considered elevated for each AJCC8-defined T category if it was ≥2 mitoses/mm2 for T1, ≥4 mitoses/mm2 for T2, ≥6 mitoses/mm2 for T3, or ≥7 mitoses/mm2 for T4. Statistical analysis was performed to assess the predictive accuracy of MR on selected outcomes while controlling for ulceration. Results: Data from 2,984 patients with complete records were analyzed. Along with Breslow thickness and ulceration, elevated MR was associated with higher risk of MSM (HR 1.816, P=0.0001). There was no difference among patients with ulcerated T1 or T2 tumors regardless of MR, but those with non-ulcerated T1 or T2 tumors and elevated MR were more likely to have positive SLNs (P<0.0001 and P=0.0043, respectively) and recurrence (P=0.0007 and P=0.0004, respectively) compared to counterparts with low MR. There were no notable differences for T3 or T4 tumors based on MR. Conclusions: Elevated MR is associated with SLN positivity and recurrence in thin melanomas, independent of ulceration. SLN biopsy should therefore be strongly considered for patients with non-ulcerated lesions <0.8 mm thick if the MR is ≥2 mitoses/mm2.

A comparison of analytical strategies for cluster randomized trials with survival outcomes in the presence of competing risks.

While statistical methods for analyzing cluster randomized trials with continuous and binary outcomes have been extensively studied and compared, little comparative evidence has been provided for analyzing cluster randomized trials with survival outcomes in the presence of competing risks. Motivated by the Strategies to Reduce Injuries and Develop Confidence in Elders trial, we carried out a simulation study to compare the operating characteristics of several existing population-averaged survival models, including the marginal Cox, marginal Fine and Gray, and marginal multi-state models. For each model, we found that adjusting for the intraclass correlations through the sandwich variance estimator effectively maintained the type I error rate when the number of clusters is large. With no more than 30 clusters, however, the sandwich variance estimator can exhibit notable negative bias, and a permutation test provides better control of type I error inflation. Under the alternative, the power for each model is differentially affected by two types of intraclass correlations-the within-individual and between-individual correlations. Furthermore, the marginal Fine and Gray model occasionally leads to higher power than the marginal Cox model or the marginal multi-state model, especially when the competing event rate is high. Finally, we provide an illustrative analysis of Strategies to Reduce Injuries and Develop Confidence in Elders trial using each analytical strategy considered.

Attention-Deficit/Hyperactivity Disorder in 2- to 5-Year-Olds: A Primary Care Network Experience.

OBJECTIVE: To assess 1) rates of primary care provider (PCP) diagnosis of attention-deficit/hyperactivity disorder (ADHD) in young children, 2) documented PCP adherence to ADHD clinical practice guidelines, and 3) patient factors influencing PCP variation in diagnosis and management. METHODS: Retrospective cohort study of electronic health records from all office visits of children aged 2 to 5 years, seen ≥2 times between 2015 and 2019, in 10 practices of a community-based primary health care network. Outcomes included ADHD diagnosis (symptom or disorder), and adherence to guidelines in 1) comorbidity documentation at or after ADHD diagnosis, 2) ADHD medication choice, and 3) follow-up of medicated patients. Logistic regressions assessed associations between outcomes and patient characteristics. RESULTS: Of 29,408 eligible children, 195 (0.7%) had ADHD diagnoses. Of those, 56% had solely symptom-level diagnoses (eg, hyperactivity); 54% had documented comorbidities. ADHD medications were prescribed only to 4- to 5-year olds (40 of 195 [21%]); 85% received stimulants as first-line medication; 48% had follow-up visits within 2 months. Likelihood of ADHD diagnosis was higher for children with public or military insurance (odds ratio [OR] 1.94; 95% confidence interval [CI] 1.40-2.66; OR 3.17; 95% CI 1.93-4.96). Likelihood of comorbidity documentation was lower for older ADHD patients (OR 0.48; 95% CI 0.32-0.71) and higher for those with military insurance (OR 3.11; 95% CI 1.13-9.58). CONCLUSION: PCPs in this network frequently used symptom-level ADHD diagnoses in 2- to 5-year olds; ADHD diagnosis rates were below estimated population prevalence, with evidence for sociodemographic disparities. PCP comorbidity documentation and choice of stimulant medications were consistent with guidelines. Rates of timely follow-up were low.

Handheld Ultrasound Device Usage and Image Acquisition Ability Among Internal Medicine Trainees: A Randomized Trial.

BACKGROUND: There is insufficient knowledge about how personal access to handheld ultrasound devices (HUDs) improves trainee learning with point-of-care ultrasound (POCUS). OBJECTIVE: To assess whether HUDs, alongside a yearlong lecture series, improved trainee POCUS usage and ability to acquire images. METHODS: Internal medicine intern physicians (n = 47) at a single institution from 2017 to 2018 were randomized 1:1 to receive personal HUDs (n = 24) for patient care/self-directed learning vs no-HUDs (n = 23). All interns received a repeated lecture series on cardiac, thoracic, and abdominal POCUS. Main outcome measures included self-reported HUD usage rates and post-intervention assessment scores using the Rapid Assessment of Competency in Echocardiography (RACE) scale between HUD and no-HUD groups. RESULTS: HUD interns reported performing POCUS assessments on patients a mean 6.8 (SD 2.2) times per week vs 6.4 (SD 2.9) times per week in non-HUD arm (P = .66). There was no relationship between the number of self-reported examinations per week and a trainee's post-intervention RACE score (rho = 0.022, P = .95). HUD interns did not have significantly higher post-intervention RACE scores (median HUD score 17.0 vs no-HUD score 17.8; P = .72). Trainee confidence with cardiac POCUS did not correlate with RACE scores. CONCLUSIONS: Personal HUDs without direct supervision did not increase the amount of POCUS usage or improve interns' acquisition abilities. Interns who reported performing more examinations per week did not have higher RACE scores. Improved HUD access and lectures without additional feedback may not improve POCUS mastery.

Social marketing for a farmer's market in an underserved community: A needs assessment.

The aim of the present paper is to assess local residents' awareness of utilizing Supplemental Nutrition Assistance Program (SNAP) benefits to purchase fresh produce at local farmers' markets, and to determine internet use and media preferences of study participants prior to implementation of a social marketing campaign. A needs assessment was conducted to collect baseline data in an underserved neighbourhood in New Orleans (La, USA). The study was carried out August 2014-May 2015. The assessment revealed that 73% of the respondents were unaware that the SNAP benefits could be used to purchase food in farmers' markets; 63% of low-income participants never attended a farmers' market compared to 27% of mid/high-income. Over 50% of the low-income respondents have access to the internet at least once per day. The results show the potential of raising awareness among a wide range of members in the community. This needs assessment will serve as the foundation for a social marketing intervention, which will be disseminated city-wide.