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Objectives Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In an effort to better align trials, the Definition for the Assessment of Time to event Endpoints in CANcer trials (DATECAN) project published recommendations in 2015 to be used in mRCC clinical trial design. We analyzed mRCC trial criteria to determine if DATECAN's recommendations were followed. Materials and methods We compared eligibility criteria across 29 phase 3 mRCC trials conducted between 2003 and 2019. We then evaluated endpoints used in 10 phase 3 trials activated between 2015 and 2019 to determine their compliance with DATECAN's recommendations. Results Among the 29 trials, performance status, renal function, and disease characteristics differed in terms of requirements and measures used. In terms of endpoints, the 10 trials did not entirely follow DATECAN's recommendations. In total, 7/10 trials' primary endpoint was progression-free survival (PFS) as recommended; 4/9 trials used PFS as an endpoint but did not publish their definition of PFS, and the 5 that did, included "death from any cause" instead of DATECAN's recommendation of "death from kidney cancer." Conclusions Key eligibility criteria were somewhat inconsistent across the phase 3 mRCC trials studied. Endpoints in the newer trials did not align with DATECAN's recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN's recommendations, greater promotion and adoption of recommendations are needed to better harmonize trial design.

Background: Generalizability of results from clinical trials with narrow in-/exclusion criteria are a concern as significant deviations in efficacy or toxicity may occur when treatments are used in populations of elderly and more comorbid patients. The cost-effectiveness of novel therapies may also be less favorable if real-world treatment effects are inferior to clinical trial results. In diffuse large B-cell lymphoma (DLBCL), a recent US study showed that baseline organ function-based eligibility criteria had substantial impact on survival with ineligible patients being at higher risk of dying from progressive lymphoma (1). Aims: The present study explored the impact of commonly used in-/exclusion criteria in key completed and ongoing first line DLBCL trials on survival in a Danish population-based study of patients with de novo DLBCL. Patients and methods: DLBCL patients enrolled in the Danish Lymphoma Registry (LYFO) and treated with R-CHOP in the period 2008-19 were screened for completeness of data to match trial eligibility criteria. The key organ/hematology eligibility criteria of completed or ongoing all-comers DLBCL studies (REMoDL-B, Goya, Polarix and Hovon84) were collected (bilirubin, ALAT, creatinine, eGFR, leucocytes, neutrophils, thrombocytes and ECOG). First, high-level trial matching on disease risk group (Ann Arbor, bulky disease, international prognostic index (IPI)) and age-groups were performed so that patients assessed for trial eligibility had a relevant risk profile. Subsequently, patients were divided into eligible or ineligible based on selected in/exclusion criteria. For each trial, overall survival (OS) from treatment start were compared for eligible and ineligible patients using inverse probability of treatment weighted Kaplan-Meier and log-rank tests. Crude OS and OS adjusted for residual imbalances in IPI and age were estimated. When possible, the OS curves from standard arms of the original trials were superimposed on OS plots. For each trial, the Shapley value of each criterion was calculated, using the HRs as well as the 5y restricted loss of lifetimes (RLOLs). The Shapley value measures the average influence of each eligibility criterion on the estimated IPI- and age-adjusted HR/5y RLOL. Results: A total of 3,150 R-CHOP treated DLBCL patients without discordant low-grade lymphoma were identified in the surveyed period. A total of 1,666 patients (52.89% of surveyed population) were available for the REMoDL-B trial, 1,431 (45.43%) for Goya, 1,125 (35.71%) for Polarix, and 1,432 (45.46%) for Hovon84. The variations of numbers for each trial evaluation were explained by trial inclusion criteria and missing data in LYFO. Crude OS estimates for patients with and without all necessary information were similar (data not shown). OS curves for eligible and ineligible patients are shown in Figure 1 and, when possible, with superimposed trial results (Goya, REMoDL-B, Hovon84). Survival differences between trial eligible and ineligible patients were robust to further adjustment of imbalances in age and IPI. Associated crude and adjusted 2 and 5-year OS rates for trial eligible and ineligible are shown in Table 1. The largest numerical difference in 2-year crude OS between eligible and ineligible was observed in the REMoDL-B trial (ineligible had 26% lower 2-year OS rate). The largest numerical difference in 2-year OS adjusted for IPI and age between eligible and ineligible was observed for the Polarix trial (ineligible had 17% lower 2-year OS rate). The strongest drivers of OS differences between trial eligible and ineligible patients in terms of the tested eligibility criteria were thrombocyte count (HR-contribution calculated from Shapley values -0.11; -0.14) and ECOG (HR-contribution -0.09; -0.21). Liver function parameters (bilirubin and ALAT) had low impact on OS (HR-contribution 0.00; -0.05 and 0.00; 0.07). Conclusions: The present population-based study confirms that trial ineligible patients have worse survival even after adjustments in imbalances in age and disease risk category. Thus, trial eligibility criteria have substantial impact on generalizability of results to a wider unselected population. Interestingly, the trial eligible patients identified in the present study had very similar outcomes to R-CHOP treated patients in the original trials supporting the possible use of RWD as synthetic control arms. Figure 1 Figure 1. Disclosures Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jørgensen: Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Celgene: Consultancy. Larsen: BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Odense University Hospital, Denmark: Current Employment; Gilead: Consultancy. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Abbvie: Consultancy; Janssen: Consultancy. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months.

The topic of extracorporeal life support (ECLS) for COVID-19 patients was also heavily addressed by a panel of experts including Dr Daniel Brodie and Dr Cara Agerstrand from Columbia University, Dr Amy Hackmann from UT Southwestern, Dr Jacob Klapper from Duke University, and Dr Asif Mustafa from Rush University This study found that post-October 2018 significantly more transplant patients received temporary MCS (31 1% vs 11 5%) and that these patients were more likely to be transplanted during their listing window than prior to the policy change (87% vs 64%) Of the nearly 5000 patients in the STS INTERMACS database who received HM3 with a median follow-up of 9 months, patients were stratified by MOMENTUM 3 trial eligibility criteria [Extracted from the article] Copyright of Artificial Organs is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission However, users may print, download, or email articles for individual use This abstract may be abridged No warranty is given about the accuracy of the copy Users should refer to the original published version of the material for the full abstract (Copyright applies to all Abstracts )

Background Eligibility criteria are a fundamental element of clinical trial design, defining who can and who should not participate in a trial. Problems with the design or application of criteria are known to occur and pose risks to participants’ safety and trial integrity, sometimes also negatively impacting on trial recruitment and generalisability. We conducted a short, exploratory survey to gather evidence on UK recruiters’ experiences interpreting and applying eligibility criteria and their views on how criteria are communicated and developed. Methods Our survey included topics informed by a wider programme of work at the Clinical Trials Research Unit, University of Leeds, on assuring eligibility criteria quality. Respondents were asked to answer based on all their trial experience, not only on experiences with our trials. The survey was disseminated to recruiters collaborating on trials run at our trials unit, and via other mailing lists and social media. The quantitative responses were descriptively analysed, with inductive analysis of free-text responses to identify themes. Results A total of 823 eligible respondents participated. In total, 79% of respondents reported finding problems with eligibility criteria in some trials, and 9% in most trials. The main themes in the types of problems experienced were criteria clarity (67% of comments), feasibility (34%), and suitability (14%). In total, 27% of those reporting some level of problem said these problems had led to patients being incorrectly included in trials; 40% said they had led to incorrect exclusions. Most respondents (56%) reported accessing eligibility criteria mainly in the trial protocol. Most respondents (74%) supported the idea of recruiter review of eligibility criteria earlier in the protocol development process. Conclusions Our survey corroborates other evidence about the existence of suboptimal trial eligibility criteria. Problems with clarity were the most often reported, but the number of comments on feasibility and suitability suggest some recruiters feel eligibility criteria and associated assessments can hinder recruitment to trials. Our proposal for more recruiter involvement in protocol development has strong support and some potential benefits, but questions remain about how best to implement this. We invite other trialists to consider our other suggestions for how to assure quality in trial eligibility criteria.

Patients with cancer who have exhausted standard treatments often seek access to investigational drugs. Often, however, such access is unavailable, due to either the unavailability of a trial, lack of an open recruiting spot on the trial, even when the trial itself is open, or the inability of the patient to meet one or more trial eligibility criteria. In such settings patients often seek access to investigational agents outside of a trial. The federal “Right to Try” legislation was passed to create an additional avenue, different from the FDA's Expanded Access, or “Compassionate Use” Program, through which patients might obtain access to investigational drugs. A year after this legislation was signed into law, there remains both a limited awareness of it and a substantial degree of misunderstanding on the part of those who are aware of it. The law creates an avenue to greatly facilitate off-study administration when patient, physician, and the manufacturer are all in agreement regarding the off study use of an eligible investigational agent. The law does not, however, empower a patient to impose a demand on either a provider or a drug manufacturer, nor does it require any entity to provide financial coverage for the drug. Eligible drugs are those which are not approved by the FDA for any indication, have completed a phase I trial, have an ongoing pivotal trial, and have an active registration plan. We review the specific law with commentary on its implications for improved access to investigational drugs outside of clinical trials.

Objectives This study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex. Background Black patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear. Methods The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines–Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria. Results Among 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p Conclusions Patients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

Generalizability of findings from cardiovascular outcomes trials (CVOTs) to patients with type 2 diabetes (T2D) in clinical practice is unknown. We assessed the proportions of patients in the Diabetes Collaborative Registry who would have met enrolment criteria for pivotal CVOTs of sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is): EMPA‐REG OUTCOME, CANVAS, DECLARE and VERTIS CV. In 172 643 patients, mean [standard deviation (SD)] age and HbA1c were 68.1 (11.8) years and 7.8% (2.2), respectively; 56.8% of patients were men and SGLT‐2i use was 4.4%. Atherosclerotic cardiovascular disease (ASCVD) prevalence was 64.3% and mean 10‐year ASCVD risk was 28.6% in patients without ASCVD. Proportions of patients eligible for CVOTs ranged from 26% (EMPA‐REG OUTCOME) to 44% (DECLARE); 48% of patients were ineligible for all CVOTs. Mean (SD) ASCVD risk was 25.4% (22.6), 32.1% (20.6) and 37.7% (19.4) in patients eligible for no, one or two CVOTs, respectively. SGLT‐2i use was low in patients eligible for no CVOTs (3.5%) and at least one CVOT (5.2%). In conclusion, applicability of CVOT results to patients with T2D in clinical practice varies based on trial eligibility criteria.

Low trial generalizability is a concern. The Food and Drug Administration had guidance on broadening trial eligibility criteria to enroll underrepresented populations. However, investigators are hesitant to do so because of concerns over patient safety. There is a lack of methods to rationalize criteria design. In this study, we used data from a large research network to assess how adjustments of eligibility criteria can jointly affect generalizability and patient safety (i.e the number of serious adverse events [SAEs]). We first built a model to predict the number of SAEs. Then, leveraging an a priori generalizability assessment algorithm, we assessed the changes in the number of predicted SAEs and the generalizability score, simulating the process of dropping exclusion criteria and increasing the upper limit of continuous eligibility criteria. We argued that broadening of eligibility criteria should balance between potential increases of SAEs and generalizability using donepezil trials as a case study.

Objective: The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Patients and Methods: mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score 2.4 mg/dL (male) or >2.0 mg/dL (female), calcium >12.0 mg/dL, platelet Results: Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, p < 0.0001; OS: 13.8 vs. 43.4 months, p < 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, p = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, p < 0.0001) and OS (HR: 2.39, p < 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. Conclusions: In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted.

Clinical trials play important roles in drug development but often suffer from expensive, inaccurate and insufficient patient recruitment. The availability of massive electronic health records (EHR) data and trial eligibility criteria (EC) bring a new opportunity to data driven patient recruitment. One key task named patient-trial matching is to find qualified patients for clinical trials given structured EHR and unstructured EC text (both inclusion and exclusion criteria). How to match complex EC text with longitudinal patient EHRs? How to embed many-to-many relationships between patients and trials? How to explicitly handle the difference between inclusion and exclusion criteria? In this paper, we proposed CrOss-Modal PseudO-SiamEse network (COMPOSE) to address these challenges for patient-trial matching. One path of the network encodes EC using convolutional highway network. The other path processes EHR with multi-granularity memory network that encodes structured patient records into multiple levels based on medical ontology. Using the EC embedding as query, COMPOSE performs attentional record alignment and thus enables dynamic patient-trial matching. COMPOSE also introduces a composite loss term to maximize the similarity between patient records and inclusion criteria while minimize the similarity to the exclusion criteria. Experiment results show COMPOSE can reach 98.0% AUC on patient-criteria matching and 83.7% accuracy on patient-trial matching, which leads 24.3% improvement over the best baseline on real-world patient-trial matching tasks., Comment: Accepted by KDD'20

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., Background: Bronchiolitis is a major cause of admission to hospital in children. Non-invasive ventilation (NIV) support with continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) oxygen is routinely used for infants in the UK with bronchiolitis. Objective: To establish UK paediatric practice regarding management of bronchiolitis, and to explore issues pertinent to the design of a potential future randomised controlled trial of NIV. Design: Screening logs were completed in hospitals in England capturing information on paediatric bronchiolitis admissions. An online national survey of clinical practice was disseminated to healthcare professionals (HCPs) across the UK to ascertain current management strategies. Results: Screening logs captured data on 393 infants from 8 hospitals. Reasons for admission were most commonly respiratory distress and/or poor fluid intake. Oxygen was administered for 54% of admissions. Respiratory (CPAP and HFNC) and non-respiratory support administered varied considerably. The national survey was completed by 111 HCPs from 76 hospitals. Data were obtained on criteria used to commence and wean NIV, responsibilities for altering NIV settings, minimum training requirements for staff managing a child on NIV, and numbers of trained staff. Most centres were interested in and capable of running a trial of NIV, even out of normal office hours. Conclusions: Respiratory and non-respiratory management of bronchiolitis in UK centres varies widely. A trial of HFNC oxygen therapy in this group of patients is feasible and HCPs would be willing to randomise patients into such a trial. Future work should focus on defining trial eligibility criteria., This research was funded by the National Institute for Health Research (NIHR), Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-1014-35081).

Aim This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial). Methods In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial. Results Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS. Conclusion Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.

Background For pts with MM, HRQL is a key determinant of treatment choice in late-line therapies such as ide-cel, a BCMA-directed CAR T cell therapy. In KarMMa (NCT03361748), 54.2% of pts showed clinically meaningful improved HRQL from baseline to quarter (Q) 3, as measured by EQ-5D-5L; 8.5% experienced deterioration (Blood. 2020;136 [Suppl]:28–29). Analysis of HRQL in pts who received alternate, non-CAR T cell therapies could contextualize the impact of ide-cel on HRQL. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of largely community-based pts with newly diagnosed MM (NDMM) at study entry. It was used for a descriptive analysis assessing HRQL outcomes in triple-class exposed real-world pts who met KarMMa trial eligibility criteria but received alternate therapies. Method From 2009-2016, the Registry enrolled 3011 pts with symptomatic NDMM diagnosed ≤2 months prior to study entry at 250 community, academic, and government sites across the US. Pts agreed to complete HRQL forms at study enrollment and every Q of follow-up. Pts with RRMM included in this analysis met KarMMa eligibility criteria. HRQL was measured from the time of KarMMa eligibility (D1) using EQ-5D-3L and FACT-MM total score instruments. Results As of data cutoff (7 Feb 2020), 32 pts with RRMM from the Registry met KarMMa eligibility criteria. Median age was 64.1 y (range, 45.5–88.8). Median time to D1 since initial diagnosis was 3.4 y (range, 1.6–5.5); 24 pts (75%) had prior stem cell transplant; median prior lines of therapy was 7.5. At D1, pts initiated regimens that included IMiDs (n=20), proteasome inhibitors (n=15) and anti-CD38 monoclonal antibodies (n=7). HRQL form completion rate at Q3 was 64.7%. The baseline index score was 0.73 for Registry pts. Median EQ-5D-3L score (range) at D1 (n=21) was 0.761 (0.263–1) and 0.708 (0.263–1) at Q3 (n=11). At D1, 30% of pts experienced clinically meaningful improvement in EQ-5D-3L from baseline; 35% each experienced no change or deterioration in HRQL. By Q3, 20%, 30%, and 50% of pts experienced improvement from baseline, no change, and deterioration in HRQL, respectively. By Q3 post treatment initiation, a substantial proportion of ide-cel–eligible real-world pts with RRMM from the Connect MM Registry who received various alternate (non-CAR T cell) MM regimens experienced meaningful deterioration of HRQL (measured by EQ-5D-3L) from D1 over time. Conclusion In the context of the KarMMa trial, it was observed that a higher proportion of pts on ide-cel experienced meaningful improvement in HRQL (measured by EQ-5D-5L) and fewer pts experienced deterioration by Q3 after treatment. Limitations of this analysis may include small sample size and use of different versions of EQ-5D assessments. HRQL remains an important goal of MM treatment, and therapies that improve HRQL should be developed explicitly. These results support the need for replication in a larger pt sample and complement clinical trial findings.

Background/Aims: A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment. Methods: We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria. Items (1)–(3) are amenable to quantitative analysis. We developed the Biomarker Prognostic Enrichment Tool for evaluating biomarkers for prognostic enrichment at varying levels of screening stringency. Results: We demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics using Biomarker Prognostic Enrichment Tool. Biomarker Prognostic Enrichment Tool is available as a webtool at http://prognosticenrichment.com and as a package for the R statistical computing platform. Conclusion: In some clinical settings, even biomarkers with modest prognostic performance can be useful for prognostic enrichment. In addition to the quantitative analysis provided by Biomarker Prognostic Enrichment Tool, investigators must consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria.

Alport syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport syndrome community, as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry representatives, academic researchers, clinicians, regulatory agency representatives, and—most critically—patients with Alport syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.

ObjectivePost-randomisation exclusions in randomised controlled trials are common and may include participants identified as not meeting trial eligibility criteria after randomisation. We report how a decision might be reached and reported on, to include or exclude these participants. We illustrate using a motivating scenario from the BREATHE trial (Trial registration ClinicalTrials.gov,NCT02426112) evaluating azithromycin for the treatment of chronic lung disease in people aged 6–19 years with HIV in Zimbabwe and Malawi.Key pointsIncluding all enrolled and randomised participants in the primary analysis of a trial ensures an unbiased estimate of the intervention effect using intention-to-treat principles, and minimises the effects of confounding through balanced allocation to trial arm. Ineligible participants are sometimes enrolled, due to measurement or human error. Of 347 participants enrolled into the BREATHE trial, 11 (3.2%) were subsequently found to be ineligible based on lung function criteria. We assumed no safety risk of azithromycin treatment; their inclusion in the trial and subsequent analysis of the intervention effect therefore mirrors clinical practice. Senior trial investigators considered diurnal variations in the measurement of lung function, advantages of retaining a higher sample size and advice from the Data Safety and Monitoring Board and Trial Steering Committee, and decided to include these participants in primary analysis. We planned and reported analyses including and excluding these participants, and in our case the interpretation of treatment effect was consistent.ConclusionThe decision, by senior investigators, on whether to exclude enrolled participants, should reflect issues of safety, treatment efficacy, statistical power and measurement error. As long as decisions are made prior to finalising the statistical analysis plan for the trial, the risk of exclusions creating bias should be minimal. The decision taken should be transparently reported and a sensitivity analysis can present the opposite decision.

94 Background: Stringent eligibility criteria may be a barrier to oncology clinical trial enrollment. We examined patients meeting basic trial eligibility criteria defined in a clinical pathway where the trial was not selected, and then performed a thorough review of full trial eligibility. Methods: Locally available trials are embedded into a pathways tool used at the point of care by medical oncologists at a tertiary cancer center. The physician can choose to have the patient fully screened for the recommended trial or bypass it. Patients where the physician bypassed the trial for eleven Phase 2 and 3 solid tumor trials from April 2018 to December 2019 were reviewed for trial eligibility. Basket trials and adoptive cellular therapy trials were excluded. Trials selected for the audit were presented for more than 20 patients and were bypassed in 80% or more cases. For each trial a random set of 20% of cases or a minimum of 15 cases minimum were reviewed. Results: Among the 184 cases reviewed, 149 (81%) were trial ineligible based upon one or more criteria. The most common reasons for patients' ineligibility were the wrong biomarker profile, prior drug treatment, and health conditions including co-morbidities, autoimmune diseases, other cancers and poor performance status. Conclusions: The majority of patients meeting basic eligibility in a clinical pathways system did not meet strict eligibility criteria. This suggests the trials may not be reflective of the needs of the cancer population being treated and may limit the applicability of trial results to the general cancer population. Use of the pathway program to define eligibility is limited by the numerous and nuanced eligibility criteria that cannot be programmed into the pathways system. Clinical trials eligibility criteria and pathway tools need to adapt to the patient population to help advance cancer research. [Table: see text]

e14050 Background: Clinical trials suffer from insufficient patient (pt) recruitment. The availability of electronic health records (EHR) and trial eligibility criteria (EC) is promising for data driven pt-trial matching. The objective is to find qualified pt given patients' EHR and trial EC in unstructured text EC. Pseudo-Siamese network is a novel subfield within information retrieval and has shown great success in the cross-modal information retrieval problems such as semantic image-text retrieval (e.g., match images with text descriptions). The objective is to find the match between pts and clinical trials using Pseudo-Siamese network based cross-modal retrieval. Our model addresses the following challenges: (1) How to match unstructured EC text with structured EHR where EC often encode more general disease concepts and EHR represent pt conditions using more specific medical codes. (2) How to capture pts' evolving health conditions. (3) How to explicitly handle the difference for inclusion and exclusion criteria. Methods: Our matching model addresses these challenges as follows: (1) we augment the medical codes in pts’ records with their textual descriptions and hierarchical taxonomies, such that concepts can be embedded in finer and more coarse levels for better concept alignment across pt data and ECs. (2) We include an attentive dynamic memory network that extracts the best matching and more recent pt EHR to match with ECs. (3) We introduce a composite loss term to maximize the similarity between pt records and inclusion criteria while minimizes the similarity between pt records and exclusion criteria. Results: We evaluated our model on a pt-trial match dataset on the ECs collected from 590 clinical trials from ClinicalTrials.gov. We also extract 83,371 pt claims data from IQVIA database collected (2002-2018), where each pt is eligible for at least one trial. We compared our model with leading pt-trial matching models. Our model significantly outperforms the best baseline model by 24.3% relatively higher accuracy score. We also tested these models in 34 oncology trials in 25 cancers. Results will be reported. Conclusions: Pseudo-Siamese network successfully solved the cross-modal information retrieval problems. We therefore propose a new pt-trial matching model based on Pseudo-Siamese network model. Experiments on real-world datasets demonstrated that our model significantly outperforms existing works in pt-trial matching for oncology trials.

The REDUCE-IT trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl in reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US

Purpose Potential cytochrome P-450 (CYP) drug–drug interactions in adults with metastatic solid tumors and their effect on eligibility for Phase I clinical trials were characterized. Methods This study included adult patients with metastatic solid tumors seen by a medical oncologist from January 2008 through July 2011. The medications used by these patients were identified. Each medication’s potential for interacting with CYP isozymes was also characterized. Medication changes required to meet Phase I trial eligibility criteria were also reviewed. Results Data from 1773 patients were analyzed: 1489 were not enrolled in a Phase I trial and 284 were enrolled in a Phase I trial. Polypharmacy was significantly more prevalent in the group enrolled in a Phase I trial compared with those not enrolled (95% versus 80%, p < 0.001). The majority of patients not enrolled in a Phase I trial were taking at least one CYP isozyme inhibitor (87%) and at least one CYP isozyme inducer (45%). In a separate analysis, four Phase I trials were evaluated. Of 295 screened patients, 3.2% could not enroll due to concurrent medications. Charts from 74 enrolled patients revealed 655 concurrent medications—93 medications required further review for eligibility involving 51 (69%) of patients. Of the 93 medications, 38 (41%) were stopped and 41 (44%) were changed for the study. Conclusion Polypharmacy and the use of medications that interact with CYP isoyzmes were common in adult patients with metastatic solid tumors. Patients enrolling in Phase I studies often require medication changes to meet eligibility requirements.

Background For patients (pts) with advanced or metastatic renal cell carcinoma (mRCC), approval of novel therapies led to continuous changes in treatment options. The Tumour Registry Renal Cell Carcinoma (TNK) analysed treatment and outcome of pts treated in Germany from 2007-2017. CARAT is the successor registry, which continues to assess longitudinal real world clinical outcome, incl. patient-reported outcomes (PROs) and decentralized biobanking. Today, we introduce CARAT and report on current changes of the treatment landscape in mRCC in Germany. Methods Since Dec 2017 150 pts have been enrolled in CARAT, expanding the previous TNK (2007-17, 1500 pts). CARAT is an observational, prospective, open, multicentre clinical research platform aiming to enrol 1000 pts by 150 sites. Pts with mRCC who start systemic 1stline treatment are eligible. Treatment characteristics, clinical outcome and physician-reported factors on treatment decision making are collected. Overall survival (OS) is assessed by the KM-method. Changes of the treatment landscape are shown descriptively. Results By April 2019 >1650 pts with mRCC have been recruited. Median age is 68 years. 60% had intermediate risk (MSKCC) at start of 1st-line. Median OS for pts with start of 1st-line 2007-17 is 19 months (>60% events). If selected by trial eligibility criteria, the median OS is 27 months. Pts who started treatment in 2018 mostly received pazopanib or sunitinib (38%/34%). Since the approval (May 2018) 18% are treated with cabozantinib. Preferred 2nd-line treatment changed from sorafenib/temsirolimus (35%/21%, 2007-09), everolimus (33% 2010-12), everolimus/axitinib/sunitinib (29%/19%/18%, 2013-15) to nivolumab (>60% since 2016). The impact of new treatment options on OS will be analysed. Conclusions Pts in routine care in Germany are older and have inferior prognosis than trial-eligible pts. CARAT complements results of RCTs with prospective data on clinical and PROs for pts with mRCC in routine care. CARAT will show changes in the choice of treatment due to new approvals, applied sequences and investigate the effectiveness in a “real world” setting. For the first time, these data will be combined with PROs and a decentralized biobank for translational research. Legal entity responsible for the study IOMEDICO. Funding Ipsen. Disclosure P.J. Goebell: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self): IOMEDICO. M. Bogemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eusa Pharma; Honoraria (self), Advisory / Consultancy: ABX; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Amgen. S. Dorfel: Shareholder / Stockholder / Stock options: IOMEDICO. N.W. Marschner: Advisory / Consultancy, Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: IOMEDICO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen. M. Staehler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche. V. Grunwald: Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: MSD; Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options: AstraZeneca; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Merck Serono; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Lilly; Honoraria (self), Non-remunerated activity/ies: PharmaMar; Honoraria (self): Nanobiotix; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.

LBA108 Background: Restrictive trial eligibility criteria limit data generalizability and patient opportunity to participate. We compared numbers and characteristics of patients (pts) eligible using traditional vs expanded criteria recommended by ASCO and Friends of Cancer Research. Methods: A retrospective, observational analysis used deidentified EHR data from ASCO’s CancerLinQ database. Study cohort included adult aNSCLC pts with ≥2 visits and ≥1 dose of systemic treatment post-advanced-disease diagnosis from 2011-2018. Recorded creatinine clearance (CrCl) or Cockcroft-Gault variables were required. Pts were grouped by traditional criteria (no brain metastases, no other malignancies and CrCl >60 mL/min) and expanded criteria (brain metastases and other malignancies allowed and CrCl >30 mL/min). Results: 10,500 pts were identified (Table). Median age 67.6 years [IQR 60.3-74.4]. 56% were male, and 65% white. 60% were Stage IV, 80% former or current smokers. 5005 (47.7%) pts were excluded by traditional exclusion criteria, while only 154 (1.5%) pts were excluded by expanded criteria. Expanded criteria patients were older (67.5 v 66.1, p

Background Conventional albuterol is a racemic mixture of (S)-albuterol and (R)-albuterol (levalbuterol). Levalbuterol is therapeutically active component of albuterol whereas (S)-albuterol is considered inert with some unwanted effects. Objectives To evaluate efficacy and safety of levalbuterol versus albuterol in acute asthma. Design Systematic review and meta-analysis. Data sources Pubmed and Cochrane databases. Trial eligibility criteria, participants, and interventions Randomized control trials comparing levalbuterol versus albuterol for acute asthma in all age groups. Data extraction and result synthesis Two authors extracted data independently. Meta-analyses were performed using Review Manager Software. Results Seven trials including a total of 1625 participants fulfilled the eligibility criteria. Respiratory rate, oxygen saturation, and percentage change in FEV1 and clinical asthma score were not significantly different between the groups with mean difference (95% CI) of 0.35 (−0.81, 1.51), −0.29 (−0.68, 0.10), −28.3 (−59.95, 3.33) and −1.01 (−5.30, 3.28) respectively. There were no significant differences in side effects between groups. Limitations Data were not available for two probable eligible trials. A few assumptions and some calculated values were used for meta-analysis. Conclusions Levalbuterol was not superior to albuterol regarding efficacy and safety in subjects with acute asthma. We suggest that levalbuterol should not be used over albuterol for acute asthma.

Background Adults SPRINT ). Estimating the size and characteristics of these excluded groups who meet the other SPRINT eligibility criteria may provide information on the potential impact of providers extending the SPRINT findings to these populations. Methods and Results We analyzed the National Health and Nutrition Examination Survey 2003–2012 (n=25 076) to estimate the percentage and characteristics of US adults ≥20 years in 3 populations (age SPRINT who otherwise meet the trial eligibility criteria: age ≥50 years, systolic blood pressure ( SBP ) 130–180 mm Hg, high cardiovascular disease risk, and not having trial exclusion criteria. Overall, 1.0% (95% CI 0.8–1.3) of US adults age CI 23.4–27.6) with diabetes mellitus, and 19.0% (95% CI 16.0–22.4) with history of stroke met the other SPRINT eligibility criteria. Among US adults with SBP ≥130 mm Hg, other SPRINT eligibility criteria were met by 7.5% (95% CI 6.1–9.2) of those age CI 30.5–35.4) with diabetes mellitus, and 23.0% (95% CI 19.4–27.0) with history of stroke. Among US adults meeting the other SPRINT eligibility criteria, antihypertensive medication was being taken by 31.0% (95% CI 23.9–41.3) of those CI 58.2–67.6) with diabetes mellitus, and 68.9% (95% CI 59.4–77.1) with a history of stroke. Conclusions A substantial percentage of US adults with diabetes mellitus or history of stroke and a small percentage SPRINT eligibility criteria.

Background: Only a minority of patients diagnosed with myelodysplastic syndromes (MDS) enroll in interventional clinical trials, which impedes development of novel therapies. Factors contributing to low trial accrual are incompletely understood but have been hypothesized to include the older age and frail nature of many patients with MDS, narrow trial eligibility criteria, lack of "precision medicine" agents, perception of MDS as an indolent or lower-risk disease, and difficulty or expense of traveling to trial centers (Steensma D et al Cancer 2018). Methods: We analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium (MDS CRC) to compare characteristics of participants in interventional trials with those patients who never enrolled in a trial during their disease course. Demographics, ZIP code of patient residence (a surrogate measure for income), distance from home to the referral center, presenting blood counts, World Health Organization (WHO) 2008 MDS classification, and Revised International Prognostic Scoring System (IPSS-R) score were compared between trial participants and non-participants. Results: Clinical trial enrollment data were available on 2,138 patients with MDS who had been evaluated at sites in the MDS CRC, of whom 515 (24.1%) participated in an interventional clinical trial. The median age of patients was 67.0 years and 63.4% were male. Patients who participated in trials were on average 1.2 years younger than non-participants (66.1 vs 67.3 years, p=0.037) while men were more likely to participate in a trial (70% of trial participants were male compared to 30% female, compare to non-participants of whom 61% were male and 39% female; p Conclusion: Even at large referral centers, only a minority of patients with MDS enroll in interventional trials. Younger, male, affluent non-Hispanic patients were more likely to enroll in studies. Understanding barriers to trial accrual may help investigators and study sponsors design trials that will accrue more rapidly and augment treatment options for patients with MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; AbbVie: Consultancy. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Authors’ Reply: We appreciate the comments of Van de Water and colleagues. Their examination of the impact of cancer trial eligibility criteria is an example of how common age-related exclusion criteria—criteria that we found to be prevalent in our systematic review of clinical trials in the general medicine literature1—significantly limit the generalizability of study results to many typical older patients. We also agree with their observation that expanding trial eligibility criteria is not without challenges, and that in some circumstances there will be unavoidable barriers to designing a randomized controlled trial (RCT) that adequately informs certain aspects of care for older adults. In these instances, as Van de Water and colleagues note, many insights can be gained from well-designed cohort and case-control studies.2 Our study revealed, however, that even when RCTs do examine the effectiveness and safety of treatment in older adults, they frequently do not use appropriate statistical methods to examine heterogeneity (variability) in treatment effects by age.3,4 In particular, few trials explore whether older adults respond differently to a treatment due to their age, or due to their overall risk for disease-related outcomes and complications (a risk that is often influenced by comorbidities, health status, and other characteristics). This information can be of great value to clinicians who are trying to determine whether an individual patient will benefit from a given therapy. Our knowledge base about treatment effects in older adults will, therefore, benefit not only from rigorous observational research and from RCTs that minimize age-related exclusion criteria, but also from more widespread use of statistical approaches that allow us to investigate whether age in itself, or other characteristics prevalent among older adults, explain heterogeneity in treatment effects among our older patients.

Introduction Differing biases may affect enrollment patterns and result in trial participants that are not representative of clinical practice nor ideal candidates for therapy. We sought to evaluate the stringency of inclusion/exclusion criteria for five recent endovascular stroke treatment (EST) trials and then measure any bias in the decision making process for EST trial enrollment at our institution. Materials and methods From a prospectively maintained registry, all patients treated in clinical practice with EST from April 2004 to June 2013 were identified. The decision to perform EST at our institution is based upon the clinical history, examination, and favorable imaging pattern of proximal vessel occlusion without evidence of significant ischemic injury. Trial eligibility criteria from EST trials active at our institution were used to determine the proportion and characteristics of patients eligible for each trial. Results Among 299 patients treated with EST, average age was 68, 57% were female, NIHSS was 17, and 45% received IV tPA. 125/269 (47%) would have been eligible for MR RESCUE, 33/208 (16%) for IMS III, 10/20 (50%) for SWIFT, 32/41 (78%) for MultiMERCI, 6/11 (55%) for TREVO2. Patients enrolled in trials numbered 57, 21% of all patients in the study time period and 17–50% of eligible patients. Using the trial with the most enrollments as an example (22 patients, MR RESCUE), reasons for inability to enrol included concurrent enrollment in another trial (43%), referring physician refusal for randomization (35%), inability to complete imaging (8%) and inability to obtain consent (7%). Compared to patients enrolled in the trial, those eligible but treated outside of a trial presented with similar distributions of age (68 vs. 69, p = 0.73) and gender (female 52% vs. 55%, p = 1.0). Eligible patients treated outside of trials presented with lower NIHSS (17 vs. 20, p Conclusions Endovascular trials excluded the majority of patients deemed suitable for ERT in routine practice. Competing interests from other trials as well as reluctance to randomise against EST limited enrollment. The population of patients enrolled in trials tended to present later, have more severe strokes, and suffer worsened outcomes. Conviction in the benefit of EST led to the treatment of patients most likely to benefit from EST outside of trials. As a result, recent EST trials may have not reflected the treatment population and outcomes of routine practice. Disclosures S. Sheth: None. J. Saver: None. R. Jahan: None. S. Starkman: None. G. Duckwiler: None. S. Tateshima: None. N. Gonzalez: None. D. Liebeskind: None.. . UCLA Stroke Investigators: None.

Results 33 breast cancer specialists ranked 39 trials in order of importance with the 12 most selected included in this study. Of 4811 women in the Tayside dataset, the number meeting eligibility criteria for the 12 trials ranged from 822 (17%) to 3419 (71%). Reasons for exclusion included age and comorbidity. Many women received a treatment evaluated in a trial but would themselves not have been eligible for the trial. For example, of 572 patients prescribed anastrazole and tamoxifen, only 281 were eligible for the trial evaluating that combination. Work to explicitly compare treatment decisions in clinical practice to trial eligibility criteria is ongoing.

6092 Background: Non-AIDS-defining cancers (NADC) have become a significant cause of mortality in persons with HIV-infection. In 2008, the Cancer Therapy Evaluation Program (CTEP) set guidelines th...

In Reply. —We share Dr Herbert's concern regarding the safety of using 200 μg of selenium in a high-selenium brewer's yeast and have been concerned about documenting both adverse and beneficial health effects of selenium supplementation, especially those that could only be identified in a doubleblind, placebo-controlled trial. The choice of a nutritional dose diminished the safety issues in the trial and was based on the upper limit of the US Estimated Safe and Adequate Intake of selenium. 1 The trial's Safety Monitoring Committee reviewed the incidence of patient-reported disease and did not identify any significant adverse health events associated with selenium supplementation. The trial eligibility criteria excluded patients with active liver and kidney disease; however, we have not identified any additional groups of patients in the trial who were at particular risk of adverse health events. For safety reasons, pregnant women were also excluded from active participation. While there may be