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Shuman, Benjamin R., Brad D. Hendershot, David C. Morgenroth, and Elizabeth Russell Esposito. "A patient-centered ‘test-drive’ strategy for ankle-foot orthosis prescription: Protocol for a randomized participant-blinded trial." PLOS ONE 19, no. 5 (May 2, 2024): e0302389. http://dx.doi.org/10.1371/journal.pone.0302389.
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Background Ankle-foot orthoses (AFOs) are commonly used to overcome mobility limitations related to lower limb musculoskeletal injury. Despite a multitude of AFOs to choose from, there is scant evidence to guide AFO prescription and limited opportunities for AFO users to provide experiential input during the process. To address these limitations in the current prescription process, this study evaluates a novel, user-centered and personalized ‘test-drive’ strategy using a robotic exoskeleton (‘AFO emulator’) to emulate commercial AFO mechanical properties (i.e., stiffness). The study will determine if brief, in-lab trials (with emulated or actual AFOs) can predict longer term preference, satisfaction, and mobility outcomes after community trials (with the actual AFOs). Secondarily, it will compare the in-lab experience of walking between actual vs. emulated AFOs. Methods and analysis In this participant-blinded, randomized crossover study we will recruit up to fifty-eight individuals with lower limb musculoskeletal injuries who currently use an AFO. Participants will walk on a treadmill with three actual AFOs and corresponding emulated AFOs for the "in-lab” assessments. For the community trial assessment, participants will wear each of the actual AFOs for a two-week period during activities of daily living. Performance-based and user-reported measures of preference and mobility will be compared between short- and long-term trials (i.e., in-lab vs. two-week community trials), and between in-lab trials (emulated vs. actual AFOs). Trial registration The study was prospectively registered at www.clininicaltrials.gov (Clinical Trials Study ID: NCT06113159). Date: November 1st 2023. https://classic.clinicaltrials.gov/ct2/show/NCT06113159.
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Wang, Shirley V., Sebastian Schneeweiss, Jessica M. Franklin, Rishi J. Desai, William Feldman, Elizabeth M. Garry, Robert J. Glynn, et al. "Emulation of Randomized Clinical Trials With Nonrandomized Database Analyses." JAMA 329, no. 16 (April 25, 2023): 1376. http://dx.doi.org/10.1001/jama.2023.4221.
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ImportanceNonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates.ObjectiveTo emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time [PICOT]) and to quantify agreement in RCT-database study pairs.Design, Setting, and ParticipantsNew-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022.ExposuresTherapies for multiple clinical conditions were included.Main Outcomes and MeasuresDatabase study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference.ResultsIn these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement).Conclusions and RelevanceReal-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.
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Amiot, Mathilde, Laurent Mortier, Stéphane Dalle, Olivier Dereure, Sophie Dalac, Caroline Dutriaux, Marie Thérèse Leccia, et al. "When to stop immunotherapy for advanced melanoma: Emulation of target trials." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): 9521. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.9521.
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9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]
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Zheng, Yingye, Paul D. Wagner, Amit G. Singal, Samir M. Hanash, Sudhir Srivastava, Ying Huang, Ying-Qi Zhao, et al. "Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers." Cancer Epidemiology, Biomarkers & Prevention 33, no. 9 (September 3, 2024): 1150–57. http://dx.doi.org/10.1158/1055-9965.epi-23-1594.
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Abstract Before implementing a biomarker in routine clinical care, it must demonstrate clinical utility by leading to clinical actions that positively affect patient-relevant outcomes. Randomly controlled early detection utility trials, especially those targeting mortality endpoint, are challenging due to their high costs and prolonged duration. Special design considerations are required to determine the clinical utility of early detection assays. This commentary reports on discussions among the National Cancer Institute’s Early Detection Research Network investigators, outlining the recommended process for carrying out single-organ biomarker-driven clinical utility studies. We present the early detection utility studies in the context of phased biomarker development. We describe aspects of the studies related to the features of biomarker tests, the clinical context of endpoints, the performance criteria for later phase evaluation, and study size. We discuss novel adaptive design approaches for improving the efficiency and practicality of clinical utility trials. We recommend using multiple strategies, including adopting real-world evidence, emulated trials, and mathematical modeling to circumvent the challenges in conducting early detection utility trials.
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Stewart, R. "How can electronic health records serve as a tool for clinical trials?" European Psychiatry 67, S1 (April 2024): S38. http://dx.doi.org/10.1192/j.eurpsy.2024.135.
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AbstractIncreasing volumes of information are being collected via electronic health records and there is growing multi-site expertise in utlising these for research. This emerging field of healthcare data science is not only concerned with the technical challenges associated with complex data, but also with the need for effective security and governance in the use of sensitive information with robust structures for stakeholder input and guidance. To date, most of the focus has been on supporting observational cohort studies nested within clinical records data - particularly investigating research questions around treatment response and course/prognosis. It is likely that electronic health records will become increasingly integrated with clinical trials, providing opportunities for pre-study feasibility scoping, targeted recruitment, and enhanced and extended follow-up. In addition, there is interest in emulated trials using routine data. For mental health data science, key challenges lie in the quality and quantity of data made accessible, with a particular need for natural language processing to derive structured data from extensive clinical text. Many of the challenges have been addressed for observational research, creating exciting prospects for a transformed trials landscape.Disclosure of InterestR. Stewart Grant / Research support from: Janssen, GSK, Takeda
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Christiaens, Antoine, Noémie Simon-Tillaux, Wade Thompson, Alan J. Sinclair, Séverine Henrard, Benoit B. Boland, Yannis Slaouti-Jégou, et al. "Impact of deintensifying hypoglycaemic drugs in older adults with type 2 diabetes: protocol for an emulation of a target trial." BMJ Open 13, no. 11 (November 2023): e073081. http://dx.doi.org/10.1136/bmjopen-2023-073081.
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IntroductionIn older adults with type 2 diabetes (T2D), overtreatment with hypoglycaemic drugs (HDs: sulfonylureas, glinides and/or insulins) is frequent and associated with increased 1-year mortality. Deintensification of HD is thus a key issue, for which evidence is though limited. The primary objective of this study will be to estimate the effect of deintensifying HD on clinical outcomes (hospital admission or death) within 3 months in older adults (≥75 years) with T2D.MethodsWe will emulate with real-world data a target trial, within The Health Improvement Network cohort, a large-scale database of data collected from electronic medical records of 2000 general practitioners in France. From 1 January 2010 to 28 February 2019, we will include eligible patients ≥75 years who will have T2D, a stable dose of HDs, glycated haemoglobin A1c (HbA1c) value <75 mmol/mol (9.0%) and no deintensification in the past year. The target trial will be sequentially emulated (ie, eligibility assessed) every month in the database. Patients will be classified at baseline of each sequential trial in the intervention arm (deintensification of HDs: decrease of ≥50% in the total dose of HDs, including complete cessation) or control arm (no deintensification of HDs). The pooled dataset for all sequential emulated trials will be analysed. The primary outcome will be time to first occurrence of hospital admission or death, within 3 months. Secondary outcomes will be hospitalisation, death, appropriateness of glycaemic control and occurrence of HbA1c >75 mmol/mol within 1 year. Participants will be followed from baseline to 12 months after randomisation, administrative censoring, or death, whichever occurs first. A pooled logistic regression will be used to estimate the treatment effect on the incidence of the outcomes.Dissemination and ethicsNo ethical approval is needed for using retrospectively this fully anonymised database. The results will be disseminated during conferences and through publications in scientific journals.
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Heyard, Rachel, Leonhard Held, Sebastian Schneeweiss, and Shirley V. Wang. "Design differences and variation in results between randomised trials and non-randomised emulations: meta-analysis of RCT-DUPLICATE data." BMJ Medicine 3, no. 1 (February 2024): e000709. http://dx.doi.org/10.1136/bmjmed-2023-000709.
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ObjectiveTo explore how design emulation and population differences relate to variation in results between randomised controlled trials (RCT) and non-randomised real world evidence (RWE) studies, based on the RCT-DUPLICATE initiative (Randomised, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology).DesignMeta-analysis of RCT-DUPLICATE data.Data sourcesTrials included in RCT-DUPLICATE, a demonstration project that emulated 32 randomised controlled trials using three real world data sources: Optum Clinformatics Data Mart, 2004-19; IBM MarketScan, 2003-17; and subsets of Medicare parts A, B, and D, 2009-17.Eligibility criteria for selecting studiesTrials where the primary analysis resulted in a hazard ratio; 29 RCT-RWE study pairs from RCT-DUPLICATE.ResultsDifferences and variation in effect sizes between the results from randomised controlled trials and real world evidence studies were investigated. Most of the heterogeneity in effect estimates between the RCT-RWE study pairs in this sample could be explained by three emulation differences in the meta-regression model: treatment started in hospital (which does not appear in health insurance claims data), discontinuation of some baseline treatments at randomisation (which would have been an unusual care decision in clinical practice), and delayed onset of drug effects (which would be under-reported in real world clinical practice because of the relatively short persistence of the treatment). Adding the three emulation differences to the meta-regression reduced heterogeneity from 1.9 to almost 1 (absence of heterogeneity).ConclusionsThis analysis suggests that a substantial proportion of the observed variation between results from randomised controlled trials and real world evidence studies can be attributed to differences in design emulation.
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Wu, Chi-Shin, Albert C. Yang, Shu-Sen Chang, Chia-Ming Chang, Yi-Hung Liu, Shih-Cheng Liao, and Hui-Ju Tsai. "Validation of Machine Learning-Based Individualized Treatment for Depressive Disorder Using Target Trial Emulation." Journal of Personalized Medicine 11, no. 12 (December 7, 2021): 1316. http://dx.doi.org/10.3390/jpm11121316.
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This study aims to develop and validate the use of machine learning-based prediction models to select individualized pharmacological treatment for patients with depressive disorder. This study used data from Taiwan’s National Health Insurance Research Database. Patients with incident depressive disorders were included in this study. The study outcome was treatment failure, which was defined as psychiatric hospitalization, self-harm hospitalization, emergency visits, or treatment change. Prediction models based on the Super Learner ensemble were trained separately for the initial and the next-step treatments if the previous treatments failed. An individualized treatment strategy was developed for selecting the drug with the lowest probability of treatment failure for each patient as the model-selected regimen. We emulated clinical trials to estimate the effectiveness of individualized treatments. The area under the curve of the prediction model using Super Learner was 0.627 and 0.751 for the initial treatment and the next-step treatment, respectively. Model-selected regimens were associated with reduced treatment failure rates, with a 0.84-fold (95% confidence interval (CI) 0.82–0.86) decrease for the initial treatment and a 0.82-fold (95% CI 0.80–0.83) decrease for the next-step. In emulation of clinical trials, the model-selected regimen was associated with a reduced treatment failure rate.
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Kjellsson, Sara, Kristiina Rajaleid, and Bitte Modin. "Using emulated clinical trials to investigate the risk of being diagnosed with psychiatric ill health following the cancer diagnosis of a sibling." PLOS ONE 19, no. 4 (April 18, 2024): e0298175. http://dx.doi.org/10.1371/journal.pone.0298175.
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Background The sibling bond is often the longest relationship in an individual’s life, spanning both good and bad times. Focusing on the latter, we investigated whether a cancer diagnosis in one adult sibling is predictive of psychiatric illness in the other, and if any such effect differs according the ‘sociodemographic closeness’ between the siblings in terms of sex, age, education, marital status and residence. Methods We used hospital records to identify psychiatric diagnoses (2005–2019) in a Swedish total-population cohort born in 1953, and cancer diagnoses (2005–2017) in their full siblings. By means of emulated clinical trials, the cohort member’s risk of a diagnosis within two years following a first exposure (or non-exposure) to a sibling’s cancer was analyzed through Cox regression. Results Exposed cohort members had a higher risk of psychiatric diagnosis than unexposed (HR = 1.15; CI: 1.08–1.23), with men displaying a higher risk (1.19; CI: 1.09–1.31) than women (HR = 1.11; CI: 1.01–1.22). Sub-analyses of the exposed group showed that women with a cancer-stricken sister had a higher risk of adverse psychiatric outcomes (HR = 1.31; CI: 1.07–1.61) than women with a cancer-stricken brother. Furthermore, unmarried cohort members ran a higher risk, both when the cancer-stricken sibling was married (HR = 2.03; CI: 1.67–2.46) and unmarried (HR = 2.61; CI: 2.16–3.15), than in cases where both siblings were married. No corresponding difference were detected for ‘closeness’ in age, education and residence. Conclusions In line with theories of linked lives, our findings suggest that negative events in one sibling’s life tend to ‘spill over’ on the other sibling’s wellbeing, at least during the 15-year-long period leading up to retirement age.
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Oh, Tae Ryom. "Integrating predictive modeling and causal inference for advancing medical science." Childhood Kidney Diseases 28, no. 3 (October 31, 2024): 93–98. http://dx.doi.org/10.3339/ckd.24.018.
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Artificial intelligence (AI) is revolutionizing healthcare by providing tools for disease prediction, diagnosis, and patient management. This review focuses on two key AI methodologies in healthcare: predictive modeling and causal inference. Predictive models excel in identifying patterns to forecast outcomes but are limited in explaining the underlying causes. In contrast, causal inference focuses on understanding cause-and-effect relationships, which makes effective medical interventions possible. Although randomized controlled trials (RCTs) are the gold standard for causal inference, they face limitations including cost and ethical concerns. As alternatives, emulated RCTs and advanced machine learning techniques have emerged for estimating causal effects, bridging the gap between prediction and causality. Additionally, Shapley values and Local Interpretable Model-Agnostic Explanations improve the interpretability of complex AI models, making them more actionable in clinical settings. Integrating prediction and causal inference holds great promise for advancing personalized medicine, enhancing patient outcomes, and optimizing healthcare delivery. However, careful application of AI tools is crucial to avoid misinterpretation and maximize their potential.
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Myers, Regina M., Kelly D. Getz, Yimei Li, Yuan-Shung V. Huang, Rebecca Citrin, Caitlin W. Elgarten, Benjamin L. Laskin, Joseph P. Horowitz, Brian T. Fisher, and Richard Aplenc. "Comparative Effectiveness of Rasburicase and Allopurinol in Children with Acute Lymphoblastic Leukemia: An Emulated Pragmatic Trial Using Observational Data." Blood 132, Supplement 1 (November 29, 2018): 830. http://dx.doi.org/10.1182/blood-2018-99-114883.
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Abstract Introduction: Children with newly diagnosed acute lymphoblastic leukemia (ALL) are at risk for developing tumor lysis syndrome (TLS), an oncologic emergency with potentially severe consequences. Effective TLS management centers on prevention, achieved in large part through control of hyperuricemia with allopurinol or rasburicase. Though rasburicase is known to be very effective for children at high TLS risk, there are limited evidence-based data to guide its usage. Currently available guidelines rely on expert opinion and provide conflicting recommendations, especially for patients at intermediate TLS risk. To address this data gap, we emulated a randomized clinical trial (RCT) to test the efficacy of rasburicase in intermediate risk TLS. We hypothesized that rasburicase would not provide benefit for children with ALL who were classified as being at intermediate TLS risk based on white blood cell count (WBC), uric acid (UA), and creatinine (Cr). Study Design: We used observational data from the Pediatric Health Information Systems (PHIS) administrative database to emulate a RCT assessing the effectiveness of rasburicase initiation (Hernan & Robins Am J Epidemiol. 2016). The source population consisted of the subset of an established cohort of newly diagnosed ALL patients, who were treated at 6 centers that contributed laboratory values to PHIS from 2007-2012. We mimicked rasburicase initiation trials ("pseudo-trials") over time, where each day of the initial diagnostic admission (up to day 4) represented the start of a new pseudo-trial. For each pseudo-trial, a child was considered eligible if he received at least one dose of allopurinol or rasburicase and had a maximum WBC <100/mL, UA <10mg/dL, and Cr <1.5 times the upper limit of normal (ULN) during the 2-day baseline evaluation window. Each child could thus contribute to a maximum of 4 pseudo-trials. For each trial, children were assigned to the non-initiator arm if they received allopurinol-only, or to the rasburicase-initiator arm if they started rasburicase. Rasburicase exposed patients were not eligible for subsequent trials. Study Outcome: The primary outcome was acute kidney injury (AKI), defined as a Cr >1.5 times the ULN. Secondary outcomes were receipt of dialysis, inpatient length of stay (LOS) and mortality. Follow-up for the outcomes started on day 3 of each pseudo-trial and ended 7 days later for AKI and dialysis or 35 days later for LOS and mortality. An intention-to-treat analysis was used. To adjust for potential confounding by baseline covariates, the propensity to receive rasburicase was estimated using a logistic regression model that informed calculation of inverse probability weights (IPW). IPW-adjusted frequency tables were constructed for AKI, dialysis, and mortality. For LOS, linear regression models with IPW and generalized estimating equations for repeated trials were used. Results: Of 945 eligible children, 44 initiated rasburicase (ever-initiators) and 901 never initiated rasburicase (never-initiators). Compared to the non-initiators, ever-initiators were more likely to be male (p=0.040), non-Hispanic white (p=0.018), have private insurance (p=0.028), and have higher WBC (p<.0001), UA (p<.0001) and creatinine (p=0.019) at baseline. The final analyses included 3,175 eligible trial patients. IPW-adjusted analyses suggested no differences in frequency of AKI (2.72% vs. 0.34%, p=0.545), receipt of dialysis (0.51% vs. 0%, p=1.000), mortality (0.06% vs. 0.04% p=1.000) or inpatient LOS (mean 14.7 days vs. 11.0 days, p=0.18) between the initiator and non-initiator arms. Conclusion: Our results suggest that administration of rasburicase may not decrease the frequency of AKI, receipt of dialysis, mortality or decrease LOS for children with newly diagnosed ALL at intermediate TLS risk. Though only 44 rasburicase initiators were identified, which limited the power, these results represent data from the largest pediatric ALL cohort with both laboratory values and resource utilization. If replicated in other cohorts, such findings have the potential to impact guidelines for rasburicase use and greater standardization of rasburicase utilization across centers. Similar to previous reports, we also found that males were more likely to initiate rasburicase, a finding that deserves further exploration, given that males are more likely to have G6PD deficiency, a contraindication to rasburicase use. Disclosures Fisher: Pfizer: Research Funding; Merck: Research Funding.
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Odd, David, Nicola F. Reeve, Jane Barnett, Judith Cutter, Rhian Daniel, Chris Gale, and Dimitris Siasakos. "PRECIOUS study (PREterm Caesarean/vaginal birth and IVH/OUtcomeS): does mode of birth reduce the risk of death or brain injury in very preterm babies? A cohort and emulated target trial protocol." BMJ Open 14, no. 9 (September 2024): e089722. http://dx.doi.org/10.1136/bmjopen-2024-089722.
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IntroductionVery preterm babies are at risk of poor neurodevelopmental outcomes and death. Intraventricular haemorrhage (IVH) after birth is the most prevalent cause of this. Birth by caesarean section may protect against IVH in very preterm babies, but the evidence is limited. The aim is to identify and obtain the quantitative evidence needed to inform a future definitive clinical trial to determine the optimal mode of delivery in preterm birth.Methods and analysisWe will use three broad workstreams (WS) to answer complementary questions. WSs 1 and 2 involve the analysis of routinely recorded national clinical data held in an established research database. In WS1 (October 2023–March 2024), we will use conventional methods to identify what is needed to undertake a trial: the population of interest, areas of equipoise and a plausible range of effect sizes. In WS2 (April 2024–October 2024), using an emulated target trial framework, we will attempt to make inferences about the treatment effect from such a future trial and will identify potential challenges in recruitment and estimate likely ‘intention-to-treat’ versus ‘per-protocol’ profiles; these analyses will also be useful for power calculations for future possible trials. In WS3 (October 2024–March 2025), we will convene a consensus meeting with key stakeholders, supported by a clinical trials unit, to develop a multicentre clinical trial to identify the optimal mode of birth for preterm deliveries.Ethics and disseminationIn this study, we will use deidentified data held in the National Neonatal Research Database (NNRD), an established national population database; parents can opt out of their baby’s data being held in the NNRD. HRA/Health and Care Research Wales and National Health Service (NHS) study-specific Research Ethics Committee approval (London—Queen Square Research Ethics Committee) (Ref: 23/LO/0826) ethical approval has been obtained. Key outputs of the PRECIOUS (PREterm Caesarean/vaginal birth and IVH/OUutcomeS) study include the identification of the data, and accordingly of the multidisciplinary team required, to develop, gain funding and complete, a clinical trial to definitively identify the optimal mode of delivery for preterm infants and their mothers.
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Krüger, Nils, Johannes Krefting, Thorsten Kessler, Raphael Schmieder, Fabian Starnecker, Alexander Dutsch, Christian Graesser, et al. "Ticagrelor vs Prasugrel for Acute Coronary Syndrome in Routine Care." JAMA Network Open 7, no. 12 (December 2, 2024): e2448389. https://doi.org/10.1001/jamanetworkopen.2024.48389.
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ImportanceIn patients with acute coronary syndrome (ACS) undergoing invasive treatment, ticagrelor and prasugrel are guideline-recommended P2Y12 receptor inhibitors. The ISAR-REACT5 randomized clinical trial demonstrated superiority for prasugrel, although concerns were raised about the generalizability of some underpowered subgroup analyses.ObjectivesTo emulate a randomized clinical trial evaluating the safety and effectiveness of ticagrelor vs prasugrel under the conditions of routine care in individuals with ACS planned to undergo an invasive treatment strategy.Design, Setting, and ParticipantsThis new-user cohort study included secondary data from a German statutory health insurance claims database between January 2012 and December 2021, using 1:1 propensity score nearest-neighbor matching to emulate ISAR-REACT5. Individuals with ACS receiving either ticagrelor or prasugrel treatment after hospital discharge were followed up for 1 year. Eligibility criteria closely emulated those of ISAR-REACT5 and included age of 18 years or older and cardiovascular risk factors. Data were analyzed from May 2023 to May 2024.ExposureOutpatient prescription of ticagrelor or prasugrel.Main Outcomes and MeasuresThe primary end point was the composite of all-cause mortality, myocardial infarction (MI), or stroke within 1 year of outpatient treatment initiation. Secondary end points included individual components of the primary end point and stent thrombosis. The safety end point was major bleeding. A Cox proportional hazards regression model was fitted to the overall cohort.ResultsOf 17 642 propensity score–matched individuals (mean [SD] age, 63.1 [10.9] years; 73.9% male), 8821 received ticagrelor and 8821 received prasugrel. Agreement was met in 11 of 12 predefined agreement metrics when comparing the results with ISAR-REACT5. The primary composite end point of all-cause mortality, MI, or stroke occurred in 815 individuals (9.2%) receiving ticagrelor and 663 (7.5%) receiving prasugrel (hazard ratio [HR], 1.24; 95% CI, 1.12-1.37). Myocardial infarction (HR, 1.20; 95% CI, 1.06-1.36) and stroke (HR, 1.33; 95% CI, 1.02-1.74) each occurred significantly more often in the ticagrelor group. Analysis of all-cause mortality (HR, 1.27; 95% CI, 0.99-1.64), stent thrombosis (HR, 1.11; 95% CI, 0.89-1.30), and major bleeding (HR, 1.12; 95% CI, 0.96-1.32) revealed no significant differences between treatment groups. Subgroup analysis showed that prasugrel was associated with the primary composite end point in fewer individuals with ST-segment elevation MI (338 of 4941 [6.8%] vs 451 of 4852 [9.3%]).Conclusions and RelevanceThis cohort study found that prasugrel was associated with lower rates of all-cause mortality, MI, or stroke compared with ticagrelor in individuals with ACS undergoing an invasive treatment strategy in routine care, particularly in individuals with ST-segment elevation MI. The findings suggest that carefully designed database studies can complement and extend findings from randomized clinical trials, informing guidelines and clinical decision-making.
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Maurel, Joan, Helena Oliveres, Vicente Alonso, Jaime Feliu, Ana Fernandez-Montes, Marta Martin-Richard, Elisa Galvez, et al. "Upfront vs deferred monoclonal antibodies in metastatic colorectal cancer: A target trial emulation using the GEMCAD 14-01 prospective cohort." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 3597. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3597.
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3597 Background: There are no randomized trials comparing the addition monoclonal antibodies (MAB: bevacizumab, cetuximab, panitumumab) to first line chemotherapy (upfront use) versus deferring their addition to the second-line chemotherapy (deferred use) in pts with metastatic colorectal cancer (mCRC). We emulated a target trial comparing upfront vs deferred use of MAB using the GEMCAD 14-01 observational registry. Methods: We first specified the (hypothetical) target trial to fully articulate the research question and then emulated it using real-world data. The eligibility criteria of the target trial were a diagnosis of mCRC, being treatment naïve, and a ECOG PS <2. The target trial would randomize pts to the following strategies: (1) initiation of MAB within 2 months of starting first line chemotherapy (“upfront MAB”) and (2) initiation of MAB within 2 months of starting second line chemotherapy (“deferred MAB”). The primary outcome of the target trial would be overall survival and the causal contrast (or estimand) would be the effect under complete adherence. We emulated this target trial using data from the GEMCAD 1401 registry (ClinicalTrials.gov identifier: NCT02254941), which collected data prospectively from 47 Spanish centers from June 2014 to June 2018. The emulation used the same definitions of eligibility criteria and treatment strategies, and classified individuals according to their baseline data using clones. The effect under complete adherence was estimated by censoring pts when they deviated from the assigned treatment strategy and by using time-varying weights to adjust for baseline and post-baseline confounding. Results: A total of 627 pts were eligible in the ‘’upfront MAB’’ and 397 pts in the ‘’deferred MAB’’. Median age was in the ‘’upfront vs deferred’’ 64.6 (interquartile range: 56-71) vs 67.8 (61-75) years, 96% vs 87% had an ECOG 0-1, 80% vs 79% had a Charlson score < 3, 46% vs 60% had a RAS mutation, 6% vs 4% had a BRAF mutation, 72% vs 69% had left side primary location, 74% in both strategies had liver metastasis and 42% vs 50% had LDH levels above the normal threshold. Pts in the “upfront MAB” group contributed a total 16,057 months of follow-up and 502 if them died. Pts in the “deferred MAB” contributed a total of 7,774 months of follow-up, and 222 of them died. The 48-month overall survival was 26.7% (95% CI 21.4-38.2%) in the “upfront MAB” group and 21.6% (14.2-41.7%) in the “deferred MAB” group, corresponding to a 48-month survival difference (“upfront MAB” is the reference) of -5.0% (95% CI -17.9 to 17.95) and a hazard ratio or 1.15 (0.88-1.40). Conclusions: Our study suggests little or no survival detrimental effect of deferring the use of MAB to the second line of treatment compared with the use of MAB as part of the first line of treatment among pts with mCRC. Clinical trial information: NCT02254941 .
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Gilbert, Michael, Andrew Dinh La, Noah Romulo Delapaz, William Kenneth Hor, Peihao Fan, Xiguang Qi, Xiaojiang Guo, Jian Ying, and Lirong Wang. "An Emulation of Randomized Trials of Administrating Benzodiazepines in PTSD Patients for Outcomes of Suicide-Related Events." Journal of Clinical Medicine 9, no. 11 (October 29, 2020): 3492. http://dx.doi.org/10.3390/jcm9113492.
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Benzodiazepines is a class of medications frequently prescribed to patients with post-traumatic stress disorder. Patients with PTSD have a notable increased risk of suicide compared to the general population. These medications have been theorized to increase suicidality and pose a risk when used in this patient population. Previous research has found little utility of using benzodiazepines in the PTSD population. However, benzodiazepines are still commonly prescribed by some clinicians for their symptomatic benefit. This study aims to identify the comparative efficacy of commonly prescribed benzodiazepines including midazolam, lorazepam, alprazolam, clonazepam, diazepam and temazepam in relation to suicide-related behaviors (SRBs). A total of 38,807 patients who had an ICD9 or ICD10 diagnosis of PTSD from January 2004 to October 2019 were identified through an electronic medical record database. Inclusion criteria include patients that initiated one of the above benzodiazepines after PTSD diagnosis. Exclusion criteria include previous history of benzodiazepine usage or history of SRBs within the last year prior to enrollment. For patients enrolled in this study, other concomitant drugs were not limited. The primary outcome was onset of SRBs with each respective benzodiazepine. SRBs were identified as ideation, attempt, or death from suicide. We emulated clinical trials of head-to-head comparison between two drugs by pooled logistic regression methods with the Firth option adjusting for baseline characteristics and post-baseline confounders. A total of 5753 patients were eligible for this study, with an average follow up of 5.82 months. The overall incidence for SRB was 1.51% (87/5753). Head-to-head comparisons identified that patients who received alprazolam had fewer SRBs compared to clonazepam (p = 0.0351) and lorazepam (p = 0.0373), and patients taking midazolam experienced fewer relative incidences of SRBs when compared to lorazepam (p = 0.0021) and clonazepam (p = 0.0297). After adjusting for the false discovery rate (FDR), midazolam still had fewer SRBs compared to lorazepam (FDR-adjusted p value = 0.0315). Certain benzodiazepines may provide a reduced risk of development of SRBs, suggesting careful consideration when prescribing benzodiazepines to the PTSD population.
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Hansford, Harrison J., Aidan G. Cashin, Matthew D. Jones, Sonja A. Swanson, Nazrul Islam, Issa J. Dahabreh, Barbra A. Dickerman, et al. "Development of the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) guideline." BMJ Open 13, no. 9 (September 2023): e074626. http://dx.doi.org/10.1136/bmjopen-2023-074626.
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BackgroundObservational studies are increasingly used to inform health decision-making when randomised trials are not feasible, ethical or timely. The target trial approach provides a framework to help minimise common biases in observational studies that aim to estimate the causal effect of interventions. Incomplete reporting of studies using the target trial framework limits the ability for clinicians, researchers, patients and other decision-makers to appraise, synthesise and interpret findings to inform clinical and public health practice and policy. This paper describes the methods that we will use to develop the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) reporting guideline.Methods/designThe TARGET reporting guideline will be developed in five stages following recommended guidance. The first stage will identify target trial reporting practices by systematically reviewing published studies that explicitly emulated a target trial. The second stage will identify and refine items to be considered for inclusion in the TARGET guideline by consulting content experts using sequential online surveys. The third stage will prioritise and consolidate key items to be included in the TARGET guideline at an in-person consensus meeting of TARGET investigators. The fourth stage will produce and pilot-test both the TARGET guideline and explanation and elaboration document with relevant stakeholders. The fifth stage will disseminate the TARGET guideline and resources via journals, conferences and courses.Ethics and disseminationEthical approval for the survey has been attained (HC220536). The TARGET guideline will be disseminated widely in partnership with stakeholders to maximise adoption and improve reporting of these studies.
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Krebs, Emanuel, Deirdre Weymann, Cheryl Ho, Samantha Pollard, and Dean A. Regier. "Target trial emulation with real-world data to determine the population-level cost-effectiveness of multi-gene panel sequencing in advanced melanoma." Journal of Clinical Oncology 42, no. 16_suppl (June 1, 2024): e21508-e21508. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.e21508.
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e21508 Background: Compared to single-gene BRAF testing to guide targeted treatment for advanced melanoma, multi-gene panels can identify additional gene mutations with known therapeutic or prognostic relevance. No randomized control trials of multi-gene panel sequencing have been completed in advanced melanoma. This study determined the population-level cost-effectiveness of multi-gene panel sequencing compared to single-gene BRAF testing for advanced melanoma. Methods: Our population-based retrospective study emulated a hypothetical pragmatic trial using comprehensive patient-level clinical and health administrative data between September 2016 and December 2018 from British Columbia, Canada. To emulate random treatment assignment, we 1:1 matched multi-gene panel patients to contemporaneous controls using a machine learning approach that maximized balance on 15 covariates. Following matching, we estimated mean three-year survival time and costs (2021 CAD), and calculated incremental net monetary benefit (INMB) for life-years gained (LYG) at $100,000/LYG using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. Besides an intention-to-treat (ITT) effect, we also estimated the per-protocol (PP) effect of initiating treatment within 90 days of receiving test results additionally using inverse probability of treatment weights. We also estimated overall survival using Weibull regression and Kaplan-Meier (KM) survival analysis. Results: We matched 147 patients receiving multi-gene panel sequencing to controls, achieving good balance for all included covariates. ITT mean incremental costs were $19,541 (95%CI: -$18,939, $77,396) and mean incremental LYG were 0.22 (95%CI: -0.06, 0.50). We did not find statistically significant different differences in overall survival using the KM (P = 0.11) and Weibull regression (HR: 0.73 [95%CI: 0.51-1.03]) survival analysis in the ITT analysis. PP incremental costs were $36,367 (95%CI: -$6,653, $120,216) and incremental LYG were 0.56 (95%CI: 0.39, 1.24), with corresponding differences in overall survival using KM (P = 0.02) and Weibull regression (HR: 0.56 [95%CI: 0.36-0.87]) survival analysis. The probability of multi-gene panel sequencing being cost-effective at $100,000/LYG was 54.9% in the ITT analysis and 64.5% in the PP analysis. Conclusions: We found the cost-effectiveness of multi-gene panel sequencing to be evenly poised, with estimates favouring multi-gene panel sequencing with respect to overall survival and cost-effectiveness when accounting for probability of treatment initiation. This real-world evidence generated using randomized trial design principles can support jurisdictions’ deliberations on the reimbursement of precision oncology interventions.
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Giannakoulis, Vassilis G., Georgios Psychogios, Christina Routsi, Ioanna Dimopoulou, and Ilias I. Siempos. "Effect of Early Versus Delayed Tracheostomy Strategy on Functional Outcome of Patients With Severe Traumatic Brain Injury: A Target Trial Emulation." Critical Care Explorations 6, no. 8 (August 2024): e1145. http://dx.doi.org/10.1097/cce.0000000000001145.
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OBJECTIVES: Optimal timing of tracheostomy in severe traumatic brain injury (TBI) is unknown due to lack of clinical trials. We emulated a target trial to estimate the effect of early vs. delayed tracheostomy strategy on functional outcome of patients with severe TBI. DESIGN: Target trial emulation using 1:1 balanced risk-set matching. SETTING: North American hospitals participating in the TBI Hypertonic Saline randomized controlled trial of the Resuscitation Outcomes Consortium. PATIENTS: The prematching population consisted of patients with TBI and admission Glasgow Coma Scale less than or equal to 8, who were alive and on mechanical ventilation on the fourth day following trial enrollment, and stayed in the ICU for at least 5 days. Patients with absolute indication for tracheostomy and patients who died during the first 28 days with a decision to withdraw care were excluded. INTERVENTIONS: We matched patients who received tracheostomy at a certain timepoint (early group) with patients who had not received tracheostomy at the same timepoint but were at-risk of tracheostomy in the future (delayed group). The primary outcome was a poor 6-month functional outcome, defined as Glasgow Outcome Scale-Extended less than or equal to 4. MEASUREMENTS AND MAIN RESULTS: Out of 1282 patients available for analysis, 275 comprised the prematching population, with 75 pairs being created postmatching. Median time of tracheostomy differed significantly in the early vs. the delayed group (7.0 d [6.0–10.0 d] vs. 12.0 d [9.8–18.3 d]; p < 0.001). Only 40% of patients in the delayed group received tracheostomy. There was no statistically significant difference between groups regarding poor 6-month functional outcome (early: 68.0% vs. delayed: 72.0%; p = 0.593). CONCLUSIONS: In a target trial emulation, early as opposed to delayed tracheostomy strategy was not associated with differences in 6-month functional outcome following severe TBI. Considering the limitations of target trial emulations, delaying tracheostomy through a “watchful waiting” approach may be appropriate.
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Strohmaier, Susanne, Christine Wallisch, Michael Kammer, Angelika Geroldinger, Georg Heinze, Rainer Oberbauer, and Maria C. Haller. "Survival Benefit of First Single-Organ Deceased Donor Kidney Transplantation Compared With Long-term Dialysis Across Ages in Transplant-Eligible Patients With Kidney Failure." JAMA Network Open 5, no. 10 (October 7, 2022): e2234971. http://dx.doi.org/10.1001/jamanetworkopen.2022.34971.
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ImportanceKidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias.ObjectiveTo compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods.Design, Setting, and ParticipantsIn this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021.ExposuresA target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available.Main Outcomes and MeasuresThe primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach.ResultsAmong the 4445 included patients (2974 men [66.9%]; mean [SD] age, 52.2 [13.2] years), transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years (95% CI, –0.14 to 1.84 years) at age 20 years, 3.01 years (95% CI, 2.50 to 3.54 years) at age 60 years, and 2.48 years (95% CI, 1.88 to 3.04 years) at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time.Conclusions and RelevanceThe findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times.
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Elwenspoek, Martha, Rachel O’Donnell, Katie Charlwood, Alice Malpass, Mary Ward, Howard Thom, Jonathan Banks, et al. "PD49 Developing Evidence-Based Optimal Testing Strategies To Monitor Long-Term Conditions In Primary Care." International Journal of Technology Assessment in Health Care 40, S1 (December 2024): S115—S116. https://doi.org/10.1017/s0266462324003088.
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IntroductionMost patients with long-term conditions (LTC) receive regular blood tests to monitor disease progression and response to treatment and to detect complications. There is currently no robust evidence to inform recommendations on monitoring. Creating this evidence base is challenging because the benefits and harms of testing are dependent on what is done in response to the test results.MethodsWe identified a list of commonly used tests. We defined a series of filtering questions to determine whether there was evidence to support the rationale of monitoring, such as “Can the general practitioner do anything in response to an abnormal test result?” Through a series of rapid reviews we identified evidence to answer each question. The evidence was presented at a consensus meeting where clinicians and patients voted for inclusion, exclusion, or further analysis. A process evaluation was performed alongside this. Further analyses were performed using routinely collected healthcare data and by performing incidence analyses, emulating randomized controlled trials (RCTs), and modeling disease progression.ResultsWe tested this methodology on three common LTCs: chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and hypertension. We found sufficient evidence to include hemoglobin A1C and estimated glomerular filtration rate (eGFR) for monitoring patients with T2DM; hemoglobin and eGFR for patients with CKD; and eGFR for patients with hypertension. The consensus panel excluded four tests, while 10 tests were selected for further analysis. The emulated RCTs will investigate the effect of regular monitoring with certain tests on health outcomes among routinely monitored patients. In addition, we will investigate the signal-to-noise ratio of each test over time using a modeling approach.ConclusionsThe cost effectiveness of the evidence-based testing panels needs to be tested in clinical practice. We are currently developing an intervention package and are planning to run a feasibility trial. This program of work has the potential to change how LTCs are monitored in primary care, ultimately improving patient outcomes and leading to more efficient use of healthcare resources.
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Figueroa, Xavier. "INNV-08. PRE-CLINICAL AND CLINICAL EVIDENCE FOR THE TREATMENT OF DMG/DIPG USING EMULATE THERAPEUTICS’ ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD SIGNAL TECHNOLOGY." Neuro-Oncology 26, Supplement_8 (November 1, 2024): viii170. http://dx.doi.org/10.1093/neuonc/noae165.0671.
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Abstract EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds via a magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical studies demonstrate an effect in slowing down and inhibiting tumor growth. The results of feasibility (Phase I/II) clinical trials testing the EMTx technology for treating recurrent GBM (rGBM) were published in CNS Oncology (CNS Oncol 2023 Pages CNS102, Accession Number: 37462385 DOI: 10.2217/cns-2022-0016). Reported results suggest that the A1A signal is non-inferior to best supportive care (BSC) and when the A1A signal is combined with BSC, a 3-month increase in overall survival (OS) was observed. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured at under 12 months, with no clinical trials demonstrating a significant increase in OS in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program (Hælo® medical device) demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months, with median survival of 17 months. EMTx recently completed an orthotopic mouse model of DIPG at University of California San Francisco. The results from exposing the mice to the A1A signal demonstrated a significant survival advantage (P = 0.0163) via the slowing down of cell division. Data to be submitted for peer review publication. The animal model is encouraging and supports the observed results of our compassionate use program. EMTX will submit these results to the FDA for regulatory approval via the Humanitarian Device Exemption pathway. The company will conduct a study with DIPG patients from both the US and India. Subject to FDA protocol approval, 30-35 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best supportive care + single therapy (Hælo®) clinical trial.
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Nicolajsen, Chalotte W., Mette Søgaard, Martin Jensen, Nikolaj Eldrup, Torben B. Larsen, Samuel Z. Goldhaber, Christian-Alexander Behrendt, and Peter B. Nielsen. "Antiplatelet Therapy in Patients With Abdominal Aortic Aneurysm Without Symptomatic Atherosclerotic Disease." JAMA Network Open 6, no. 10 (October 25, 2023): e2339715. http://dx.doi.org/10.1001/jamanetworkopen.2023.39715.
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ImportancePatients with abdominal aortic aneurysm have a high risk of ischemic events associated with concomitant atherosclerotic cardiovascular disease, and current clinical practice guidelines recommend antiplatelet therapy to mitigate this risk. However, in patients with aneurysms without symptomatic atherosclerosis, the benefit of antiplatelet therapy has been sparsely investigated.ObjectiveTo estimate the effect of antiplatelets on the risk of ischemic events and bleeding in individuals with abdominal aneurysms with no symptomatic atherosclerotic vascular disease.Design, Setting, and ParticipantsA comparative effectiveness research study using a target trial emulation framework was performed. Population-based, cross-linked observational data from Danish national health registries containing comprehensive, individual-level information on all Danish citizens were used to evaluate patients who were antiplatelet-naive and diagnosed with abdominal aortic aneurysms, with no record of symptomatic atherosclerotic vascular disease, from January 1, 2010, through August 21, 2021.ExposurePrescription filled for aspirin or clopidogrel.Main Outcomes and MeasuresRisk of ischemic events (myocardial infarction and/or ischemic stroke) and risk of major bleeding. For target trial emulation, trials were emulated as sequential, contingent on patient eligibility at the time of inclusion, and were evaluated by means of pooled logistic regression models to estimate the intention-to-treat and as-treated effects, expressed as hazard ratio (HR) and event-free survival.ResultsA total of 6344 patients (65.2% men; age, 72 [IQR, 64-78] years) provided 131 047 trial cases; 3363 of these cases involved initiation of antiplatelet therapy and 127 684 did not. A total of 182 ischemic events occurred among initiators and 5602 ischemic events occurred among noninitiators, corresponding to an intention-to-treat HR of 0.91 (95% CI, 0.73-1.17) and an estimated absolute event-free survival difference of −0.6% (95% CI, −1.7% to 0.5%). After censoring nonadherent person-time, the treatment HR was 0.90 (95% CI, 0.68-1.20), with similar risk difference. For bleeding, the intention-to-treat HR was 1.26 (95% CI, 0.97-1.58) and the event-free survival difference was 1.0%. The treatment HR was 1.21 (95% CI, 0.82-1.72); the risk difference was similar.Conclusions and RelevanceIn this study, no evidence of effectiveness of antiplatelet therapy to lower the risk of ischemic events and a trend toward higher bleeding risk was noted. The observed differences between the treatment groups were minimal, suggesting limited clinical relevance of antiplatelet treatment.
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Bergqvist, Rita, Viktor H. Ahlqvist, Michael Lundberg, Maria-Pia Hergens, Johan Sundström, Max Bell, and Cecilia Magnusson. "HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry-based cohort study." PLOS Medicine 18, no. 10 (October 14, 2021): e1003820. http://dx.doi.org/10.1371/journal.pmed.1003820.
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Background The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. Methods and findings This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. Conclusions Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.
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Figueroa, Xavier. "INNV-27. LOW/ULTRA-LOW RADIO FREQUENCY MAGNETIC FIELD THERAPIES FOR THE TREATMENT OF CNS TUMORS: RGBM AND DIPG – PAST AND CURRENT RESULTS USING THE EMULATE THERAPEUTICS INC. TECHNOLOGY." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v162. http://dx.doi.org/10.1093/neuonc/noad179.0616.
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Abstract EMulate Therapeutics, Inc. (EMTx) has developed a technology that emulates the effects of chemical compounds, via an alternating magnetic field. Our research has led to the development of a radio frequency energy (RFE) signal (A1A) that emulates the effects of paclitaxel. Pre-clinical and animal studies demonstrate an effect in slowing down and inhibiting tumor growth. EMTx has developed a portable medical device that allows for continuous delivery of our A1A signal for up to 14 hours before recharging. The device can be used in combination with current best-supportive-care (BSC) and new investigational treatments. Our technology has been tested in recurrent glioblastoma (rGBM) with very encouraging results in overall survival (OS), especially in combination with BSC. Phase II OS alone was equivalent to BSC (7.2 months BSC OS vs. 7.0 months A1A alone OS) and a considerably improved OS when combined with conventional drug treatment (7.2 months BSC OS versus 10.0 months A1A + BSC OS). EMTx is in the process of seeking humanitarian device exemption (HDE) from the US Food & Drug Administration (FDA) for the Hælo® therapeutic system, our pediatric treatment option. Diffuse intrinsic pontine gliomas (DIPG) are a rare pediatric central nervous system (CNS) tumor. Survival is measured in under 12 months, with no clinical trials demonstrating a significant increase in overall survival in 20 years (9 months median survival post radiation therapy). EMTx’s compassionate use program demonstrated safety and suggested a clinical benefit, with 12 of 14 patients surviving more than 12 months. EMTx is committed to run and complete a pivotal pediatric trial for children diagnosed with DMG/DIPG. The trial will recruit study patients from both the US and India. A total of 35-40 patients will be recruited to participate in this pediatric neuro-oncology trial, which will be a best-supportive-care + single therapy (Hælo®) clinical trial.
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Wilson, Thomas W., Joseph T. Dye, Sarah Spark, Nicholas J. Robert, Janet L. Espirito, and E. Susan Amirian. "Feasibility of Using Oncology-Specific Electronic Health Record (EHR) Data to Emulate Clinical Trial Eligibility Criteria." Pharmacoepidemiology 2, no. 2 (May 5, 2023): 140–47. http://dx.doi.org/10.3390/pharma2020013.
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We examined eligibility criteria from recent oncology clinical trials to see whether real-world data (RWD) from electronic health records (EHRs) could be used to create external control groups for clinical trials. Trials were identified from the Aggregate Analysis of ClinicalTrials.gov database; the selected trials were for oncology drugs approved by the FDA in 2020. Verbatim text from trial inclusion and exclusion criteria was qualitatively assessed by an expert panel to determine if criteria could be ascertained from structured and unstructured EHR data. Identified criteria were categorized (cancer-related, comorbidity-related, demographic, functional status, and trial operations) and subcategorized. Among 53 identified trials, 20 met the requirements for study inclusion, which included 463 eligibility criteria. Percentages of criteria by category were as follows: cancer-related factors (46%), comorbidities (20%), functional status (18%), trial operations (14%), and demographics (2%). For 18 of the 20 trials, 80% of the eligibility criteria could be ascertained with RWD; for 4 of the 20, it was 100%. When trial operation-specific criteria were excluded, all 20 met the 100% threshold. Our study indicates that both structured and unstructured data from community-based oncology-specific EHRs can be used for determining patient eligibility for external control arms for clinical trials.
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Govier, Diana J., Meike Niederhausen, Yumie Takata, Alex Hickok, Mazhgan Rowneki, Holly McCready, Valerie A. Smith, et al. "Risk of Potentially Preventable Hospitalizations After SARS-CoV-2 Infection." JAMA Network Open 7, no. 4 (April 10, 2024): e245786. http://dx.doi.org/10.1001/jamanetworkopen.2024.5786.
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ImportanceResearch demonstrates that SARS-CoV-2 infection is associated with increased risk of all-cause hospitalization. However, no prior studies have assessed the association between SARS-CoV-2 and potentially preventable hospitalizations—that is, hospitalizations for conditions that can usually be effectively managed in ambulatory care settings.ObjectiveTo examine whether SARS-CoV-2 is associated with potentially preventable hospitalization in a nationwide cohort of US veterans.Design, Setting, and ParticipantsThis cohort study used an emulated target randomized trial design with monthly sequential trials to compare risk of a potentially preventable hospitalization among veterans with SARS-CoV-2 and matched comparators without SARS-CoV-2. A total of 189 136 US veterans enrolled in the Veterans Health Administration (VHA) who were diagnosed with SARS-CoV-2 between March 1, 2020, and April 30, 2021, and 943 084 matched comparators were included in the analysis. Data were analyzed from May 10, 2023, to January 26, 2024.ExposureSARS-CoV-2 infection.Main Outcomes and MeasuresThe primary outcome was a first potentially preventable hospitalization in VHA facilities, VHA-purchased community care, or Medicare fee-for-service care. Extended Cox models were used to examine adjusted hazard ratios (AHRs) of potentially preventable hospitalization among veterans with SARS-CoV-2 and comparators during follow-up periods of 0 to 30, 0 to 90, 0 to 180, and 0 to 365 days. The start of follow-up was defined as the date of each veteran’s first positive SARS-CoV-2 diagnosis, with the same index date applied to their matched comparators.ResultsThe 1 132 220 participants were predominantly men (89.06%), with a mean (SD) age of 60.3 (16.4) years. Most veterans were of Black (23.44%) or White (69.37%) race. Veterans with SARS-CoV-2 and comparators were well-balanced (standardized mean differences, all &lt;0.100) on observable baseline clinical and sociodemographic characteristics. Overall, 3.10% of veterans (3.81% of those with SARS-CoV-2 and 2.96% of comparators) had a potentially preventable hospitalization during 1-year follow-up. Risk of a potentially preventable hospitalization was greater among veterans with SARS-CoV-2 than comparators in 4 follow-up periods: 0- to 30-day AHR of 3.26 (95% CI, 3.06-3.46); 0- to 90-day AHR of 2.12 (95% CI, 2.03-2.21); 0- to 180-day AHR of 1.69 (95% CI, 1.63-1.75); and 0- to 365-day AHR of 1.44 (95% CI, 1.40-1.48).Conclusions and RelevanceIn this cohort study, an increased risk of preventable hospitalization in veterans with SARS-CoV-2, which persisted for at least 1 year after initial infection, highlights the need for research on ways in which SARS-CoV-2 shapes postinfection care needs and engagement with the health system. Solutions are needed to mitigate preventable hospitalization after SARS-CoV-2.
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Krebs, Emanuel, Deirdre Weymann, Samantha Pollard, and Dean Regier. "OP61 Target Trial Emulation To Determine The Population-Level Cost-Effectiveness Of Multigene Panel Sequencing For Advanced Melanoma." International Journal of Technology Assessment in Health Care 40, S1 (December 2024): S27. https://doi.org/10.1017/s0266462324001211.
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IntroductionCompared to single-gene BRAF testing to guide targeted treatment with BRAF/MEK inhibitors for advanced melanoma, multigene panels can identify additional gene mutations with known therapeutic or prognostic relevance. Implementation of multigene panels remains uneven across healthcare systems given an uncertain clinical and economic evidence base. We determined the population-level cost-effectiveness of multigene panels compared to single-gene BRAF testing for advanced melanoma.Methods Our population-based retrospective study emulated a hypothetical pragmatic trial comparing multigene panel sequencing to single-gene BRAF testing. We drew on comprehensive patient-level clinical and health administrative data between September 2016 and December 2018 in British Columbia, Canada. To emulate random treatment assignment, we 1:1 matched multigene panel patients to contemporaneous single-gene tested controls using genetic algorithm-based matching. We estimated three-year overall survival and healthcare costs (2021 CAD), and incremental net monetary benefit (INMB) for life years gained (LYG) using inverse probability of censoring weighted linear regression and nonparametric bootstrapping. We also estimated overall survival using Weibull regression and Kaplan–Meier survival analysis.ResultsWe matched 147 patients with advanced melanoma receiving multigene panel sequencing to contemporaneous single-gene-tested controls, achieving good balance for all 15 baseline clinical and sociodemographic covariates. After matching, mean incremental costs were CAD19,447 (USD14,217) (95% confidence interval [CI]: −CAD18,517 [−USD13,537], CAD76,006 [USD55,565]; p=0.41) and mean incremental LYG were 0.22 (95% CI: −0.05, 0.49; p=0.12). We found uncertain differences on overall survival using Kaplan–Meier (stratified Log-rank test p=0.11) and Weibull regression (HR: 0.73 [95% CI: 0.51, 1.03]; p=0.07) survival analysis. Cost differences were driven by systemic therapy (∆C: CAD8,665 [USD6,334]; 95% CI: −CAD36,387 [−USD26,600], CAD53,716 [USD39,268]; p=0.71). The INMB at CAD100,000(USD73,104)/LYG was CAD2,646 (USD1,934) (95% CI: −CAD30,044 [−USD21,963], CAD43,416 [USD31,739]; p=0.89), with a 52.8 percent probability of being cost effective.Conclusions There were clinically relevant but uncertain differences in improved survival associated with multigene panel sequencing for advanced melanoma, and the cost-effectiveness of panel-based testing was finely balanced. This real-world evidence generated using randomized trial design principles can support jurisdictions’ deliberations on the reimbursement of precision oncology interventions.
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Prasad, Vinay, Paul R. Massey, and Tito Fojo. "Oral Anticancer Drugs: How Limited Dosing Options and Dose Reductions May Affect Outcomes in Comparative Trials and Efficacy in Patients." Journal of Clinical Oncology 32, no. 15 (May 20, 2014): 1620–29. http://dx.doi.org/10.1200/jco.2013.53.0204.
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Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials.
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Sarwal, Amara, Jincheng Shen, Ravinder Singh, Mckenna R. Nevers, Sydney E. Hartsell, Guo Wei, Robert E. Boucher, et al. "Increased Mortality Risk with Insulin Glargine in Veterans with Type 2 Diabetes: An Emulated Clinical Trial Observational Study." Journal of the American Society of Nephrology 34, no. 11S (November 2023): 858. http://dx.doi.org/10.1681/asn.20233411s1858b.
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Keyes, Anthony, Nidhi M. Atri, and Prince S. Nuamah. "2097 Johns Hopkins School of Medicine ClinicalTrials.gov Program challenges and successes." Journal of Clinical and Translational Science 2, S1 (June 2018): 84. http://dx.doi.org/10.1017/cts.2018.291.
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OBJECTIVES/SPECIFIC AIMS: Educate the general public, investigators, and institutional leadership on the importance of clinical trial registration and results reporting. Share success as a means to develop national best practices. METHODS/STUDY POPULATION: Developed a Project Charter; Spoke to several peer institutions; Update institutional policy. RESULTS/ANTICIPATED RESULTS: Since launching the Program in June 2016, the number of records submitted to ClinicalTrials.gov has increased 14% (852–971). At the same time, compliance with late results has increased by over 92% (111–9). DISCUSSION/SIGNIFICANCE OF IMPACT: Clinical Trial registration and results reporting is sub-par at many institutions. We have established a successful program that others can emulate. Institutions can increase transparency of clinical trials as well as prevent civil monetary penalties ($11,569/d/study) and loss of grant funding.
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Fogt, Jennifer Swingle, and Nick Fogt. "Studies of Vision in Cricket—A Narrative Review." Vision 7, no. 3 (August 28, 2023): 57. http://dx.doi.org/10.3390/vision7030057.
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Vision is thought to play a substantial role in hitting and fielding in cricket. An understanding of which visual skills contribute during cricket play could inform future clinical training trials. This paper reviews what has been reported thus far regarding the relationship of visual skills to cricket performance and reviews the results of clinical trials in which the impact of visual skills training on cricket performance has been addressed. Fundamental or low-level visual skills, with the exception of color vision and perhaps near stereopsis and dynamic visual acuity, are similar between cricket players and the general population. Simple reaction time has been found to be shorter in cricket players in some but not all studies. While there is mixed or no evidence that the aforementioned visual skills are superior in cricket players compared to non-players, comparisons of eye and head movements and gaze tracking have revealed consistent differences between elite cricket batters and sub-elite batters. Future training studies could examine whether teaching sub-elite batters to emulate the gaze tracking patterns of elite batters is beneficial for batting. Lastly, clinical trials in which visual skills of cricket players have been trained have in many cases resulted in positive effects on visual skills, or judgments required in cricket, or cricket play. However, clinical trials with larger and more diverse groups of participants and correlations to on-field metrics and on-field performance (i.e., domain-specific assessments) are necessary before conclusions can be drawn regarding the efficacy of vision training.
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Sarwal, Amara, Jincheng Shen, Ravinder Singh, Mckenna R. Nevers, Sydney E. Hartsell, Guo Wei, Robert E. Boucher, et al. "Increased Risk of Serious Hypoglycemia with Insulin Glargine in Veterans with Type 2 Diabetes: An Emulated Clinical Trial Observational Study." Journal of the American Society of Nephrology 34, no. 11S (November 2023): 858. http://dx.doi.org/10.1681/asn.20233411s1858a.
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Perry, James R. "Bias, benefit, or both: evaluating new glioma therapies." Neurosurgical Focus 4, no. 6 (June 1998): E11. http://dx.doi.org/10.3171/foc.1998.4.6.12.
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Despite the development of many new promising therapies for malignant glioma, virtually all randomized controlled trials testing them have proven negative. These disappointing results are largely due to complex mechanisms of treatment resistance, but increasingly there is evidence that experimental bias rather than benefit accounts for both the promising early phase I/II trial results and later phase III failures. This paper highlights the aspects of clinical trial design and outcome analysis that specifically affect interpretation of results from therapeutic trials for malignant glioma. Phase II trials of both tumor response and tumor control are subject to selection bias; the early promising results seen with interstitial brachytherapy and intraarterial chemotherapy and yet negative phase III results are examples of this. Methods for detecting selection bias include modeling techniques in which databases of patients with known outcomes are used to emulate phase III outcomes. Modeling may assist in the determination of whether a given phase II result appears to exceed that expected by selection bias alone. Such an experiment on paper is quite unlikely to replace a well-designed randomized trial; however, in this time of increasing numbers of novel therapies but shrinking resources, these techniques should find utility in selecting those therapies most suitable for testing in cooperative group randomized trials.
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Himmelreich, Jelle C. L., Saverio Virdone, John Camm, Karen Pieper, Ralf E. Harskamp, Ali Oto, Barry F. Jacobson, et al. "Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF." Open Heart 11, no. 2 (July 2024): e002708. http://dx.doi.org/10.1136/openhrt-2024-002708.
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BackgroundThe extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)—the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF—were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry.MethodsVitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA.ResultsAmong patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs.ConclusionApixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.
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Qiao, Nidan, Ming Shen, Wenqiang He, Min He, Zhaoyun Zhang, Hongying Ye, Xuefei Shou, Yongfei Wang, and Yao Zhao. "Comparative effectiveness of endoscopic versus microscopic transsphenoidal surgery for patients with growth hormone secreting pituitary adenoma: An emulated trial." Clinical Neurology and Neurosurgery 207 (August 2021): 106781. http://dx.doi.org/10.1016/j.clineuro.2021.106781.
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Wilson, T., J. Dye, S. Spark, J. Bian, ES Amirian, J. Espirito, and N. Robert. "P31 Feasibility of Using Oncology Specific Electronic Health Records (EHR) Data to Emulate Clinical Trial Inclusion and Exclusion Criteria." Value in Health 25, no. 7 (July 2022): S293. http://dx.doi.org/10.1016/j.jval.2022.04.041.
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Auberle, Christine, Feng Gao, Ningying Wu, Stuart Kornfeld, Joel Picus, Douglas Adkins, Morey Blinder, et al. "Integration of clinical trial development in hematology and oncology fellowship training: Washington university school of medicine experience." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 11012. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.11012.
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11012 Background: Education in clinical trial design and development is highly variable among Hematology and Medical oncology fellowship programs. The Clinical Trial Development (CTD) program at Washington University in St. Louis (WUSM) is an experiential learning curriculum designed to provide a structured and personalized education to fellows about clinical investigation in Hematology and Oncology. We describe the results of the CTD program and its impact on subsequent academic faculty appointments. Methods: The CTD program was initiated at WUSM in 2002 as a hands-on learning experience for Hematology and Oncology fellows in the design, implementation, evaluation, and publication of clinical trials. Each fellow was required to identify a mentor in their first year of training and propose at least one CTD project, determined as a prospective investigator-initiated clinical trial involving human subjects or materials. Outcome data were collected from an internal registry of fellow CTD projects, Clinical Trials Management System (OnCore), PubMed, ClinicalTrials.gov and e-mail inquiries to fellows and mentors. Descriptive statistics were collected for the characteristics of CTD projects, including the phase of study, site (single center or multicenter), disease subtype, projects that received IRB approval, and projects that resulted in publication. Logistic regression and odds ratios (OR) were also used to assess the association between these characteristics and academic faculty appointments. Results: We included 118 fellows who began fellowship from 2002 to 2021 for this analysis with 16 still in training. Many trials were phase I/II (n = 53; 45%), phase I (n = 34; 29%) and phase II trials (n = 17; 14%) and most trials were single center studies (n = 93; 79%). Disease types of the investigations were evenly distributed between Oncology (n = 60, 51%) or Hematology (n = 58, 49%). Most fellows were successful in obtaining IRB approval for their CTD project (n = 93, 79%) and approximately two thirds of those with IRB approval went on to publish their results in peer-reviewed journals (n = 60, 65%). Forty-five percent of fellows who published their CTD projects were first authors (n = 27) and 38% published in journals with an impact factor of greater than 10. Among the graduating fellows, two-thirds (n = 67, 66%) secured an academic faculty appointment. Fellows with IRB approved CTD projects had significantly higher odds of obtaining an academic faculty appointment (OR 4.96, 95% CI 1.54-15.98, p < 0.05). Conclusions: The CTD program is a well-established clinical investigation program for fellows with a track record of success and impact on subsequent academic faculty appointments. The CTD program is a model that other fellowship programs can emulate for education related to clinical trials.
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Granger, Emily, Ruth H. Keogh, and Freddy Frost. "The long-term effects of insulin use in incident cystic fibrosis-related diabetes: a target trial emulated using longitudinal national registry data." ERJ Open Research 8, no. 4 (October 2022): 00170–2022. http://dx.doi.org/10.1183/23120541.00170-2022.
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IntroductionCystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis and is associated with deleterious clinical outcomes. Insulin is recommended as a treatment by international guidelines. However, there are scarce clinical trial data to support the use of insulin, and little is known about the long-term outcomes of treatment. The aim of this study was to compare the long-term impacts of insulin useversusnon-use in CFRD.MethodsWe used data from the national UK Cystic Fibrosis Registry and adopted a target trial framework. Eligible individuals included those 12 years and older with a new diagnosis of CFRD. Outcomes were change in % predicted forced expiratory volume in 1 s (FEV1%) and body mass index z-scores (BMI) over a 5-year follow-up period. Treatment strategies were to receive insulin or not for the duration of follow-up. Treatment effect estimates were obtained using two methods to control for confounding: inverse-probability-of-treatment weighted estimation of marginal structural models and the G-formula.ResultsWe identified 1613 individuals diagnosed with CFRD between 2008 and 2016 and included 1196 and 1192 in the FEV1% and BMI outcome analyses respectively. We found no evidence of an effect of insulin on FEV1% over the 5-year study period. Similarly, we found no overall effect of insulin on BMI; however, there was some evidence for a positive treatment effect in patients with lower baseline BMI.ConclusionUsing well-established national registry data, we found no evidence of long-term treatment effects for insulin on FEV1% or BMI in people with incident CFRD.
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Cain, Lauren E., Michael S. Saag, Maya Petersen, Margaret T. May, Suzanne M. Ingle, Roger Logan, James M. Robins, et al. "Using observational data to emulate a randomized trial of dynamic treatment-switching strategies: an application to antiretroviral therapy." International Journal of Epidemiology 45, no. 6 (December 31, 2015): 2038–49. http://dx.doi.org/10.1093/ije/dyv295.
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Abstract Background: When a clinical treatment fails or shows suboptimal results, the question of when to switch to another treatment arises. Treatment switching strategies are often dynamic because the time of switching depends on the evolution of an individual’s time-varying covariates. Dynamic strategies can be directly compared in randomized trials. For example, HIV-infected individuals receiving antiretroviral therapy could be randomized to switching therapy within 90 days of HIV-1 RNA crossing above a threshold of either 400 copies/ml (tight-control strategy) or 1000 copies/ml (loose-control strategy). Methods: We review an approach to emulate a randomized trial of dynamic switching strategies using observational data from the Antiretroviral Therapy Cohort Collaboration, the Centers for AIDS Research Network of Integrated Clinical Systems and the HIV-CAUSAL Collaboration. We estimated the comparative effect of tight-control vs. loose-control strategies on death and AIDS or death via inverse-probability weighting. Results: Of 43 803 individuals who initiated an eligible antiretroviral therapy regimen in 2002 or later, 2001 met the baseline inclusion criteria for the mortality analysis and 1641 for the AIDS or death analysis. There were 21 deaths and 33 AIDS or death events in the tight-control group, and 28 deaths and 41 AIDS or death events in the loose-control group. Compared with tight control, the adjusted hazard ratios (95% confidence interval) for loose control were 1.10 (0.73, 1.66) for death, and 1.04 (0.86, 1.27) for AIDS or death. Conclusions: Although our effective sample sizes were small and our estimates imprecise, the described methodological approach can serve as an example for future analyses.
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Villa-Berges, Enrique, Ana Alejandra Laborda Soriano, Orosia Lucha-López, José Miguel Tricas-Moreno, Mar Hernández-Secorún, Miguel Gómez-Martínez, and César Hidalgo-García. "Motor Imagery and Mental Practice in the Subacute and Chronic Phases in Upper Limb Rehabilitation after Stroke: A Systematic Review." Occupational Therapy International 2023 (January 24, 2023): 1–12. http://dx.doi.org/10.1155/2023/3752889.
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Introduction. Motor imagery and mental practice can be defined as a continuous mechanism in which the subject tries to emulate a movement using cognitive processes, without actually performing the motor action. The objective of this review was to analyse and check the efficacy of motor imagery and/or mental practice as a method of rehabilitating motor function in patients that have suffered a stroke, in both subacute and chronic phases. Material and Methods. We performed a bibliographic search from 2009 to 2021 in the following databases, Medline (PubMed), Scopus, WOS, Cochrane, and OTSeeker. The search focused on randomized clinical trials in which the main subject was rehabilitating motor function of the upper limb in individuals that had suffered a stroke in subacute or chronic phases. Results. We analysed a total of 11 randomized clinical trials, with moderate and high methodological quality according to the PEDro scale. Most of the studies on subacute and chronic stages obtained statistically significant short-term results, between pre- and postintervention, in recovering function of the upper limb. Conclusions. Motor imagery and/or mental practice, combined with conventional therapy and/or with other techniques, can be effective in the short term in recovering upper limb motor function in patients that have suffered a stroke. More studies are needed to analyse the efficacy of this intervention during medium- and long-term follow-up.
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Wallach, Joshua D., Audrey D. Zhang, Joshua J. Skydel, Victoria L. Bartlett, Sanket S. Dhruva, Nilay D. Shah, and Joseph S. Ross. "Feasibility of Using Real-world Data to Emulate Postapproval Confirmatory Clinical Trials of Therapeutic Agents Granted US Food and Drug Administration Accelerated Approval." JAMA Network Open 4, no. 11 (November 9, 2021): e2133667. http://dx.doi.org/10.1001/jamanetworkopen.2021.33667.
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Caniglia, Ellen C., L. Paloma Rojas-Saunero, Saima Hilal, Silvan Licher, Roger Logan, Bruno Stricker, M. Arfan Ikram, and Sonja A. Swanson. "Emulating a target trial of statin use and risk of dementia using cohort data." Neurology 95, no. 10 (August 4, 2020): e1322-e1332. http://dx.doi.org/10.1212/wnl.0000000000010433.
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ObjectiveObservational data can be used to attempt to emulate a target trial of statin use and estimate analogues of intention-to-treat and per protocol effects on dementia risk.MethodsUsing data from a prospective cohort study in the Netherlands, we conceptualized a sequence of “trials” in which eligible individuals ages 55–80 years were classified as statin initiators or noninitiators for every consecutive month between 1993 and 2007 and were followed until diagnosis of dementia, death, loss to follow-up, or the end of follow-up. We estimated 2 types of effects of statin use on dementia and a combined endpoint of dementia or death: the effect of initiation vs no initiation and the effect of sustained use vs no use. We estimated risk by statin treatment strategy over time via pooled logistic regression. We used inverse-probability weighting to account for treatment-confounder feedback in estimation of per-protocol effects.ResultsOf 233,526 eligible person-trials (6,373 individuals), there were 622 initiators and 232,904 noninitiators. Comparing statin initiation with no initiation, the 10-year risk differences (95% confidence interval) were −0.1% (−2.3% to 1.8%) for dementia and 0.3% (−2.7% to 3.3%) for dementia or death. Comparing sustained statin use vs no use, the 10-year risk differences were −2.2% (−5.2% to 1.6%) for dementia and −5.1% (−10.5% to −1.1%) for dementia or death.ConclusionsIndividuals with sustained statin use, but not statin initiation alone, had reduced 10-year risks of dementia and dementia or death. Our results should be interpreted with caution due to the small number of initiators and events and potential for residual confounding.
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Morsink, Margaretha, Niels Willemen, Jeroen Leijten, Ruchi Bansal, and Su Shin. "Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications." Micromachines 11, no. 9 (September 12, 2020): 849. http://dx.doi.org/10.3390/mi11090849.
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Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system’s function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed.
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Wallach, Joshua D., Yihong Deng, Eric C. Polley, Sanket S. Dhruva, Jeph Herrin, Kenneth Quinto, Charu Gandotra, et al. "Assessing the use of observational methods and real-world data to emulate ongoing randomized controlled trials." Clinical Trials, August 17, 2023. http://dx.doi.org/10.1177/17407745231193137.
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Background/aims There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. Methods This study compared participants’ demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials’ using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). Results The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. Conclusion Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.
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Kwee, Sandi A., Linda L. Wong, Christina Ludema, Chris K. Deng, Deborah Taira, Todd Seto, and Douglas Landsittel. "Target Trial Emulation: A Design Tool for Cancer Clinical Trials." JCO Clinical Cancer Informatics, no. 7 (January 2023). http://dx.doi.org/10.1200/cci.22.00140.
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PURPOSE To apply target trial emulation to explore the potential impact of eligibility criteria on the primary outcome of a randomized controlled trial. METHODS Simulations of a real-world explanatory trial of transarterial radioembolization for advanced unresectable hepatocellular carcinoma with portal vein invasion were performed to examine the effects of cohort specification on survival outcomes and patient sample size. Simulations comprised 24 different permutations of the trial varied on three disease nonspecific eligibility parameters. Treatment and control arms for these emulated trials were drawn from the National Cancer Database and matched by treatment propensity. Target trial emulation served as the causal framework for this analysis, allowing the architecture of a true controlled experiment to address forms of bias routinely encountered in comparative effectiveness studies involving real-world observational data. RESULTS Twenty-four propensity score–matched cohorts comprising a wider clinical spectrum of patients than specified by the original target trial were successfully generated using the National Cancer Database. The arms for each of the emulated trials demonstrated exchangeability across all eligibility criteria and other clinical covariates. Significant treatment benefits were associated with only a narrow range of eligibility criteria, indicating that the original target trial was well specified. CONCLUSION The impact of patient selection on treatment outcomes can be studied using target trial emulation. This analytical framework can furthermore serve to leverage existing real-world data to inform the task of cohort specification for a randomized controlled trial, facilitating a more data-driven approach for this important step in clinical trial design.
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Wang, Shirley V., Kueiyu Joshua Lin, and Sebastian Schneeweiss. "Emulation of randomized trials of direct oral anticoagulants with claims data and implications for new Factor XI inhibitors." Pharmacoepidemiology and Drug Safety 33, no. 5 (May 2024). http://dx.doi.org/10.1002/pds.5813.
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AbstractDirect oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large‐scale outcome trials. What role can non‐randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT‐DUPLICATIVE Initiative emulated the design of eight DOAC randomized clinical trials (RCT) using non‐randomized claims database studies. RCT study design parameters and measurements were closely emulated by the database studies and produced highly concordant results. The results of the single database study that did not meet all agreement metrics with the specific RCT it was emulating were aligned with a meta‐analysis of six trials studying similar questions, suggesting the trial result was an outlier. Well‐designed database studies using fit‐for‐purpose data came to the same conclusions as DOAC trials, illustrating how database studies could complement RCTs for Factor XI inhibitors—by accelerating insights in underrepresented populations, demonstrating effectiveness and safety in clinical practice, and testing broader indications.
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Boyer, Christopher, and Marc Lipsitch. "Emulating target trials of postexposure vaccines using observational data." American Journal of Epidemiology, September 12, 2024. http://dx.doi.org/10.1093/aje/kwae350.
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Abstract Postexposure vaccination has the potential to prevent or modify the course of clinical disease among those exposed to a pathogen. However, due to logistical constraints, postexposure vaccine trials have been difficult to implement in practice. In place of trials, investigators have used observational data to estimate the effectiveness or optimal timing window for postexposure vaccines, but the relationship between these analyses and those that would be conducted in a trial is often unclear. Here, we define several possible target trials for postexposure vaccination and show how, under certain conditions, they can be emulated using observational data. We emphasize the importance of the incubation period and the timing of vaccination in trial design and emulation. As an example, we specify a protocol for postexposure vaccination against mpox and provide a step-by-step description of how to emulate it using data from a healthcare database or contact tracing program. We further illustrate some of the benefits of the target trial approach through simulation.
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Maguen, Shira, Erin Madden, Nicholas Holder, Yongmei Li, Karen H. Seal, Thomas C. Neylan, Callan Lujan, Olga V. Patterson, Scott L. DuVall, and Brian Shiner. "Effectiveness and comparative effectiveness of evidence-based psychotherapies for posttraumatic stress disorder in clinical practice." Psychological Medicine, May 18, 2021, 1–10. http://dx.doi.org/10.1017/s0033291721001628.
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Abstract Background While evidence-based psychotherapy (EBP) for posttraumatic stress disorder (PTSD) is a first-line treatment, its real-world effectiveness is unknown. We compared cognitive processing therapy (CPT) and prolonged exposure (PE) each to an individual psychotherapy comparator group, and CPT to PE in a large national healthcare system. Methods We utilized effectiveness and comparative effectiveness emulated trials using retrospective cohort data from electronic medical records. Participants were veterans with PTSD initiating mental healthcare (N = 265 566). The primary outcome was PTSD symptoms measured by the PTSD Checklist (PCL) at baseline and 24-week follow-up. Emulated trials were comprised of ‘person-trials,’ representing 112 discrete 24-week periods of care (10/07–6/17) for each patient. Treatment group comparisons were made with generalized linear models, utilizing propensity score matching and inverse probability weights to account for confounding, selection, and non-adherence bias. Results There were 636 CPT person-trials matched to 636 non-EBP person-trials. Completing ⩾8 CPT sessions was associated with a 6.4-point greater improvement on the PCL (95% CI 3.1–10.0). There were 272 PE person-trials matched to 272 non-EBP person-trials. Completing ⩾8 PE sessions was associated with a 9.7-point greater improvement on the PCL (95% CI 5.4–13.8). There were 232 PE person-trials matched to 232 CPT person-trials. Those completing ⩾8 PE sessions had slightly greater, but not statistically significant, improvement on the PCL (8.3-points; 95% CI 5.9–10.6) than those completing ⩾8 CPT sessions (7.0-points; 95% CI 5.5–8.5). Conclusions PTSD symptom improvement was similar and modest for both EBPs. Although EBPs are helpful, research to further improve PTSD care is critical.
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Manuel, Astrid M., Assaf Gottlieb, Leorah Freeman, and Zhongming Zhao. "Montelukast as a repurposable additive drug for standard-efficacy multiple sclerosis treatment: Emulating clinical trials with retrospective administrative health claims data." Multiple Sclerosis Journal, April 25, 2024. http://dx.doi.org/10.1177/13524585241240398.
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Background: Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach. Objective: The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS). Methods: In this retrospective case–control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18–65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum’s Clinformatics® Data Mart (CDM) and IQVIA PharMetrics® Plus for Academics. Cases included 483 pwMS on montelukast and with medication adherence in CDM and 208 in PharMetrics Plus for Academics. We randomly sampled controls from 35,330 pwMS without montelukast prescriptions in CDM and 10,128 in PharMetrics Plus for Academics. Relapses were measured over a 2-year period through inpatient hospitalization and corticosteroid claims. A doubly robust causal inference model estimated the effects of montelukast, adjusting for confounders and censored patients. Results: pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared to non-users in 67.3% of emulated RCTs. Conclusion: Real-world evidence suggested that montelukast reduces MS relapses, warranting future clinical trials and further research on LTRAs’ potential mechanism in MS.
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Loureiro, Hugo, Theresa M. Kolben, Astrid Kiermaier, Dominik Rüttinger, Narges Ahmidi, Tim Becker, and Anna Bauer-Mehren. "Correlation Between Early Trends of a Prognostic Biomarker and Overall Survival in Non–Small-Cell Lung Cancer Clinical Trials." JCO Clinical Cancer Informatics, no. 7 (September 2023). http://dx.doi.org/10.1200/cci.23.00062.
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PURPOSE Overall survival (OS) is the primary end point in phase III oncology trials. Given low success rates, surrogate end points, such as progression-free survival or objective response rate, are used in early go/no-go decision making. Here, we investigate whether early trends of OS prognostic biomarkers, such as the ROPRO and DeepROPRO, can also be used for this purpose. METHODS Using real-world data, we emulated a series of 12 advanced non–small-cell lung cancer (aNSCLC) clinical trials, originally conducted by six different sponsors and evaluated four different mechanisms, in a total of 19,920 individuals. We evaluated early trends (until 6 months) of the OS biomarker alongside early OS within the joint model (JM) framework. Study-level estimates of early OS and ROPRO trends were correlated against the actual final OS hazard ratios (HRs). RESULTS We observed a strong correlation between the JM estimates and final OS HR at 3 months (adjusted [Formula: see text] = 0.88) and at 6 months (adjusted [Formula: see text] = 0.85). In the leave-one-out analysis, there was a low overall prediction error of the OS HR at both 3 months (root-mean-square error [RMSE] = 0.11) and 6 months (RMSE = 0.12). In addition, at 3 months, the absolute prediction error of the OS HR was lower than 0.05 for three trials. CONCLUSION We describe a pipeline to predict trial OS HRs using emulated aNSCLC studies and their early OS and OS biomarker trends. The method has the potential to accelerate and improve decision making in drug development.